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  • 51. Pålsson, Erik
    et al.
    Söderlund, Göran
    Stockholm University, Faculty of Humanities, Department of Linguistics.
    Klamer, Daniel
    Bergquist, Filip
    Noise benefit in prepulse inhibition of the acoustic startle reflex2011In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 214, no 3, p. 675-685Article in journal (Refereed)
    Abstract [en]

    Under some conditions, external sensory noise enhances cognitive functions, a phenomenon possibly involving stochastic resonance and/or enhanced central dopamine transmission. Prepulse inhibition (PPI) of the startle reflex is a robust measure of sensorimotor gating and can be modulated by activity in the cortex and basal ganglia, including the central dopamine pathways. Previous empirical studies suggest a differential effect of acoustic noise in normal children and children with attention-deficit hyperactivity disorder (ADHD). This study investigated the effect of acoustic noise on PPI and if dopamine transmission interacts with acoustic noise effects in a rat ADHD model. The effect of background acoustic noise on acoustic startle response and PPI were measured with a constant prepulse to background noise ratio of 9 dB(A). Spontaneously hypertensive (SH) rats were used as the ADHD model and compared with Wistar and Sprague-Dawley rats. Microdialysis, methylphenidate treatment and 6-OHDA lesions were used to investigate interaction with dopamine transmission. Background noise facilitated PPI differently in SH rats and controls. The prefrontal cortex in SH rats had low basal dopamine concentrations, a high DOPAC/dopamine ratio and blunted dopamine release during PPI testing. Methylphenidate had small, but strain-specific, effects on startle and PPI. Bilateral 6-hydroxydopamine lesions did not alter startle or PPI. Prefrontal dopamine transmission is altered in SH rats during the sensorimotor gating task of PPI of the acoustic startle, indicating increased dopamine reuptake in this ADHD rat model. We propose that noise benefit could be explored as a non-pharmacological alternative for treating neuropsychiatric disorders.

  • 52.
    Robinson, J. E.
    et al.
    University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
    Fish, E. W.
    University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
    Krouse, M. C.
    University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Heilig, Marcus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Malanga, C. J.
    University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
    Potentiation of brain stimulation reward by morphine: effects of neurokinin-1 receptor antagonism2012In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 220, no 1, p. 215-224Article in journal (Refereed)
    Abstract [en]

    RATIONALE: The abuse potential of opioids may be due to their reinforcing and rewarding effects, which may be attenuated by neurokinin-1 receptor (NK1R) antagonists.

    OBJECTIVE: This study was conducted to measure the effects of opioid and NK1R blockade on the potentiation of brain stimulation reward (BSR) by morphine using the intracranial self-stimulation method.

    METHODS: Adult male C57BL/6J mice (n = 15) were implanted with unipolar stimulating electrodes in the lateral hypothalamus and trained to respond for varying frequencies of rewarding electrical stimulation. The BSR threshold (θ(0)) and maximum response rate (MAX) were determined before and after intraperitoneal administration of saline, morphine (1.0-17.0 mg/kg), or the NK1R antagonists L-733,060 (1.0-17.0 mg/kg) and L-703,606 (1.0-17.0 mg/kg). In morphine antagonism experiments, naltrexone (0.1-1.0 mg/kg) or 10.0 mg/kg L-733,060 or L-703,606 was administered 15 min before morphine (1.0-10.0 mg/kg) or saline.

    RESULTS: Morphine dose-dependently decreased θ(0) (maximum effect = 62% of baseline) and altered MAX when compared to saline. L-703,606 and L-733,060 altered θ(0); 10.0 mg/kg L-733,060 and L-703,606, which did not affect θ(0) or MAX, attenuated the effects of 3.0 and 10.0 mg/kg morphine, and 1.0 and 0.3 mg/kg naltrexone blocked the effects of 10.0 mg/kg morphine. Naltrexone given before saline did not affect θ(0) or MAX.

