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  • 1.
    Ahlenius, Sven
    et al.
    Göteborgs universitet.
    Heimann, Mikael
    Göteborgs universitet.
    Larsson, Knut
    Göteborgs universitet.
    Prolongation of the ejaculation latency in the male rat by thioridazine and chlorimipramine.1979In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 65, no 2, p. 137-140Article in journal (Refereed)
    Abstract [en]

    Thioridazine (3 mg/kg) and chlorimipramine (1.5–6.0 mg/kg) prolonged the ejaculation latency and increased the number of mounts but did not change the number of intromissions preceding ejaculation. Blockade of peripheral and central noradrenaline receptors by phentolamine and phenoxybenzamine respectively resulted in a suppression of all aspects of the sexual behavior with increasing doses. dl-5-HTP (25–100 mg/kg) in combination with an inhibitor of peripheral 5-HTP decarboxylase (benserazide, 25 mg/kg) produced, like chlorimipramine and thioridazine, a prolongation of ejaculation latency and an increase in the number of mounts preceding ejaculation. Selective inhibition of 5-HT reuptake however, by zimelidine (0–20 mg/kg) or alaproclate (0–20 mg/kg) did not affect the mating behavior. At higher doses of these drugs some animals failed to initiate sexual activities. There was an increase in the postejaculatory interval but no change in the ejaculatory latency.It is concluded that the prolonged ejaculation latencies observed following treatment with thioridazine or chlorimipramine is not due to a blockade of central or peripheral adrenergic -receptors.

  • 2.
    Allard, Per
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Eriksson, K
    Ross, S B
    Marcusson, J O
    Unaltered [3H]GBR-12935 binding after chronic treatment with dopamine active drugs.1990In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 102, no 3, p. 291-4Article in journal (Refereed)
    Abstract [en]

    Rats were injected intraperitoneally with haloperidol 0.5 mg/kg, raclopride 1 mg/kg, bromocriptine 2.5 mg/kg, d-amphetamine 2.5 mg/kg, or cocaine 10 mg/kg twice daily for 21 days. The animals were sacrificed 72 h after last injection. Control rats were injected with saline, following the same schedule. The radioligand [3H]GBR-12935 was used as a presynaptic marker for dopamine neurites. There were no significant differences in [3H]GBR-12935 binding to striatum between drug-treated rats and controls.

  • 3.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Nilsson, S. R. O.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Gastambide, F.
    Eli Lilly & Co Ltd, Lilly Ctr Cognit Neurosci, Erl Wood Manor, Windlesham GU20 6PH, Surrey, England..
    Wang, R. A. H.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Dam, S. A.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Mar, A. C.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Tricklebank, M.
    Eli Lilly & Co Ltd, Lilly Ctr Cognit Neurosci, Erl Wood Manor, Windlesham GU20 6PH, Surrey, England..
    Robbins, T. W.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    The role of 5-HT2C receptors in touchscreen visual reversal learning in the rat: a cross-site study2015In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 232, no 21-22, p. 4017-4031Article in journal (Refereed)
    Abstract [en]

    Reversal learning requires associative learning and executive functioning to suppress non-adaptive responding. Reversal-learning deficits are observed in e.g. schizophrenia and obsessive-compulsive disorder and implicate neural circuitry including the orbitofrontal cortex (OFC). Serotonergic function has been strongly linked to visual reversal learning in humans and experimental animals but less is known about which receptor subtypes are involved. The objectives of the study were to test the effects of systemic and intra-OFC 5-HT2C-receptor antagonism on visual reversal learning in rats and assess the psychological mechanisms underlying these effects within novel touchscreen paradigms. In experiments 1-2, we used a novel 3-stimulus task to investigate the effects of 5-HT2C-receptor antagonism through SB 242084 (0.1, 0.5 and 1.0 mg/kg i.p.) cross-site. Experiment 3 assessed the effects of SB 242084 in 2-choice reversal learning. In experiment 4, we validated a novel touchscreen serial visual reversal task suitable for neuropharmacological microinfusions by baclofen-/muscimol-induced OFC inactivation. In experiment 5, we tested the effect of intra-OFC SB 242084 (1.0 or 3.0 mu g/side) on performance in this task. In experiments 1-3, SB 242084 reduced early errors but increased late errors to criterion. In experiment 5, intra-OFC SB 242084 reduced early errors without increasing late errors in a reversal paradigm validated as OFC dependent (experiment 4). Intra-OFC 5-HT2C-receptor antagonism decreases perseveration in novel touchscreen reversal-learning paradigms for the rat. Systemic 5-HT2C-receptor antagonism additionally impairs late learning-a robust effect observed cross-site and potentially linked to impulsivity. These conclusions are discussed in terms of neural mechanisms underlying reversal learning and their relevance to psychiatric disorders.

  • 4. Andersson, Jan
    et al.
    Berggren, Peter
    Grönkvist, Mikael
    Swedish Defence Research Agency.
    Magnusson, Staffan
    Svensson, Erland
    Oxygen saturation and cognitive performance.2002In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 162, no 2, p. 119-128Article in journal (Refereed)
    Abstract [en]

    The purpose of the experiments was to investigate how inhalation of 100% oxygen affected cognitive performance. A test battery was developed that was designed to capture different aspects of cognitive processes, i.e., perception, attention, working memory, long-term memory and prospective memory. All tests were verbally based, thus reducing cognitive spatial processes to a minimum. In experiment 1, 48 participants volunteered in a complete factorial within-participant design. Two different conditions for type of gas were used, inhalation of 100% oxygen and inhalation of breathing air (approximately 21% oxygen balanced with nitrogen). The inhalation was performed during the 1 min prior to starting each separate test. The instructions for each test were given during the inhalation period. All participants inhaled oxygen or breathing air through a Swedish military pilot mask. Physiological (heartbeats per minute and blood oxygen saturation level) reactions were recorded continuously throughout the session. Participants also completed a mood-state questionnaire before and after the test battery. The results revealed that cognitive performance were not affected by inhalation. Hence, this experiment does not replicate previous findings that suggest that inhalation of 100% oxygen could increase cognitive performance. Another experiment was performed to control for methodological issues. Experiment 2 revealed exactly the same pattern, i.e., inhalation of oxygen did not affect cognitive functioning.

  • 5.
    Andréen, Lotta
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Sundström-Poromaa, Inger
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Allopregnanolone concentration and mood: a bimodal association in postmenopausal women treated with oral progesterone.2006In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 187, no 2, p. 209-221Article in journal (Refereed)
  • 6. Apelqvist, G
    et al.
    Wikell, C.
    Hindfeldt, B
    Bergqvist, PBF
    Andersson, G.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Altered open-field behavior in experimental chronic hepatic encephalopathy after single venlafaxine and citalopram challenges.1999In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 143, p. 408-416Article in journal (Refereed)
  • 7.
    Atkins, Alison Lynn
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Helms, M L
    Department of Behavioral Neuroscience, Oregon Health & Sciences University, 3710 SW US Veterans Hospital Road, R & D5, Portland, OR 97201, USA.
    O'Toole, L A
    Department of Behavioral Neuroscience, Oregon Health & Sciences University, 3710 SW US Veterans Hospital Road, R & D5, Portland, OR 97201, USA.
    Belknap, J K
    Department of Behavioral Neuroscience, Oregon Health & Sciences University, 3710 SW US Veterans Hospital Road, R & D5, Portland, OR 97201, USA.
    Stereotypic behaviors in mice selectively bred for high and low methamphetamine-induced stereotypic chewing.2001In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 157, no 1, p. 96-104Article in journal (Refereed)
    Abstract [en]

    RATIONALE: At high doses, methamphetamine produces repetitive stereotypic behaviors, and the degree to which this occurs is heritable.

    OBJECTIVES: Mice of a B6D2F2 genetic background were selectively bred for four generations for high (HMA) and low (LMA) numbers of stereotyped chewing episodes measured for 1 min at 33 min post-injection following 10 mg/kg methamphetamine (changed to 7 mg/kg for the high line and 15 mg/kg for the low line in the third selected generation to avoid ceiling and floor effects, respectively). We sought to determine whether stereotypic behaviors other than number of repetitive chewing episodes were altered by the selective breeding process.

    METHODS: HMA and LMA mice of the third and fourth selected generations were tested for chewing stereotypy, for a number of other stereotypic behaviors previously observed in rodents, and for several other non-stereotypic responses to methamphetamine. Testing in the third selected generation was conducted by observing behaviors on videotape following 7 mg/kg methamphetamine. In the fourth selected generation, mice were also tested in automated activity monitors following 10 mg/kg methamphetamine and in climbing chimneys following 16 mg/kg methamphetamine. Dose-response curves with doses of 1, 2, 3.5, 7, 10, and 15 mg/kg methamphetamine were constructed for the most commonly observed behaviors.

    RESULTS: LMA mice, which exhibited low stereotyped chewing, exhibited high stereotyped circling and climbing, and the reverse was true for these behaviors for HMA mice. For most of the other behaviors measured, there were drug effects but no differences between selected lines.

    CONCLUSIONS: These results suggest that these three stereotyped behaviors, chewing, circling, and climbing, at least partly share the same mechanisms, and therefore are influenced by at least some of the same genes, since animals selectively bred for low methamphetamine-induced stereotyped chewing exhibited high amounts of circling and climbing when given methamphetamine. This also suggests that the other stereotypic behaviors that we measured do not occur by the same genetically determined mechanisms as stereotypic chewing.

  • 8.
    Aziz, Abdul Maruf Asif
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Brothers, Shaun
    University of Miami Health System, University of Miami, Miami, USA.
    Sartor, Gregory
    University of Miami Health System, University of Miami, Miami, USA.
    Holm, Lovisa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Social and Affective Neuroscience (CSAN). Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Wahlestedt, Claes
    University of Miami Health System, University of Miami, Miami, USA.
    Thorsell, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    The nociceptin/orphanin FQ receptor agonist SR-8993 as a candidate therapeutic for alcohol use disorders: validation in rat models2016In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, no 19-20, p. 3553-3563Article in journal (Refereed)
    Abstract [en]

    RATIONALE: Alcoholism is a complex disorder in which diverse pathophysiological processes contribute to initiation and progression, resulting in a high degree of heterogeneity among patients. Few pharmacotherapies are presently available, and patient responses to these are variable. The nociceptin/orphanin FQ (NOP) receptor has been suggested to play a role both in alcohol reward and in negatively reinforced alcohol seeking. Previous studies have shown that NOP-receptor activation reduces alcohol intake in genetically selected alcohol-preferring as well as alcohol-dependent rats. NOP activation also blocks stress- and cue-induced reinstatement of alcohol-seeking behavior.

    OBJECTIVES: Here, we aimed to examine a novel, potent, and brain-penetrant small-molecule NOP-receptor agonist, SR-8993, in animal models of alcohol- as well as anxiety-related behavior using male Wistar rats.

    RESULTS: SR-8993 was mildly anxiolytic when given to naïve animals and potently reversed acute alcohol withdrawal-induced ("hangover") anxiety. SR-8993 reduced both home-cage limited access drinking, operant responding for alcohol, and escalation induced through prolonged intermittent access to alcohol. SR-8993 further attenuated stress- as well as cue-induced relapse to alcohol seeking. For the effective dose (1.0 mg/kg), non-specific effects such as sedation may be limited, since a range of control behaviors were unaffected, and this dose did not interact with alcohol elimination.