    CONCLUSIONS: The decrease in θ(0) by morphine reflects its rewarding effects, which were attenuated by NK1R and opioid receptor blockade. These results demonstrate the importance of substance P signaling during limbic reward system activation by opioids.

  • 53. Rowland, N E
    et al.
    Marshall, Misty
    Roth, J D
    Comparison of either norepinephrine-uptake inhibitors or phentermine combined with serotonergic agents on food intake in rats2000In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 149, no 1Article in journal (Refereed)
    Abstract [en]

    RATIONALE: We have shown previously that the anorectic effects of the catecholamine-releasing agent phentermine (PHEN) and the serotonin (5-HT)-releasing agent dexfenfluramine (DFEN) are greater than additive in rats. In the present study, we examined whether the norepinephrine-uptake inhibitors desmethylimipramine (DMI) and thionisoxetine (TNIX) have additive effects with either DFEN or with the 5-HT-uptake inhibitor fluoxetine (FLX). We also examined whether PHEN interacts with a postsynaptically acting 5-HT agonist.

    METHODS: Undeprived rats were trained to eat a daily sweet-milk dessert and on test days were systemically administered single or combination drugs and the intakes recorded.

    RESULTS: Both DMI and TNIX produced dose-related suppressions of food intake. However, by isobolographic analysis, they did not enhance the anorectic actions of either DFEN or FLX. In contrast, confirming and extending our previous work, PHEN had a greater potentiating effect on the anorectic actions of DFEN and FLX than TNIX. Further, the anorectic action of the 5-HT2c receptor agonist TFMPP was enhanced by PHEN.

    CONCLUSIONS: These and other data are consistent with the idea that 5-HT agents may work "upstream" of critical catecholaminergic synapses in the production of anorexia, and explain the diminished efficacy of norepinephrine-uptake inhibitors relative to PHEN. The implications for clinically useful anorectic agents are discussed briefly.

  • 54.
    Schank, Jesse R.
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Pickens, Charles L.
    National Institute on Drug Abuse, NIH, Bethesda, MD, USA.
    Rowe, Kelly E.
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Cheng, Kejun
    National Institute on Drug Abuse, NIH, Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Rice, Kenner C.
    National Institute on Drug Abuse, NIH, Bethesda, MD, USA.
    Shaham, Yavin
    National Institute on Drug Abuse, NIH, Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Stress-induced reinstatement of alcohol-seeking in rats is selectively suppressed by the neurokinin 1 (NK1) antagonist L8224292011In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 218, no 1, p. 111-119Article in journal (Refereed)
    Abstract [en]

    RATIONALE: Genetic inactivation or pharmacological antagonism of neurokinin 1 (NK1) receptors blocks morphine and alcohol reward in rodents, while NK1 antagonism decreases alcohol craving in humans. The role of the NK1 system for relapse-like behavior has not previously been examined.

    OBJECTIVE: Divergence between human and rodent NK1 receptors has limited the utility of NK1 antagonists developed for the human receptor species for preclinical studies of addiction-related behaviors in rats. Here we used L822429, an NK1 antagonist specifically engineered to bind at high affinity to the rat receptor, to assess the effects of NK1 receptor antagonism on alcohol-seeking behaviors in rats.

    METHODS: L822429 (15 and 30 mg/kg) was used to examine effects of NK1 receptor antagonism on operant self-administration of 10% alcohol in 30-min daily sessions, as well as intermittent footshock stress- and cue-induced reinstatement of alcohol-seeking after extinction of lever responding.

    RESULTS: At the doses used, L822429 did not significantly affect alcohol self-administration or cue-induced reinstatement, but potently and dose dependently suppressed stress-induced reinstatement of alcohol seeking, with an essentially complete suppression at the highest dose. The effect of L822429 on stress-induced reinstatement was behaviorally specific. The drug had no effect on conditioned suppression of operant responding following fear conditioning, locomotor activity, or self-administration of a sucrose solution.

    CONCLUSIONS: To the degree that the reinstatement model provides a model of drug relapse, the results provide support for NK1 antagonism as a promising mechanism for pharmacotherapy of alcoholism, acting through suppression of stress-induced craving and relapse.