    CONCLUSION: These findings provide further support for NOP-receptor agonism as a promising candidate treatment for alcoholism and establish SR-8993 or related molecules as suitable for further development as therapeutics.

  • 9.
    Bjartmar, Lisa
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Geriatrics.
    Johansson, Inga-Maj
    Department of Public Health and Clinical Medicine, Medicine, Umeå University Hospital, Umeå, Sweden.
    Marcusson, Jan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Geriatrics. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine.
    Ross, S-B
    Astra Arcus AB, Södertälje, Sweden.
    Seckl, JR
    Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, UK.
    Olsson, T
    Department of Public Health and Clinical Medicine, Medicine, Umeå University Hospital, Umeå, Sweden.
    Selective effects on NGFI-A, MR, GR and NGFI-B hippocampal mRNA expression after chronic treatment with different subclasses of antidepressants in the rat2000In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 151, no 1, p. 7-12Article in journal (Refereed)
    Abstract [en]

    There is a latency period of several weeks before the onset of clinical effect of antidepressant drugs. The detailed mechanisms underlying drug-induced adaptive neuronal changes are not known. To elucidate the involvement of changes in gene expression of candidate transcription factors, we treated rats for 21 days with buspirone, fluoxetine, 8-OH-DPAT and moclobemide. In situ hybridization was used to study mRNAs encoding NGFI-A, NGFI-B and the glucocorticoid receptors, MR and GR. NGFI-A mRNA expression increased profoundly in the hippocampal formation and the cerebral cortex after all drug treatments, especially after moclobemide treatment (77-122% increase), with the exception of buspirone. MR mRNA expression was induced in hippocampal CA1/CA2 subregions (27-37%) by all antidepressants, while moclobemide and 8-OH-DPAT significantly increased GR gene expression mainly in the CA1 region (31-44%). NGFI-B mRNA was significantly decreased in the hippocampal CA3 subfield (23%) and restrosplenial granular cortex (38%) by moclobemide treatment. There are selective effects of antidepressant drugs on specific transcription factors. These may be important for adaptive neuronal and neuroendocrine changes after antidepressant treatment including HPA axis negative feedback regulation.

  • 10.
    Björk, Karl
    et al.
    Karolinska Institute, Stockholm, Sweden .
    Tronci, Valeria
    Psychobiology Section, NIDA, National Institutes of Health, Baltimore, MD, USA .
    Thorsell, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Tanda, Gianluigi
    Psychobiology Section, NIDA, National Institutes of Health, Baltimore, MD, USA .
    Hirth, Natalie
    University of Heidelberg, Mannheim, Germany .
    Heilig, Markus
    Laboratory of Clinical and Translational Studies, NIAAA, National Institutes of Health, Bethesda, MD, USA .
    Hansson, Anita C.
    Laboratory of Clinical and Translational Studies, NIAAA, National Institutes of Health, Bethesda, MD, USA.
    Sommer, Wolfgang H
    Laboratory of Clinical and Translational Studies, NIAAA, National Institutes of Health, Bethesda, MD, USA.
    β-Arrestin 2 knockout mice exhibit sensitized dopamine release and increased reward in response to a low dose of alcohol2013In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 230, no 3, p. 439-449Article in journal (Refereed)
    Abstract [en]

    Rationale

    The rewarding effects of alcohol have been attributed to interactions between opioid and dopaminergic system within the mesolimbic reward pathway. We have previously shown that ablation of β-arrestin 2 (Arrb2), a crucial regulator of μ-opioid receptor function, attenuates alcohol-induced hyperlocomotion and c-fos activation in the nucleus accumbens.

    Objectives

    Here, we further investigated the role of Arrb2 in modulating alcohol-induced dopamine (DA) release and conditioned place preference (CPP). We also assessed the functional importance of Arrb2 for μ-opioid receptor surface expression and signaling following an acute alcohol challenge.

    Methods

    Alcohol-evoked (0.375, 0.75, and 1.5 g/kg intraperitoneally) DA release was measured by in vivo microdialysis in the shell of nucleus accumbens. Reward was assessed by the CPP paradigm. Receptor function was assessed by μ-receptor binding and [35S]GTP-γ-S autoradiography.

    Results

    In Arrb2 knockout mice accumbal DA levels reach maximum response at a lower dose compared to wild-type (wt) animals. In line with these results, Arrb2 knockout mice display increased CPP for alcohol as compared to wt mice. Finally, Arrb2 mutant mice display increased μ-opioid receptor signaling in the ventral and dorsal striatum and amygdala in response to a low dose of alcohol, indicating impaired desensitization mechanisms in these mice.

    Conclusions

    Our results show that Arrb2 modulates the response to low doses of alcohol on various levels including μ-opioid receptor signaling, DA release, and reward. They also reveal a clear dissociation between the effects of Arrb2 on psychomotor and reward behaviors.

  • 11.
    Brooks, Samantha J.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. UCT Department of Psychiatry and Mental Health Groote Schuur Hospital Cape Town South Africa.
    Wiemerslage, L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Burch, K H
    Maiorana, S A
    Cocolas, E
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kamaloodien, K
    Stein, D J
    The impact of cognitive training in substance use disorder: the effect of working memory training on impulse control in methamphetamine users2017In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 234, no 12, p. 1911-1921Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Impulsivity is a vulnerability trait for poor self-regulation in substance use disorder (SUD). Working memory (WM) training improves impulsivity and self-regulation in psychiatric disorders. Here we test WM training in methamphetamine use disorder (MUD).

    METHODS: There are 15 MUD patients receiving inpatient treatment as usual (TAU) and 20 who additionally completed WM cognitive training (CT) and 25 healthy controls (HC). MANCOVA repeated measures analyses examined changes in impulsivity and self-regulation at baseline and after 4 weeks.

    RESULTS:  = 0.3523, p < 0.05). Compared to follow-up TAU, follow-up CT group had higher self-reported mood scores (t = 2.784, p = 0.01) and higher compared to CT baseline (t = 2.386, p = 0.036). Feelings of self-control were higher in CT than TAU at follow-up (t = 2.736, p = 0.012) and also compared to CT baseline (t = 3.390, p = 0.006), lack of planning significantly improved in CT between baseline and follow-up (t = 2.219, p = 0.048), as did total impulsivity scores (t = 2.085, p = 0.048). Measures of self-regulation were improved in the CT group compared to TAU at follow-up, in total score (t = 2.442, p = 0.038), receiving score (t = 2.314, p = 0.029) and searching score (t = 2.362, p = 0.027). Implementing self-regulation was higher in the CT group compared to TAU (t = 2.373, p = 0.026).

    CONCLUSIONS: WM training may improve control of impulsivity and self-regulation in people with MUD.

  • 12.
    Cippitelli, Andrea
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Damadzic, Ruslan
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Hansson, Anita C.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Singley, Erick
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Sommer, Wolfgang H.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Eskay, Robert
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Neuropeptide Y (NPY) suppresses yohimbine-induced reinstatement of alcohol seeking2010In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 208, no 3, p. 417-426Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Reinstatement of responding to a previously alcohol-associated lever following extinction is an established model of relapse-like behavior and can be triggered by stress exposure. Here, we examined whether neuropeptide Y (NPY), an endogenous anti-stress mediator, blocks reinstatement of alcohol-seeking induced by the pharmacological stressor yohimbine.

    MATERIALS AND METHODS: NPY [5.0 or 10.0 mug/rat, intracerebroventricularly (ICV)] dose-dependently blocked the reinstatement of alcohol seeking induced by yohimbine (1.25 mg/kg, i.p.) but failed to significantly suppress the maintenance of alcohol self-administration. We then used c-fos expression mapping to examine neuronal activation following treatment with yohimbine or NPY alone or yohimbine following NPY pre-treatment.

    RESULTS AND DISCUSSION: The analysis was focused on a network of structures previously implicated in yohimbine-induced reinstatement, comprised of central (CeA) and basolateral (BLA) amygdala and the shell of the nucleus accumbens (Nc AccS). Within this network, both yohimbine and NPY potently induced neuronal activation, and their effects were additive, presumably indicating activation of excitatory and inhibitory neuronal populations, respectively.

    CONCLUSION: These results suggest that NPY selectively suppresses relapse to alcohol seeking induced by stressful events and support the NPY system as an attractive target for the treatment of alcohol addiction.

  • 13.
    Cippitelli, Andrea
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Karlsson, Camilla
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Shaw, Janice L.
    Eli Lilly, Indianapolis, IN, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Gehlert, Donald R.
    Eli Lilly, Indianapolis, IN, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Suppression of alcohol self-administration and reinstatement of alcohol seeking by melanin-concentrating hormone receptor 1 (MCH1-R) antagonism in Wistar rats2010In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 211, no 4, p. 367-375Article in journal (Refereed)
    Abstract [en]

    RATIONALE: Melanin-concentrating hormone (MCH) is involved in regulation of appetitive behaviors as well as emotional reactivity and reward, behavioral domains relevant to alcohol addiction.

    MATERIALS AND METHODS: We evaluated the effects of the non-peptide MCH1 receptor antagonist, GW803430 [6-(4-chloro-phenyl)-3-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3H-thieno[3,2-d]pyrimidin-4-one; 3-30 mg/kg, i.p.] on alcohol-related behaviors in Wistar rats.

    RESULTS: Ex vivo binding experiments demonstrated that the GW803430 dose range used resulted in high central MCH1 receptor occupancy. Alcohol self-administration was dose-dependently and potently suppressed, by approximately 80% at the highest dose. Reinstatement of alcohol-seeking induced by alcohol-associated cues was essentially eliminated. In contrast, reinstatement induced by footshock stress was not significantly altered. Taste preference for a quinine/saccharin solution, locomotor activity, and alcohol elimination were unaffected.

    CONCLUSION: Together, these observations support a specific involvement of the MCH system in mediating alcohol reward and cue-induced relapse to alcohol seeking. MCH1-R antagonism may constitute an attractive treatment target for alcohol use disorders.

  • 14. De Luca, Maria Antonietta
    et al.
    Bimpisidis, Zisis
    Bassareo, Valentina
    Di Chiara, Gaetano
    Influence of morphine sensitization on the responsiveness of mesolimbic and mesocortical dopamine transmission to appetitive and aversive gustatory stimuli2011In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 216, p. 345-353Article in journal (Refereed)
  • 15.
    Ekström, Johan G.
    et al.
    Mid Sweden University, Faculty of Human Sciences, Department of Health Sciences.
    Beaven, C. Martyn
    Mid Sweden University, Faculty of Human Sciences, Department of Health Sciences.
    Effects of blue light and caffeine on mood2014In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 231, no 18, p. 3677-3683Article in journal (Refereed)
    Abstract [en]

    Both short wavelength (blue) light and caffeine have been studied for their mood enhancing effects on humans. The ability of blue light to increase alertness, mood and cognitive function via non-image forming neuropathways has been suggested as a non-pharmacological countermeasure for depression across a range of occupational settings. This experimental study compared blue light and caffeine and aimed to test the effects of blue light/placebo (BLU), white light/240-mg caffeine (CAF), blue light/240-mg caffeine (BCAF) and white light/placebo (PLA), on mood. A randomised, controlled, crossover design study was used, in a convenience population of 20 healthy volunteers. The participants rated their mood on the Swedish Core Affect Scales (SCAS) prior to and after each experimental condition to assess the dimensions of valence and activation. There was a significant main effect of light (p = 0.009), and the combination of blue light and caffeine had clear positive effects on core effects (ES, ranging from 0.41 to 1.20) and global mood (ES, 0.61 +/- 0.53). The benefits of the combination of blue light and caffeine should be further investigated across a range of applications due to the observed effects on the dimensions of arousal, valence and pleasant activation.

  • 16. Frånberg, Olivia
    et al.
    Wiker, Charlotte
    Marcus, Monica M
    Konradsson, Asa
    Jardemark, Kent
    Schilström, Björn
    Shahid, Mohammed
    Wong, Erik H F
    Svensson, Torgny H
    Asenapine, a novel psychopharmacologic agent: preclinical evidence for clinical effects in schizophrenia.2008In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 196, no 3Article in journal (Refereed)
    Abstract [en]

    RATIONALE: Asenapine is a novel psychopharmacologic agent being developed for the treatment of schizophrenia and bipolar disorder.

    MATERIALS AND METHODS: The present study was undertaken to investigate the effects of asenapine using animal models predictive of antipsychotic efficacy (conditioned avoidance response [CAR]) and extrapyramidal side effects (EPS; catalepsy). In parallel, the effects of asenapine on regional dopamine output using in vivo microdialysis in freely moving rats, dopamine output in the core and shell subregions of nucleus accumbens (NAc) using in vivo voltammetry in anesthetized rats, and N-methyl-D: -aspartate (NMDA)-induced currents in pyramidal neurons of the medial prefrontal cortex (mPFC) using the electrophysiological technique intracellular recording in vitro were assessed.

    RESULTS: Asenapine (0.05-0.2 mg/kg, subcutaneous [s.c.]) induced a dose-dependent suppression of CAR (no escape failures recorded) and did not induce catalepsy. Asenapine (0.05-0.2 mg/kg, s.c.) increased dopamine efflux in both the mPFC and the NAc. Low-dose asenapine (0.01 mg/kg, intravenous [i.v.]) increased dopamine efflux preferentially in the shell compared to the core of NAc, whereas at a higher dose (0.05 mg/kg, i.v.), the difference disappeared. Finally, like clozapine (100 nM), but at a considerably lower concentration (5 nM), asenapine significantly potentiated the NMDA-induced responses in pyramidal cells of the mPFC.

    CONCLUSIONS: These preclinical data suggest that asenapine may exhibit highly potent antipsychotic activity with very low EPS liability. Its ability to increase both dopaminergic and glutamatergic activity in rat mPFC suggests that asenapine may possess an advantageous effect not only on positive symptoms in patients with schizophrenia, but also on negative and cognitive symptoms.

  • 17.
    Ghersi, Marisa S
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Gabach, L A
    Buteler, F
    Vilcaes, A A
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Perez, M F
    de Barioglio, S R
    Ghrelin increases memory consolidation through hippocampal mechanisms dependent on glutamate release and NR2B-subunits of the NMDA receptor2015In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 232, no 10, p. 1843-1857Article in journal (Refereed)
    Abstract [en]

    RATIONALE: Ghrelin (Ghr) is a peptide that participates in the modulation of several biological processes. Ghr administration into the hippocampus improves learning and memory in different memory tests. However, the possible mechanisms underlying this effect on memory have not yet been clarified.

    OBJECTIVE: The purpose of the present work is to add new insights about the mechanisms by which Ghr modulates long-term memory consolidation in the hippocampus. We examined Ghr effects upon processes related to increased synaptic efficacy as presynaptic glutamate release and changes in the expression of the NR2B-subunits containing n-methyl-d-aspartate receptors (NMDAR), which are critical for LTP induction. We also attempted to determine the temporal window in which Ghr administration induces memory facilitation and if the described effects depend on GHS-R1a stimulation.

    RESULTS: The present research demonstrated that Ghr increased glutamate release from hippocampal synaptosomes; intra-hippocampal Ghr administration increased NR2B-subunits expression in CA1 and DG subareas and also reversed the deleterious effects of the NR2B-subunit-specific antagonist, Ro 25-6981, upon memory consolidation and LTP generation in the hippocampus. These effects are likely to be the consequence of GHS-R1a activation.

    CONCLUSION: According to the results above mentioned and previous findings, we can hypothesize some of the mechanisms by which Ghr modulates memory consolidation. At presynaptic level, Ghr stimulates glutamate release, probably by enhancing [Ca(2+)]i. At postsynaptic level, the glutamate released activates NMDAR while Ghr also mediates effects directly activating its specific receptors and increases NR2B-subunit expression.

  • 18.
    Granholm, Linnea
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Rowley, S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ellgren, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Segerström, Lova
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Impact of adolescent ethanol exposure and adult amphetamine self-administration on evoked striatal dopamine release in male rats2015In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 232, no 24, p. 4421-4431Article in journal (Refereed)
    Abstract [en]

    Adolescent binge drinking is common and associated with increased risk of substance use disorders. Transition from recreational to habitual ethanol consumption involves alterations in dorsal striatal function, but the long-term impact of adolescent ethanol exposure upon this region remains unclear. This study aimed to characterise and describe relationships between adolescent ethanol exposure, amphetamine self-administration and adult dopamine dynamics in dorsal striatum, including response to amphetamine challenge, in male Wistar rats. Ethanol (2 g/kg) or water was administered intragastrically in an episodic binge-like regimen (three continuous days/week) between 4 and 9 weeks of age (i.e. post-natal days 28-59). In adulthood, animals were divided into two groups. In the first, dorsal striatal potassium-evoked dopamine release was examined via chronoamperometry, in the basal state and after a single amphetamine challenge (2 mg/kg, i.v.). In the second, amphetamine self-administration behaviour was studied (i.e. fixed and progressive ratio) before chronoamperometric analysis was conducted as described above. Adolescent ethanol exposure suppressed locally evoked dopamine response after amphetamine challenge in adulthood, whereas in the basal state, no differences in dopamine dynamics were detected. Ethanol-exposed animals showed no differences in adult amphetamine self-administration behaviour but an abolished effect on dopamine removal in response to a single amphetamine challenge after self-administration. Amphetamine challenges in adult rats revealed differences in in vivo dopamine function after adolescent ethanol exposure. The attenuated drug response in ethanol-exposed animals may affect habit formation and contribute to increased risk for substance use disorders as a consequence of adolescent ethanol.

  • 19.
    Guitart-Masip, Marc
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). University College London, England.
    Economides, Marcos
    Huys, Quentin J. M.
    Frank, Michael J.
    Chowdhury, Rumana
    Duzel, Emrah
    Dayan, Peter
    Dolan, Raymond J.
    Differential, but not opponent, effects of L-DOPA and citalopram on action learning with reward and punishment2014In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 231, no 5, p. 955-966Article in journal (Refereed)
    Abstract [en]

    Decision-making involves two fundamental axes of control namely valence, spanning reward and punishment, and action, spanning invigoration and inhibition. We recently exploited a go/no-go task whose contingencies explicitly decouple valence and action to show that these axes are inextricably coupled during learning. This results in a disadvantage in learning to go to avoid punishment and in learning to no-go to obtain a reward. The neuromodulators dopamine and serotonin are likely to play a role in these asymmetries: Dopamine signals anticipation of future rewards and is also involved in an invigoration of motor responses leading to reward, but it also arbitrates between different forms of control. Conversely, serotonin is implicated in motor inhibition and punishment processing. To investigate the role of dopamine and serotonin in the interaction between action and valence during learning. We combined computational modeling with pharmacological manipulation in 90 healthy human volunteers, using levodopa and citalopram to affect dopamine and serotonin, respectively. We found that, after administration of levodopa, action learning was less affected by outcome valence when compared with the placebo and citalopram groups. This highlights in this context a predominant effect of levodopa in controlling the balance between different forms of control. Citalopram had distinct effects, increasing participants' tendency to perform active responses independent of outcome valence, consistent with a role in decreasing motor inhibition. Our findings highlight the rich complexities of the roles played by dopamine and serotonin during instrumental learning.

  • 20.
    Gunes, Arzu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Scordo, Maria Gabriella
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Jaanson, Peeter
    Dahl, Marja-Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Serotonin and dopamine receptor gene polymorphisms and the risk of extrapyramidal side effects in perphenazine-treated schizophrenic patients2007In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 190, no 4, p. 479-484Article in journal (Refereed)
    Abstract [en]

    Rationale: Perphenazine, a classical antipsychotic drug, has the potential to induce extrapyramidal side effects (EPS). Dopaminergic and serotonergic pathways are involved in the therapeutic and adverse effects of the drug. Objectives: To evaluate the impact of polymorphisms in the dopamine D 2 and D3 and serotonin 2A and 2C receptor genes (DRD2, DRD3, HTR2A, and HTR2C) on short-term effects of perphenazine monotherapy in schizophrenic patients. Materials and methods: Forty-seven Estonian inpatients were evaluated before and after 4-6 weeks of treatment by Simpson-Angus rating scale, Barnes scale, and Positive and Negative Symptom Scale. Genotyping was performed for common DRD2, DRD3, HTR2A, and HTR2C gene polymorphisms, previously reported to influence receptor expression and/or function. Results: Most of the patients (n = 37) responded to the treatment and no significant association was observed between the polymorphisms and antipsychotic response. The 102C allele of HTR2A and the -697C and 23Ser alleles of HTR2C were more frequent among patients with EPS (n = 25) compared to patients without EPS (n = 22) (p = 0.02, 0.01, and 0.02, respectively). The difference between patients with and without EPS in variant allele frequencies remained significant after multiple model analyses including age, gender, and duration of antipsychotic treatment as covariants. There was no significant association between EPS occurrence and polymorphisms in the DRD2 and DRD3 genes. Conclusions: An association was observed between polymorphisms in HTR2A and HTR2C genes and occurrence of acute EPS in schizophrenic patients treated with perphenazine monotherapy. Larger study populations are needed to confirm our findings.

  • 21.
    Hedström, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bixo, Marie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Spigset, Olav
    Zingmark, Elisabeth
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Studies of pharmacokinetic and pharmacodynamic properties of isoallopregnanolone in healthy women2009In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 203, no 1, p. 85-98Article in journal (Refereed)
    Abstract [en]

    Rationale  The pharmacokinetics and behavioral effects of isoallopregnanolone (3β-hydoxy-5α-pregnan-20-one) in women are not known. Objectives  Allopregnanolone (3α-hydoxy-5α-pregnan-20-one) is a well-known neurosteroid, acting via the GABAA receptor in the human brain. The naturally occurring progesterone metabolite isoallopregnanolone is the 3β-stereoisomer of allopregnanolone. Prior studies have concluded that isoallopregnanolone has no effect on the GABAA receptor. However, an antagonistic effect of isoallopregnanolone to allopregnanolone on the GABAA receptor has been shown in animal and in vitro studies. The purpose of this study was to evaluate the pharmacokinetics and behavioral effects of isoallopregnanolone in humans.

    Materials and methods  Six healthy women were given three increasing doses of isoallopregnanolone intravenously in the follicular phase. Repeated blood samples for analyses of isoallopregnanolone and allopregnanolone concentrations were drawn. Saccadic eye movement variables, self-rated sedation, and mood rating scales were used during the test day. A Likert scale for prospective symptoms was used to measure daily fluctuations during the ongoing menstrual cycle.

    Results  Exogenously administered isoallopregnanolone produced a dose-dependent increase in the serum concentration of isoallopregnanolone. In parallel, there was also a rise in the allopregnanolone concentration. There was a decrease in saccadic eye movement variables, but no effect was found on self-rated sedation or mood and no changes were seen in prospective symptoms during the menstrual cycle.

    Conclusions  After administration of isoallopregnanolone at a cumulative dose of 0.20 mg/kg, no adverse effects were observed. There is a metabolism of isoallopregnanolone to allopregnanolone, most likely explaining the effects on the saccadic eye movements.

  • 22.
    Hjalmdahl, Magnus
    et al.
    Swedish Road and Transport Research Institute, Linköping.
    Vadeby, Anna
    Swedish Road and Transport Research Institute, Linköping.
    Forsman, Asa
    Swedish Road and Transport Research Institute, Linköping.
    Fors, Carina
    Swedish Road and Transport Research Institute, Linköping.
    Ceder, Gunnel
    Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Woxler, Per
    Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Effects of d-amphetamine on simulated driving performance before and after sleep deprivation2012In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 222, no 3, p. 401-411Article in journal (Refereed)
    Abstract [en]

    Stimulant drugs are commonly abused and also used to promote wakefulness, yet their effects on driving performance during sleep deprivation have not been thoroughly researched in experimental studies. The aims were to assess the effects on fundamental driving parameters during simulated driving of two doses of d-amphetamine and further to assess the interaction between d-amphetamine and sleep deprivation. A double-blind, placebo-controlled experiment including 18 healthy male volunteers was conducted. The participants felt more alert when taking a dose of d-amphetamine than when taking placebo, and the effect was stronger for the higher dose. However, the data did not show any evidence that taking d-amphetamine prevented the subjects from becoming successively sleepier during the night. A significant main effect of the dose was found for three out of the five primary indicators where the lower dose led to improved driving. These indicators were crossing-car reaction time, and coherence and delay from a car-following event. Regarding sleep deprivation, a main effect was found for four of the primary indicators and three of the secondary indicators. The results showed overall impaired driving with respect to standard deviation of lateral position and delay in reaction time when the sleep-deprived conditions were compared to the alert condition. We found no interactions between dose and sleep deprivation for any of the performance indicators. Our results suggest that administration of d-amphetamine does not compensate for impairment of driving due to fatigue. The positive effects of 10 mg were not further improved or even sustained when increasing the dose to 40 mg.

  • 23.
    Hjälmdahl, Magnus
    et al.
    Swedish National Road and Transport Research Institute, Society, environment and transport.
    Vadeby, Anna
    Swedish National Road and Transport Research Institute, Traffic and road users, Traffic safety, society and road-user.
    Forsman, Åsa
    Swedish National Road and Transport Research Institute, Traffic and road users, Traffic safety, society and road-user.
    Fors, Carina
    Swedish National Road and Transport Research Institute, Traffic and road users, Human-vehicle-transport system interaction.
    Ceder, Gunnel
    National Board for Forensic Medicine, Linköping.
    Woxler, Per
    Östergötlands Läns Landsting, Psykiatriska kliniken.
    Kronstrand, Robert
    Linköpings universitet, Avdelningen för läkemedelsforskning.
    Effects of d-amphetamine on simulated driving performance before and after sleep deprivation2012In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 222, no 3, p. 401-411Article in journal (Refereed)
    Abstract [en]

    Stimulant drugs are commonly abused and also used to promote wakefulness, yet their effects on driving performance during sleep deprivation have not been thoroughly researched in experimental studies. The aims were to assess the effects on fundamental driving parameters during simulated driving of two doses of d-amphetamine and further to assess the interaction between d-amphetamine and sleep deprivation. A double-blind, placebo-controlled experiment including 18 healthy male volunteers was conducted. The participants felt more alert when taking a dose of d-amphetamine than when taking placebo, and the effect was stronger for the higher dose. However, the data did not show any evidence that taking d-amphetamine prevented the subjects from becoming successively sleepier during the night. A significant main effect of the dose was found for three out of the five primary indicators where the lower dose led to improved driving. These indicators were crossing-car reaction time, and coherence and delay from a car-following event. Regarding sleep deprivation, a main effect was found for four of the primary indicators and three of the secondary indicators. The results showed overall impaired driving with respect to standard deviation of lateral position and delay in reaction time when the sleep-deprived conditions were compared to the alert condition. We found no interactions between dose and sleep deprivation for any of the performance indicators. Our results suggest that administration of d-amphetamine does not compensate for impairment of driving due to fatigue. The positive effects of 10 mg were not further improved or even sustained when increasing the dose to 40 mg.

  • 24.
    Homman, Lina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Department of Psychology, University of Sussex, Brighton, UK.
    Seglert, Jessica
    Department of Psychology, University of Sussex, Brighton, UK.
    Morgan, Michael J.
    Department of Psychology, University of Sussex, Brighton, UK; Norwegian Center for Addiction Research, University of Oslo, Oslo, Norway.
    An observational study on the sub-acute effects of mephedrone on mood, cognition, sleep and physical problems in regular mephedrone users2018In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 235, no 9, p. 2609-2618Article in journal (Refereed)
    Abstract [en]

    Mephedrone (4-methylmethcathinone; 4-MMC) is a novel recreational drug similar to methylenedioxymethamphetamine (MDMA) and amphetamine. Several adverse effects have been reported, but little is known about its sub-acute effects. To study sub-acute effects of mephedrone over a period of 9 days. Recreational mephedrone users were recruited and followed over a time period of 9 days. It was recorded whether participants consumed mephedrone or not within the period of testing; those who did were compared to those who did not. Forty-six regular mephedrone users (22 males, 24 females) participated, 21 participants voluntarily opted to consume mephedrone 1-3 days after baseline and 25 opted to abstain. Participants were assessed at baseline on a multitude of measures and provided daily reports on cognition, sleep, mood, physical problems, mephedrone cravings and substance use on each subsequent day of the study. The study controlled for psychopathology, sleep, past and current substance use, impulsivity and demographics. Those who consumed mephedrone reported persistent negative mood, physical problems and fatigue, compared to those who did not-after controlling for baseline group differences in sleep and subsequent alcohol and cannabis use. The results provide the first prospective evidence of the duration and extent of specific undesirable sub-acute effects of mephedrone in regular recreational users and indicate sub-acute effects of mephedrone on mood, fatigue and physical symptoms.

  • 25.
    Hvoslef-Eide, M.
    et al.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, MRC, Cambridge CB2 3EB, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Mar, A. C.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, MRC, Cambridge CB2 3EB, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England.;NYU, Med Ctr, Dept Neurosci & Physiol, New York, NY 10016 USA..
    Nilsson, S. R. O.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, MRC, Cambridge CB2 3EB, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Alsioe, J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Heath, C. J.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, MRC, Cambridge CB2 3EB, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Saksida, L. M.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, MRC, Cambridge CB2 3EB, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Robbins, T. W.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, MRC, Cambridge CB2 3EB, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Bussey, T. J.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, MRC, Cambridge CB2 3EB, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    The NEWMEDS rodent touchscreen test battery for cognition relevant to schizophrenia2015In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 232, no 21-22, p. 3853-3872Article, review/survey (Refereed)
    Abstract [en]

    The NEWMEDS initiative (Novel Methods leading to New Medications in Depression and Schizophrenia, http://www.newmeds-europe.com) is a large industrial-academic collaborative project aimed at developing new methods for drug discovery for schizophrenia. As part of this project, Work package 2 (WP02) has developed and validated a comprehensive battery of novel touchscreen tasks for rats and mice for assessing cognitive domains relevant to schizophrenia. This article provides a review of the touchscreen battery of tasks for rats and mice for assessing cognitive domains relevant to schizophrenia and highlights validation data presented in several primary articles in this issue and elsewhere. The battery consists of the five-choice serial reaction time task and a novel rodent continuous performance task for measuring attention, a three-stimulus visual reversal and the serial visual reversal task for measuring cognitive flexibility, novel non-matching to sample-based tasks for measuring spatial working memory and paired-associates learning for measuring long-term memory. The rodent (i.e. both rats and mice) touchscreen operant chamber and battery has high translational value across species due to its emphasis on construct as well as face validity. In addition, it offers cognitive profiling of models of diseases with cognitive symptoms (not limited to schizophrenia) through a battery approach, whereby multiple cognitive constructs can be measured using the same apparatus, enabling comparisons of performance across tasks. This battery of tests constitutes an extensive tool package for both model characterisation and pre-clinical drug discovery.

  • 26.
    Johansson, Maja
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology. Umecrine Cognition AB, Karolinska Institutet Science Park, Fogdevreten 2, SE-171 65 Solna, Sweden.
    Månsson, Maria
    Lins, Lars-Eric
    Scharschmidt, Bruce
    Doverskog, Magnus
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology. Umecrine Cognition AB, Karolinska Institutet Science Park, Fogdevreten 2, SE-171 65 Solna, Sweden.
    GR3027 reversal of neurosteroid-induced, GABA-A receptor-mediated inhibition of human brain function: an allopregnanolone challenge study2018In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 235, no 5, p. 1533-1543Article in journal (Refereed)
    Abstract [en]

    RATIONALE: GR3027 is a novel small molecule GABA-A receptor-modulating steroid antagonist, which in non-clinical studies has shown promise for treatment of human disorders due to allosteric over-activation of GABA-A receptors by neurosteroids, such as allopregnanolone. We here studied its safety, pharmacokinetics, and ability to inhibit allopregnanolone effects in humans.

    METHODS: Safety and pharmacokinetics were studied in healthy adult males receiving ascending single or multiple oral GR3027 vs. placebo. GR3027-mediated reversal of allopregnanolone effect on maximal saccadic eye velocity (SEV), and self-rated somnolence was studied in a double-blind, placebo-controlled, three-part cross-over study in which 3 or 30 mg oral GR3027 preceded 0.05 mg/kg of i.v. allopregnanolone.

    RESULTS: ]) varied linearly with dose; with dose-dependent accumulation ratios of 1.3-1.6. Allopregnanolone decreased SEV and induced somnolence in most, but not all subjects. By predefined analyses, 30 mg GR3027 significantly inhibited allopregnanolone-induced decrease in SEV (p = 0.03); 3 and 30 mg GR3027 non-significantly inhibited allopregnanolone-induced sedation. By post hoc analyses restricted to subjects with allopregnanolone-induced changes and the time period over which they occurred, GR3027 dose dependently inhibited allopregnanolone-induced decrease in SEV (p = 0.04 at 30 mg, non-significant at 3 mg) and allopregnanolone-induced sedation (p = 0.01/0.05 at 3/30 mg doses).

    CONCLUSION: Oral GR3027 mitigates inhibition of brain function induced by allopregnanolone at doses which are clinically well tolerated and associated with linear pharmacokinetics.

  • 27. Kadir, Ahmadul
    et al.
    Almkvist, Ove
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Nordberg, Agneta
    PET imaging of cortical 11C-nicotine binding correlates with the cognitive function of attention in Alzheimer's disease2006In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 188, no 4, p. 509-520Article in journal (Refereed)
    Abstract [en]

    RATIONALE:

    Patients suffering from Alzheimer's disease (AD) experience a marked reduction in cortical nicotinic acetylcholine receptors (nAChRs). In particular, selective loss of the alpha4beta2 nAChR subtype was observed in postmortem AD brain tissue. The alpha4 and alpha7 nAChR subunits were suggested to play an important role in cognitive function. Positron emission tomography (PET) has so far been used to visualize neuronal nAChRs in vivo by 11C-nicotine binding.

    OBJECTIVES:

    To investigate the relationship between measures of cognitive function and in vivo 11C-nicotine binding in mild AD brain as assessed by PET.

    MATERIALS AND METHODS:

    Twenty-seven patients with mild AD were recruited in this study. A dual tracer model with administration of 15O-water for regional cerebral blood flow and (S)(-)11C-nicotine was used to assess nicotine binding sites in the brain by PET. Cognitive function was assessed using neuropsychological tests of global cognition, episodic memory, attention, and visuospatial ability.

    RESULTS:

    Mean cortical 11C-nicotine binding significantly correlated with the results of attention tests [Digit Symbol test (r = -0.44 and p = 0.02) and Trail Making Test A (TMT-A) (r = 0.42 and p = 0.03)]. No significant correlation was observed between 11C-nicotine binding and the results of tests of episodic memory or visuospatial ability. Regional analysis showed that 11C-nicotine binding in the frontal and parietal cortex, which are the main areas for attention, correlated significantly with the Digit Symbol test and TMT-A results.

    CONCLUSION:

    Cortical nicotinic receptors in vivo in mild AD patients are robustly associated with the cognitive function of attention.

  • 28. Kadir, Ahmadul
    et al.
    Darreh-Shori, Taher
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Wall, Anders
    Langstrom, Bengt
    Nordberg, Agneta
    Changes in brain C-11-nicotine binding sites in patients with mild Alzheimer's disease following rivastigmine treatment as assessed by PET2007In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 191, no 4, p. 1005-1014Article in journal (Refereed)
    Abstract [en]

    Rationale Marked reduction in the cortical nicotinic acetylcholine receptors is observed in the brain of patients suffering from Alzheimer's disease (AD). Although cholinesterase inhibitors are used for symptomatic treatment of mild to moderate AD patients, numerous long-term treatment studies indicate that they might stabilize or halt the progression of the disease by restoring the central cholinergic neurotransmission. Thus, we used positron emission tomography (PET) technique as a sensitive approach to assess longitudinal changes in the nicotine binding sites in the brains of patients with AD. Objectives To evaluate changes in brain nicotinic binding sites in relation to inhibition level of cholinesterases in cerebrospinal fluid (CSF) and plasma and changes in cognitive performance of the patients in different neuropsychological tests after rivastigmine treatment. Materials and methods Ten mild AD patients received rivastigmine for 12 months. A dual-tracer PET model with administration of O-15-water and (S)(-)C-11-nicotine was used to assess C-11-nicotine binding sites in the brain at baseline and after 3 and 12 months of the treatment. Cholinesterase activities in CSF and plasma were assessed colorimetrically. Results The 11C-nicotine binding sites were significantly increased 12-19% in several cortical brain regions after 3 months compared with baseline, while the increase was not significant after 12 months of the treatment. After 3 months treatment, low enzyme inhibition in CSF and plasma was correlated with higher cortical C-11-nicotine binding. The C-11-nicotine binding positively correlated with attentional task at the 12-month follow-up. Conclusions Changes in the C-11-nicotine binding during rivastigmine treatment might represent remodeling of the cholinergic and related neuronal network.

  • 29. Kadir, Ahmadul
    et al.
    Darreh-Shori, Taher
    Almkvist, Ove
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Nordberg, Agneta
    Changes in brain 11C-nicotine binding sites in patients with mild Alzheimer's disease following rivastigmine treatment as assessed by PET2007In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 191, no 4, p. 1005-1014Article in journal (Refereed)
    Abstract [en]

    Rationale  

    Marked reduction in the cortical nicotinic acetylcholine receptors is observed in the brain of patients suffering from Alzheimer’s disease (AD). Although cholinesterase inhibitors are used for symptomatic treatment of mild to moderate AD patients, numerous long-term treatment studies indicate that they might stabilize or halt the progression of the disease by restoring the central cholinergic neurotransmission. Thus, we used positron emission tomography (PET) technique as a sensitive approach to assess longitudinal changes in the nicotine binding sites in the brains of patients with AD.

    Objective  

    To evaluate changes in brain nicotinic binding sites in relation to inhibition level of cholinesterases in cerebrospinal fluid (CSF) and plasma and changes in cognitive performance of the patients in different neuropsychological tests after rivastigmine treatment.

    Materials and methods  

    Ten mild AD patients received rivastigmine for 12 months. A dual-tracer PET model with administration of 15O–water and (S)(–)11C–nicotine was used to assess 11C–nicotine binding sites in the brain at baseline and after 3 and 12 months of the treatment. Cholinesterase activities in CSF and plasma were assessed colorimetrically.

    Results  

    The 11C–nicotine binding sites were significantly increased 12–19% in several cortical brain regions after 3 months compared with baseline, while the increase was not significant after 12 months of the treatment. After 3 months treatment, low enzyme inhibition in CSF and plasma was correlated with higher cortical 11C–nicotine binding. The 11C–nicotine binding positively correlated with attentional task at the 12-month follow-up.

    Conclusion  

    Changes in the 11C–nicotine binding during rivastigmine treatment might represent remodeling of the cholinergic and related neuronal network.

  • 30. Kadir, Ahmadul
    et al.
    Darreh-Shori, Taher
    Almkvist, Ove
    Wall, Anders
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Nordberg, Agneta
    Changes in brain 11C-nicotine binding sites in patients with mild Alzheimer's disease following rivastigmine treatment as assessed by PET2007In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 191, no 4, p. 1005-1014Article in journal (Refereed)
    Abstract [en]

    Rationale  Marked reduction in the cortical nicotinic acetylcholine receptors is observed in the brain of patients suffering from Alzheimer’s disease (AD). Although cholinesterase inhibitors are used for symptomatic treatment of mild to moderate AD patients, numerous long-term treatment studies indicate that they might stabilize or halt the progression of the disease by restoring the central cholinergic neurotransmission. Thus, we used positron emission tomography (PET) technique as a sensitive approach to assess longitudinal changes in the nicotine binding sites in the brains of patients with AD. Objective  To evaluate changes in brain nicotinic binding sites in relation to inhibition level of cholinesterases in cerebrospinal fluid (CSF) and plasma and changes in cognitive performance of the patients in different neuropsychological tests after rivastigmine treatment. Materials and methods  Ten mild AD patients received rivastigmine for 12 months. A dual-tracer PET model with administration of 15O–water and (S)(–)11C–nicotine was used to assess 11C–nicotine binding sites in the brain at baseline and after 3 and 12 months of the treatment. Cholinesterase activities in CSF and plasma were assessed colorimetrically. Results  The 11C–nicotine binding sites were significantly increased 12–19% in several cortical brain regions after 3 months compared with baseline, while the increase was not significant after 12 months of the treatment. After 3 months treatment, low enzyme inhibition in CSF and plasma was correlated with higher cortical 11C–nicotine binding. The 11C–nicotine binding positively correlated with attentional task at the 12-month follow-up. Conclusion  Changes in the 11C–nicotine binding during rivastigmine treatment might represent remodeling of the cholinergic and related neuronal network.

  • 31.
    Karlsson, Camilla
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Rehman, Faazal
    NIAAA, MD USA.
    Damadzic, Ruslan
    NIAAA, MD USA.
    Atkins, Alison Lynn
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Schank, Jesse R.
    University of Georgia, GA 30602 USA.
    Gehlert, Donald R.
    Lilly Research Labs, IN USA.
    Steensland, Pia
    Karolinska Institute, Sweden.
    Thorsell, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Social and Affective Neuroscience (CSAN). Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Correction: The melanin-concentrating hormone-1 receptor modulates alcohol-induced reward and DARPP-32 phosphorylation (vol 233, nr 12, pp. 2355–2363, 2016)2016In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, no 21-22, p. 3825-3825Article in journal (Other academic)
    Abstract [en]

    n/a

  • 32.
    Karlsson, Camilla
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Rehman, Faazal
    NIH, MD 20892 USA.
    Damdazic, Ruslan
    NIH, MD 20892 USA.
    Atkins, Alison Lynn
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Schank, Jesse R.
    University of Georgia, GA 30602 USA.
    Gehlert, Donald R.
    Eli Lilly and Co, IN 46285 USA.
    Steensland, Pia
    Karolinska Institute, Sweden.
    Thorsell, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Social and Affective Neuroscience (CSAN). Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    The melanin-concentrating hormone-1 receptor modulates alcohol-induced reward and DARPP-32 phosphorylation2016In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, no 12, p. 2355-2363Article in journal (Refereed)
    Abstract [en]

    Melanin-concentrating hormone (MCH) is involved in the regulation of food intake and has recently been associated with alcohol-related behaviors. Blockade of MCH-1 receptors (MCH1-Rs) attenuates operant alcohol self-administration and decreases cue-induced reinstatement, but the mechanism through which the MCH1-R influences these behaviors remains unknown. MCH1-Rs are highly expressed in the nucleus accumbens shell (NAcSh) where they are co-expressed with dopamine (DA) receptors. MCH has been shown to potentiate responses to dopamine and to increase phosphorylation of DARPP-32, an intracellular marker of DA receptor activation, in the NAcSh. In the present study, we investigated the role of the MCH1-R in alcohol reward using the conditioned place preference (CPP) paradigm. We then used immunohistochemistry (IHC) to assess activation of downstream signaling after administration of a rewarding dose of alcohol. We found that alcohol-induced CPP was markedly decreased in mice with a genetic deletion of the MCH1-R as well as after pharmacological treatment with an MCH1-R antagonist, GW803430. In contrast, an isocaloric dose of dextrose did not produce CPP. The increase in DARPP-32 phosphorylation seen in wildtype (WT) mice after acute alcohol administration in the NAcSh was markedly reduced in MCH1-R knock-out (KO) mice. Our results suggest that MCH1-Rs regulate the rewarding properties of alcohol through interactions with signaling cascades downstream of DA receptors in the NAcSh.

  • 33.
    Karlsson, Louise
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Hiemke, Christoph
    Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany .
    Carlsson, Björn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Josefsson, Martin
    Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Artillerigatan 12, Sweden.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Schmitt, Ulrich
    Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany .
    Kugelberg, Fredrik C
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Effects on enantiomeric drug disposition and open-field behavior after chronic treatment with venlafaxine in the P-glycoprotein knockout mice model2011In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 215, no 2, p. 367-377Article in journal (Refereed)
    Abstract [en]

    Our results show that P-gp at the blood-brain barrier plays an important role in limiting brain entry of the enantiomers of venlafaxine and its metabolites after chronic dosing. Taken together, the present pharmacokinetic and pharmacodynamic findings offer the possibility that the expression of P-gp in patients may be a contributing factor for limited treatment response.

  • 34.
    Karlsson, Rose-Marie
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Choe, Jessica S.
    National Institute of Mental Health, NIH, Bethesda, MD, USA .
    Cameron, Heather A
    National Institute of Mental Health, NIH, Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Crawley, Jacqueline N
    National Institute of Mental Health, NIH, Bethesda, MD, USA.
    Holmes, Andrew
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    The neuropeptide Y Y1 receptor subtype is necessary for the anxiolytic-like effects of neuropeptide Y, but not the antidepressant-like effects of fluoxetine, in mice2008In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 195, no 4, p. 547-557Article in journal (Refereed)
    Abstract [en]

    RATIONALE: Neuropeptide Y (NPY) is implicated in the pathophysiology of affective illness. Multiple receptor subtypes (Y1R, Y2R, and Y5R) have been suggested to contribute to NPY's effects on rodent anxiety and depression-related behaviors.

    OBJECTIVES: To further elucidate the role of Y1R in (1) NPY's anxiolytic-like effects and (2) fluoxetine's antidepressant-like and neurogenesis-inducing effects.

    METHODS: Mice lacking Y1R were assessed for spontaneous anxiety-like behavior (open field, elevated plus-maze, and light/dark exploration test) and Pavlovian fear conditioning, and for the anxiolytic-like effects of intracerebroventricularly (icv)-administrated NPY (elevated plus-maze). Next, Y1R -/- were assessed for the antidepressant-like effects of acute fluoxetine in the forced swim test and chronic fluoxetine in the novelty-induced hypophagia test, as well as for chronic fluoxetine-induced hippocampal neurogenesis.

    RESULTS: Y1R -/- exhibited largely normal baseline behavior as compared to +/+ littermate controls. Intraventricular administration of NPY in Y1R -/- mice failed to produce the normal anxiolytic-like effect in the elevated plus-maze test seen in +/+ mice. Y1R mutant mice showed higher immobility in the forced swim test and longer latencies in the novelty-induced hypophagia test. In addition, Y1R -/- mice responded normally to the acute and chronic effects of fluoxetine treatment in the forced swim test and the novelty-induced hypophagia test, respectively, as well as increased neuronal precursor cell proliferation in the hippocampus.

    CONCLUSIONS: These data demonstrate that Y1R is necessary for the anxiolytic-like effects of icv NPY, but not for the antidepressant-like or neurogenesis-inducing effects of fluoxetine. The present study supports targeting Y1R as a novel therapeutic target for anxiety disorders.

  • 35.
    Kask, Kristiina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Bäckström, Torbjörn
    Department of Clinical Science, Obstetrics and Gynecology, Umeå University, Umeå, Sweden.
    Nilsson, Lars-Göran
    Department of Psychology, Stockholm University, Stockholm, Sweden.
    Sundström Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Allopregnanolone impairs episodic memory in healthy women2008In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 199, no 2, p. 161-168Article in journal (Refereed)
    Abstract [en]

    Allopregnanolone is an endogenous neuroactive steroid that, through its binding to the γ-aminobutyric acid (GABA) A receptor, has GABA-active properties. Animal studies indicate that allopregnanolone administration results in diminished learning and memory impairment. The aim of the current study was to investigate the effect of intravenously administered allopregnanolone on episodic memory, semantic memory, and working memory in healthy women.

    Twenty-eight healthy women were included in the study. The participants were scheduled for the memory tests twice in the follicular phase. During the test sessions, an intravenous allopregnanolone and placebo infusion were administered in a double-blinded, randomized order at intervals of 48 h. Before and 10 min after the allopregnanolone/placebo injections, memory tasks were performed.The study demonstrated that allopregnanolone impaired episodic memory in healthy women. There was a significant difference between pre- and postallopregnanolone injection episodic memory scores (p < 0.05), whereas there was no change in episodic memory performance following the placebo injections. There was also a significant difference between allopregnanolone and placebo postinjection episodic memory scores (p < 0.05). There were no effects of allopregnanolone on the semantic memory task or working memory task.Intravenous allopregnanolone impairs episodic memory in healthy women, but there is a high degree of individual variability.

  • 36.
    Kask, Kristiina
    et al.
    1.Uppsala University Department Women’s and Children’s Health, University Hospital, Uppsala Sweden.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Nilsson, Lars-Göran
    3.Stockholm University Department of Psychology Stockholm Sweden.
    Sundström-Poromaa, Inger
    1.Uppsala University Department Women’s and Children’s Health, University Hospital, Uppsala Sweden.
    Allopregnanolone impairs episodic memory in healthy women2008In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 199, no 2, p. 161-168Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Allopregnanolone is an endogenous neuroactive steroid that, through its binding to the gamma-aminobutyric acid (GABA) A receptor, has GABA-active properties. Animal studies indicate that allopregnanolone administration results in diminished learning and memory impairment. The aim of the current study was to investigate the effect of intravenously administered allopregnanolone on episodic memory, semantic memory, and working memory in healthy women. MATERIALS AND METHODS: Twenty-eight healthy women were included in the study. The participants were scheduled for the memory tests twice in the follicular phase. During the test sessions, an intravenous allopregnanolone and placebo infusion were administered in a double-blinded, randomized order at intervals of 48 h. Before and 10 min after the allopregnanolone/placebo injections, memory tasks were performed. RESULTS: The study demonstrated that allopregnanolone impaired episodic memory in healthy women. There was a significant difference between pre- and postallopregnanolone injection episodic memory scores (p < 0.05), whereas there was no change in episodic memory performance following the placebo injections. There was also a significant difference between allopregnanolone and placebo postinjection episodic memory scores (p < 0.05). There were no effects of allopregnanolone on the semantic memory task or working memory task. CONCLUSION: Intravenous allopregnanolone impairs episodic memory in healthy women, but there is a high degree of individual variability.

  • 37. Kask, Kristiina
    et al.
    Bäckström, Torbjörn
    Nilsson, Lars-Göran
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Sundström-Poromaa, Inger
    Allopregnanolone impairs episodic memory in healthy women2008In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 199, no 2, p. 161-168Article in journal (Refereed)
    Abstract [en]

    Allopregnanolone is an endogenous neuroactive steroid that, through its binding to the γ-aminobutyric acid (GABA) A receptor, has GABA-active properties. Animal studies indicate that allopregnanolone administration results in diminished learning and memory impairment. The aim of the current study was to investigate the effect of intravenously administered allopregnanolone on episodic memory, semantic memory, and working memory in healthy women. Twenty-eight healthy women were included in the study. The participants were scheduled for the memory tests twice in the follicular phase. During the test sessions, an intravenous allopregnanolone and placebo infusion were administered in a double-blinded, randomized order at intervals of 48 h. Before and 10 min after the allopregnanolone/placebo injections, memory tasks were performed. The study demonstrated that allopregnanolone impaired episodic memory in healthy women. There was a significant difference between pre- and postallopregnanolone injection episodic memory scores (p < 0.05), whereas there was no change in episodic memory performance following the placebo injections. There was also a significant difference between allopregnanolone and placebo postinjection episodic memory scores (p < 0.05). There were no effects of allopregnanolone on the semantic memory task or working memory task. Intravenous allopregnanolone impairs episodic memory in healthy women, but there is a high degree of individual variability.

  • 38.
    Kuzmin, Alexander
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jerlhag, E
    Liljequist, S
    Engel, J
    Effects of subunit selective nACh receptors on operant ethanol self-administration and relapse-like ethanol-drinking behavior2009In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 203, no 1, p. 99-108Article in journal (Refereed)
    Abstract [en]

    RATIONALE AND OBJECTIVES:

    The sensitivity to ethanol central effects is partially determined by the subunit composition of brain nicotinic acetylcholine receptors (nAChRs). Thus, the effects of intraventral tegmental area (VTA) administration of the nicotinic subunit-specific antagonist, alpha-conotoxin MII (alphaCtxMII, alpha(3)beta(2)*, beta(3)*, alpha(6)*), were compared to those of systemic mecamylamine (MEC, an allosteric negative modulator of the nAChR), dihydro-beta-erythroidine (DHbetaE, alpha(4)beta(2)*), and methyllycaconitine (MLA, alpha(7)*) to elucidate involvement of different subunits of nAChRs in operant ethanol self-administration and relapse-like activation of ethanol consumption after ethanol deprivation in rats.

    METHODS:

    The effects of drugs were studied in rats trained for operant oral self-administration of ethanol (FR = 1). For ethanol deprivation, trained animals were subjected to a period of alcohol deprivation for 10 days. alphaCtxMII was given directly into the VTA through implanted permanent intracranial cannulae, whereas MEC, DHbetaE, and MLA were administered systemically.

    RESULTS:

    alphaCtxMII reduced operant ethanol self-administration and blocked the deprivation-induced relapse-like ethanol consumption. MEC reduced operant ethanol self-administration and inhibited the deprivation-induced increase in alcohol consumption. DHbetaE did not alter ethanol self-administration in the lower-dose range but inhibited ethanol intake at a higher dose (4 mg/kg), although this effect might have been nonspecific. MLA failed to block self-administration of ethanol and relapse-like drinking after deprivation.

    CONCLUSIONS:

    Our results indicate that nAChRs are involved in the modulation of operant alcohol self-administration and relapse-like alcohol drinking behavior in rats. Our observations support the working hypothesis that systemically active selective ligands for nAChR alpha(3)beta(2)*, beta(3), and/or alpha(6)* receptor subunits might be of therapeutic value for the treatment of alcoholism.

  • 39.
    Kuzmin, Alexander
    et al.
    Department of Clinical Neuroscience, Division of Drug Dependence, Karolinska University Hospital, Stockholm, Sweden.
    Jerlhag, Elisabet
    Institute of Neuroscience and Physiology, Section of Pharmacology, Göteborg University, Göteborg, Sweden.
    Liljequist, Sture
    Department of Clinical Neuroscience, Division of Drug Dependence, Karolinska University Hospital, Stockholm, Sweden.
    Engel, Jörgen
    Institute of Neuroscience and Physiology, Section of Pharmacology, Göteborg University, Göteborg, Sweden.
    Effects of subunit selective nACh receptors on operant ethanol self-administration and relapse-like ethanol-drinking behavior2009In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 203, no 1, p. 99-108Article in journal (Refereed)
    Abstract [en]

    RATIONALE AND OBJECTIVES: The sensitivity to ethanol central effects is partially determined by the subunit composition of brain nicotinic acetylcholine receptors (nAChRs). Thus, the effects of intraventral tegmental area (VTA) administration of the nicotinic subunit-specific antagonist, alpha-conotoxin MII (alphaCtxMII, alpha(3)beta(2)*, beta(3)*, alpha(6)*), were compared to those of systemic mecamylamine (MEC, an allosteric negative modulator of the nAChR), dihydro-beta-erythroidine (DHbetaE, alpha(4)beta(2)*), and methyllycaconitine (MLA, alpha(7)*) to elucidate involvement of different subunits of nAChRs in operant ethanol self-administration and relapse-like activation of ethanol consumption after ethanol deprivation in rats. METHODS: The effects of drugs were studied in rats trained for operant oral self-administration of ethanol (FR = 1). For ethanol deprivation, trained animals were subjected to a period of alcohol deprivation for 10 days. alphaCtxMII was given directly into the VTA through implanted permanent intracranial cannulae, whereas MEC, DHbetaE, and MLA were administered systemically. RESULTS: alphaCtxMII reduced operant ethanol self-administration and blocked the deprivation-induced relapse-like ethanol consumption. MEC reduced operant ethanol self-administration and inhibited the deprivation-induced increase in alcohol consumption. DHbetaE did not alter ethanol self-administration in the lower-dose range but inhibited ethanol intake at a higher dose (4 mg/kg), although this effect might have been nonspecific. MLA failed to block self-administration of ethanol and relapse-like drinking after deprivation. CONCLUSIONS: Our results indicate that nAChRs are involved in the modulation of operant alcohol self-administration and relapse-like alcohol drinking behavior in rats. Our observations support the working hypothesis that systemically active selective ligands for nAChR alpha(3)beta(2)*, beta(3), and/or alpha(6)* receptor subunits might be of therapeutic value for the treatment of alcoholism.

  • 40.
    Lindström, Leif H.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine.
    Meyerson, Bengt J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine.
    The effect of pilocarpine, oxotremorine and arecoline in combination with methyl-atropine or atropine on hormone activated oestrous behaviour in ovariectomized rats1967In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 11, no 5, p. 405-405Article in journal (Refereed)
    Abstract [en]

    The effects of pilocarpine, oxotremorine and arecoline were studied on oestradiol/progesterone activated oestrous behaviour in ovariectomized rats. A heat-inhibitory effect was obtained, which could be more effectively counteracted by atrophie than methyl-atropine.No positive correlation was seen between the inhibitory effect on oestrous behaviour and the ability of the different cholinergic compounds to induce tremor or decrease the locomotor activity.The data indicate that in addition to earlier described monoaminergic pathways mediating inhibition of oestrous behaviour, cholinergic mechanisms are also involved.The results of this study were presented in part at the XII Scandinavian Congress of Physiology 1966 at Turku, Finland.

  • 41.
    Mar, Adam C.
    et al.
    NYU Med Ctr, Neurosci Inst, New York, NY 10016 USA.;NYU Med Ctr, Dept Neurosci & Physiol, New York, NY 10016 USA.;Univ Cambridge, Dept Psychol, Cambridge, England.;Univ Cambridge, MRC, Cambridge, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge, England..
    Nilsson, Simon R. O.
    NYU Med Ctr, Neurosci Inst, New York, NY 10016 USA.;NYU Med Ctr, Dept Neurosci & Physiol, New York, NY 10016 USA.;Univ Cambridge, Dept Psychol, Cambridge, England.;Univ Cambridge, MRC, Cambridge, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge, England..
    Gamallo-Lana, Begona
    NYU Med Ctr, Neurosci Inst, New York, NY 10016 USA.;NYU Med Ctr, Dept Neurosci & Physiol, New York, NY 10016 USA.;Univ Cambridge, Dept Psychol, Cambridge, England.;Univ Cambridge, MRC, Cambridge, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge, England..
    Lei, Ming
    Univ Cambridge, Dept Psychol, Cambridge, England.;Univ Cambridge, MRC, Cambridge, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge, England.;Beijing Int Studies Univ, Dept Hlth Ind Management, 1 Dingfuzhuang Nanli, Beijing, Peoples R China..
    Dourado, Theda
    Univ Cambridge, Dept Psychol, Cambridge, England.;Univ Cambridge, MRC, Cambridge, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge, England..
    Alsiö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Univ Cambridge, Dept Psychol, Cambridge, England.;Univ Cambridge, MRC, Cambridge, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge, England..
    Saksida, Lisa M.
    Univ Cambridge, Dept Psychol, Cambridge, England.;Univ Cambridge, MRC, Cambridge, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge, England.;Western Univ, Robarts Res Inst, Mol Med Res Grp, London, ON, Canada.;Western Univ, Schulich Sch Med & Dent, Dept Physiol & Pharmacol, London, ON, Canada.;Western Univ, Brain & Mind Inst, London, ON, Canada..
    Bussey, Timothy J.
    Univ Cambridge, Dept Psychol, Cambridge, England.;Univ Cambridge, MRC, Cambridge, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge, England.;Western Univ, Robarts Res Inst, Mol Med Res Grp, London, ON, Canada.;Western Univ, Schulich Sch Med & Dent, Dept Physiol & Pharmacol, London, ON, Canada.;Western Univ, Brain & Mind Inst, London, ON, Canada..
    Robbins, Trevor W.
    Univ Cambridge, Dept Psychol, Cambridge, England.;Univ Cambridge, MRC, Cambridge, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge, England..
    MAM-E17 rat model impairments on a novel continuous performance task: effects of potential cognitive enhancing drugs2017In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 234, no 19, p. 2837-2857Article in journal (Refereed)
    Abstract [en]

    Impairments in attention and inhibitory control are endophenotypic markers of neuropsychiatric disorders such as schizophrenia and represent key targets for therapeutic management. Robust preclinical models and assays sensitive to clinically relevant treatments are crucial for improving cognitive enhancement strategies. We assessed a rodent model with neural and behavioral features relevant to schizophrenia (gestational day 17 methylazoxymethanol acetate treatment (MAM-E17)) on a novel test of attention and executive function, and examined the impact of putative nootropic drugs. MAM-E17 and sham control rats were trained on a novel touchscreen-based rodent continuous performance test (rCPT) designed to closely mimic the human CPT paradigm. Performance following acute, systemic treatment with an array of pharmacological compounds was investigated. Two cohorts of MAM-E17 rats were impaired on rCPT performance including deficits in sensitivity (d') and increased false alarm rates (FARs). Sulpiride (0-30 mg/kg) dose-dependently reduced elevated FAR in MAM-E17 rats whereas low-dose modafinil (8 mg/kg) only improved d' in sham controls. ABT-594 (5.9-19.4 mu g/kg) and modafinil (64 mg/kg) showed expected stimulant-like effects, while LSN2463359 (5 mg/kg), RO493858 (10 mg/kg), atomoxetine (0.3-1 mg/kg), and sulpiride (30 mg/kg) showed expected suppressant effects on performance across all animals. Donepezil (0.1-1 mg/kg) showed near-significant enhancements in d', and EVP-6124 (0.3-3 mg/kg) exerted no effects in the rCPT paradigm. The MAM-E17 model exhibits robust and replicable impairments in rCPT performance that resemble attention and inhibitory control deficits seen in schizophrenia. Pharmacological profiles were highly consistent with known drug effects on cognition in preclinical and clinical studies. The rCPT is a sensitive and reliable tool with high translational potential for understanding the etiology and treatment of disorders affecting attention and executive dysfunction.

  • 42.
    Mayo, Leah
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. University of Chicago, Chicago, USA.
    Paul, Elisabeth
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    De Arcangelis, Jessica
    University of Chicago, Chicago, USA.
    Van Hedger, Kathryne
    University of Western Ontario, London,, Canada.
    de Wit, Harriet
    University of Chicago, Chicago, USA.
    Gender differences in the behavioral and subjective effects of methamphetamine in healthy humans2019In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 236, no 8, p. 2413-2423Article in journal (Refereed)
    Abstract [en]

    Rationale

    Methamphetamine (MA) use is steadily increasing and thus constitutes a major public health concern. Women seem to be particularly vulnerable to developing MA use disorder, as they initiate use at a younger age and transition more quickly to problematic use. Initial drug responses may predict subsequent use, but little information exists on potential gender differences in the acute effects of MA prior to dependence.

    Objective

    We examined gender differences in the acute effects of MA on subjective mood and reward-related behavior in healthy, non-dependent humans.

    Methods

    Men (n = 44) and women (n = 29) completed 4 sessions in which they received placebo or MA under double-blind conditions twice each. During peak drug effect, participants completed the monetary incentive delay task to assess reaction times to cues signaling potential monetary losses or gains, in an effort to determine if MA would potentiate reward-motivated behavior. Cardiovascular and subjective drug effects were assessed throughout sessions.

    Results

    Overall, participants responded more quickly to cues predicting incentivized trials, particularly large-magnitude incentives, than to cues predicting no incentive. MA produced faster reaction times in women, but not in men. MA produced typical stimulant-like subjective and cardiovascular effects in all participants, but subjective ratings of vigor and (reduced) sedation were greater in women than in men.

    Conclusions

    Women appear to be more sensitive to the psychomotor-related behavioral and subjective effects of MA. These findings provide initial insight into gender differences in acute effects of MA that may contribute to gender differences in problematic MA use.

  • 43. Melkersson, Kristina
    et al.
    Dahl, Marja-Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hulting, Anna-Lena
    Guidelines for prevention and treatment of adverse effects of antipsychotic drugs on glucose-insulin homeostasis and lipid metabolism2004In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 175, no 1, p. 1-6Article in journal (Refereed)
    Abstract [en]

    RATIONALE: With the antipsychotic drugs available today, especially with some of the newer, atypical antipsychotics, metabolic side effects, such as weight gain, diabetes mellitus and lipid abnormalities, have become a complication to the drug therapy that have to be recognized and treated. OBJECTIVE: The aim of this article is to suggest guidelines for prevention and treatment of adverse effects of antipsychotics on glucose-insulin homeostasis and lipid metabolism, whereas strategies for management of antipsychotic-induced weight gain are summarized elsewhere. METHOD: The guidelines are based on results of experimental and clinical studies presented in the article, as well as on a recently published review of 180 articles in the field. RESULTS: Both conventional and atypical antipsychotics can indirectly, by causing obesity, promote development of insulin resistance and type-2 diabetes. In addition, some atypical agents probably directly induce hyperinsulinemia, followed by weight gain, insulin resistance and drug-induced, sometimes insulin-dependent, diabetes. CONCLUSION: In this article, guidelines for the management of adverse metabolic effects of antipsychotics are described.

  • 44. Merenäkk, Liis
    et al.
    Mäestu, Jarek
    Nordquist, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Parik, Jüri
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Loit, Helle-Mai
    Harro, Jaanus
    Effects of the serotonin transporter (5-HTTLPR) and alpha(2A)-adrenoceptor (C-1291G) genotypes on substance use in children and adolescents: a longitudinal study2011In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 215, no 1, p. 13-22Article in journal (Refereed)
    Abstract [en]

    Twin studies suggest that substance use initiation in children and adolescents is determined primarily by environmental influences, whereas the establishment of use patterns is strongly controlled by genetic factors. The present study analysed the effects of the serotonin transporter promoter polymorphism [5-HT transporter gene-linked polymorphic region (5-HTTLPR)] and the alpha(2A)-adrenoceptor C-1291G genotype (ADRA2A C-1291G) as well as their interaction effects on alcohol, tobacco and drug use from preadolescence to the late adolescence. Initial sample of 9-year-old children of Estonian Children Personality Behaviour and Health Study (n = 583) was recalled at ages 15 and 18. Participants reported in all waves how frequently they smoked and used alcohol and illicit drugs. 5-HTTLPR had age-dependent effects on alcohol, tobacco and drug use: substance use did not differ by genotype at age 9, but at age 15, the participants with the short (s)/s genotype had higher tobacco use, and at age 18, they were more active alcohol, drug and tobacco users. Effects of ADRA2A C-1291G on drug use were dependent on gender, age and 5-HTTLPR. Males (age 18) with ADRA2A CG genotype, when compared to other participants, tended to have higher drug use especially when they had s/s genotype of 5-HTTLPR. Our results reveal that expression of genetic vulnerability for substance use in children and adolescents may depend on age, gender, interaction of genes, and type of substance.

  • 45.
    Nylander, Ingrid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Is the rodent maternal separation model a valid and effective model for studies on the early-life impact on ethanol consumption?2013In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 229, no 4, p. 555-569Article in journal (Refereed)
    Abstract [en]

    RATIONALE: Early-life events can cause long-term neurobiological and behavioural changes with a resultant effect upon reward and addiction processes that enhance risk to develop alcohol use disorders. Maternal separation (MS) is used to study the mediating mechanisms of early-life influences in rodents. In MS studies, the pups are exposed to maternal absence during the first postnatal weeks. The outcome of MS experiments exhibits considerable variation and questions have been raised about the validity of MS models.

    OBJECTIVES: This short review aims to provide information about experimental conditions that are important to consider when assessing the impact of early-life environment on voluntary ethanol consumption.

    RESULTS: The results from currently used MS protocols are not uniform. However, studies consistently show that longer separations of intact litters predispose for higher ethanol consumption and/or preference in adult male rats as compared to shorter periods of MS. Studies using individual pup MS paradigms, other controls, low ethanol concentrations, adult females or examining adolescent consumption reported no differences or inconsistent results.

    CONCLUSIONS: There is no "a rodent MS model", there are several models and they generate different results. The compiled literature shows that MS is a model of choice for analysis of early-life effects on voluntary ethanol consumption but there are examples of MS paradigms that are not suitable. These studies emphasize the importance to carefully designed MS experiments to supply the optimal conditions to definitely test the research hypothesis and to be particulate in the interpretation of the outcome.

  • 46.
    Olofsson, Jonas K.
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Gospic, Katarina
    Petrovic, Predrag
    Ingvar, Martin
    Wiens, Stefan
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Effects of oxazepam on affective perception, recognition, and event-related potentials2011In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 215, no 2, p. 301-309Article in journal (Refereed)
    Abstract [en]

    Background Little is known about how rapid electrocortical responses (event-related potentials; ERPs) to affective pictures are modulated by benzodiazepine agonists. The present study investigated effects of oxazepam (20 mg p.o.) on behavioral measures and ERPs associated with affective picture processing during perception and recognition memory retrieval. Methods Forty-three healthy young adults were given oxazepam or placebo treatment under a double-blind experimental procedure. Affective pictures (negatively arousing or neutral) elicited ERP responses and participants rated pictures for emotionality (during incidental encoding) and recognition. Results Oxazepam did not affect perceptual (P1, P2) or emotional (early posterior negativity and late parietal positivity) ERPs or ratings during perception. However, oxazepam impaired recognition performance and decreased positive mid-frontal ERP component at 420-450 ms for old vs. new pictures. The memory impairment was retained at the delayed memory test. Conclusions Oxazepam does not selectively influence electrocortical or perceptual indexes of emotional perception or emotional memory. Rather, it blocks memory consolidation independent of valence category. These findings indicate that ERPs can be of use in assessing effects of benzodiazepines on memory-related processes.

  • 47. Paaver, Marika
    et al.
    Nordquist, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Parik, Jüri
    Harro, Maarike
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Harro, Jaanus
    Platelet MAO activity and the 5-HTT gene promoter polymorphism are associated with impulsivity and cognitive style in visual information processing2007In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 194, no 4, p. 545-554Article in journal (Refereed)
    Abstract [en]

    Low capacity of the central serotonergic system has been associated with impulsive behaviour. Both low platelet monoamine oxidase (MAO) activity and the short (S) allele of the serotonin transporter gene promoter region polymorphism (5-HTTLPR) are proposed to be markers of less efficient serotonergic functioning.The effect of the two markers for serotonin system efficiency on performance in a visual comparison task (VCT) and self-reported impulsiveness (Barratt Impulsiveness Scale, BIS-11) were investigated in healthy adolescents participating in the Estonian Children Personality Behaviour and Health Study. Possible confounding effect of general cognitive abilities on the performance in VCT was controlled for.Low platelet MAO activity and carrying of the S allele of 5-HTTLPR were both associated with higher error-rate and more impulsive performance in VCT. Platelet MAO activity and 5-HTTLPR S allele had a significant interactive effect on self-reported impulsivity (BIS-11). The effect of platelet MAO activity on both self-reported and performance impulsivity was significant only in the S allele carriers. The effect of 5-HTTLPR S allele on impulsive performance remained significant after controlling for general cognitive abilities.The two markers of lower serotonergic capacity, 5-HTTLPR S allele and low platelet MAO activity, have a similar and partly synergistic influence on self-reported as well as performance measures of impulsivity.

  • 48.
    Persson, Jonas
    et al.
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Bringlöv, Eva
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Nilsson, Lars-Göran
    Department of Psychology, Stockholm University.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    The memory-enhancing effects of Ginseng and Ginkgo biloba in healthy volunteers2004In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 172, no 4, p. 430-434Article in journal (Refereed)
    Abstract [en]

    Rationale: The use of herbal remedies, such as Ginkgo biloba and Ginseng, for improving cognitive performance has become increasingly popular during recent years. Several previous studies have indicated that administration of Ginkgo biloba and Ginseng may improve aspects of learning and memory in healthy volunteers. These results, however, are generally not supported by well-controlled clinical studies. Also, positive results have often been reported from studies investigating effects related to short-term, chronic administration of the extract. Nonetheless, both Ginkgo biloba and Ginseng are marketed as having the capacity to enhance cognitive functions, such as memory and learning, in the long term.

    Objective: This study aimed at investigating whether the use of Ginkgo biloba and Ginseng for a long period of time has positive effects on performance on learning and memory.

    Methods: Community-dwelling volunteers ( n=3500) from The Betula prospective cohort study: memory, health, and aging were included in the study.

    Results: It was found that the use of neither Ginkgo biloba ( n=40) nor Ginseng ( n=86) was associated with enhanced memory performance in any of the eight memory tests examined, relative to control groups either using or not using nutritional supplements.

    Conclusions: These findings indicate that use of Ginkgo biloba or Ginseng does not provide any quantifiable beneficial effects on memory performance in the long-term in healthy adult volunteers.

  • 49.
    Pickering, Chris
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Alsiö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Hulting, Anna-Lena
    Department of Endocrinology, Metabolism and Diabetology, Karolinska Institutet, Stockholm.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Withdrawal from free-choice high-fat high-sugar diet induces craving only in obesity-prone animals2009In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 204, no 3, p. 431-443Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION:

    Vulnerability for weight gain is an individual trait. Obese people undertake dieting, but permanent weight loss is difficult to attain due to repeated phases of relapse to excess consumption.

    MATERIALS AND METHODS:

    In this study, male Wistar rats were trained to operantly self-administer pellets followed by free-choice access in the homecage to high-fat high-sugar (HFHS) diet consisting of 30% sucrose, lard, standard rodent chow and water. Animals were divided into obesity-prone (OP) and obesity-resistant (OR) groups based on relative weight gain compared to normally fed controls despite equal consumption of HFHS.

    RESULTS AND DISCUSSION:

    After 4 weeks of HFHS access, OP and OR animals did not differ in motivation for food pellets in terms of progressive ratio break point, lever pressing or response rate. However, upon discontinuation of the HFHS diet, differences between the OP and OR groups were noted. OP animals increased their motivation (i.e. craving) during the second withdrawal week and reduced time spent in the centre of an open field (increased anxiety) compared to the OR animals. Both OP and OR animals consumed less of the standard rodent chow during the first week of withdrawal when compared to normally fed controls. But, while the OR animals quickly returned to control levels of food consumption, OP animals continued to consume less standard rodent chow.

    CONCLUSION:

    The results show for the first time that withdrawal from free-choice HFHS induces craving that is specific to the OP animals and suggests that OP individuals may have withdrawal symptoms that are similar to those induced by addictive drugs.

  • 50.
    Poretti, María Belén
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Instituto de Fisiología, Instituto de Investigaciones en Ciencias de la Salud (INICSA, UNC-CONICET), Facultad de Ciencias Médicas, CONICET and Universidad Nacional de Córdoba, Córdoba, Argentina .
    Sawant, Rahul S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    de Cuneo, Marta Fiol
    Instituto de Fisiología, Instituto de Investigaciones en Ciencias de la Salud (INICSA, UNC-CONICET), Facultad de Ciencias Médicas, CONICET and Universidad Nacional de Córdoba, Córdoba, Argentina .
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Farmakologi 3.
    Perez, Mariela F
    Departamento de Farmacología, Instituto de Farmacología Experimental de Córdoba (IFEC-CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina .
    Carlini, Valeria Paola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Instituto de Fisiología, Instituto de Investigaciones en Ciencias de la Salud (INICSA, UNC-CONICET), Facultad de Ciencias Médicas, CONICET and Universidad Nacional de Córdoba, Córdoba, Argentina .
    Reduced vasopressin receptors activation mediates the anti-depressant effects of fluoxetine and venlafaxine in bulbectomy model of depression2016In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, no 6, p. 1077-1086Article in journal (Refereed)
    Abstract [en]

    RATIONALE: In response to stress, corticotropin releasing hormone (CRH) and vasopressin (AVP) are released from the hypothalamus, activate their receptors (CRHR1, CRHR2 or AVPr1b), and synergistically act to induce adrenocorticotropic hormone (ACTH) release from the anterior pituitary. Overstimulation of this system has been frequently associated with major depression states.

    OBJECTIVE: The objective of the study is to assess the role of AVP and CRH receptors in fluoxetine and venlafaxine effects on the expression of depression-related behavior.

    METHODS: In an animal model of depression (olfactory bulbectomy in mice, OB), we evaluated the effects of fluoxetine or venlafaxine (both 10 mg/kg/day) chronic administration on depression-related behavior in the tail suspension test. Plasma levels of AVP, CRH, and ACTH were determined as well as participation of their receptors in the expression of depression related-behavior and gene expression of AVP and CRH receptors (AVPr1b, CRHR1, and CRHR2) in the pituitary gland.

    RESULTS: The expression of depressive-like behavior in OB animals was reversed by treatment with both antidepressants. Surprisingly, OB-saline mice exhibited increased AVP and ACTH plasma levels, with no alterations in CRH levels when compared to sham mice. Chronic fluoxetine or venlafaxine reversed these effects. In addition, a significant increase only in AVPr1b gene expression was found in OB-saline.

    CONCLUSION: The antidepressant therapy used seems to be more likely related to a reduced activation of AVP rather than CRH receptors, since a positive correlation between AVP levels and depressive-like behavior was observed in OB animals. Furthermore, a full restoration of depressive behavior was observed in OB-fluoxetine- or venlafaxine-treated mice only when AVP was centrally administered but not CRH.

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