  • 55.
    Schroeder, Jennifer R.
    et al.
    Johns Hopkins Bayview Med Ctr, MD 21224 USA.
    Phillips, Karran A.
    NIDA, MD 21224 USA.
    Epstein, David H.
    NIDA, MD 21224 USA.
    Jobes, Michelle L.
    NIDA, MD 21224 USA.
    Furnari, Melody A.
    NIDA, MD 21224 USA.
    Kennedy, Ashley P.
    NIDA, MD 21224 USA.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Preston, Kenzie L.
    NIDA, MD 21224 USA.
    Assessment of pioglitazone and proinflammatory cytokines during buprenorphine taper in patients with opioid use disorder2018In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 235, no 10, p. 2957-2966Article in journal (Refereed)
    Abstract [en]

    Background Preliminary evidence suggested that the PPAR gamma agonist pioglitazone reduces opioid-withdrawal symptoms, possibly by inhibiting increases in proinflammatory cytokines. Methods A randomized, placebo-controlled clinical trial was conducted utilizing two different study designs (entirely outpatient, and a combination of inpatient and outpatient) to evaluate the safety and efficacy of pioglitazone as an adjunct medication for people with opioid physical dependence undergoing a buprenorphine taper. Participants were stabilized on buprenorphine/naloxone (sublingual, up to 16/4 mg/day), then randomized to receive oral pioglitazone (up to 45 mg/day) or placebo before, during, and after buprenorphine taper. Outcome measures included the Subjective Opiate Withdrawal Scale (SOWS) and Clinical Opiate Withdrawal Scale, use of rescue medications to alleviate opioid withdrawal symptoms, and opioid-positive urine specimens. Cerebrospinal fluid (CSF) and plasma were collected during the taper in a subset of participants for measurement of proinflammatory cytokines. Results The clinical trial was prematurely terminated due to slow enrollment; 40 participants per group were required for adequate statistical power to test study hypotheses. Twenty-four participants enrolled; 17 received at least one dose of study medication (6 pioglitazone, 11 placebo). SOWS scores were higher in the pioglitazone arm than in the placebo arm after adjusting for use of rescue medications; participants in the pioglitazone arm needed more rescue medications than the placebo arm during the post-taper phase. SOWS scores were positively correlated with monocyte chemoattractant protein-1 (MCP-1) in CSF (r = 0.70, p = 0.038) and plasma (r = 0.77, p = 0.015). Participants having higher levels of plasma MCP-1 reported higher SOWS, most notably after the buprenorphine taper ended. Conclusions Results from this study provide no evidence that pioglitazone reduces opioid withdrawal symptoms during buprenorphine taper. High correlations between MCP-1 and opioid withdrawal symptoms support a role of proinflammatory processes in opioid withdrawal.

  • 56.
    Snyder, Gretchen L.
    et al.
    Intra-Cellular Therapies Inc, USA.
    Prickaerts, Jos
    Maastricht University, The Netherlands.
    Wadenberg, Marie-Louise
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Zhang, Lei
    Intra-Cellular Therapies Inc, USA.
    Zheng, Hailin
    Intra-Cellular Therapies Inc, USA.
    Yao, Wei
    Intra-Cellular Therapies Inc, USA.
    Akkerman, Sven
    Maastricht University, The Netherlands.
    Zhu, Hongwen
    Tianjin Hospital, China.
    Hendrick, Joseph P.
    Intra-Cellular Therapies Inc, USA.
    Vanover, Kimberly E.
    Intra-Cellular Therapies Inc, USA.
    Davis, Robert
    Intra-Cellular Therapies Inc, USA.
    Li, Peng
    Intra-Cellular Therapies Inc, USA.
    Mates, Sharon
    Intra-Cellular Therapies Inc, USA.
    Wennogle, Lawrence P.
    Intra-Cellular Therapies Inc, USA.
    Preclinical profile of ITI-214, an inhibitor of phosphodiesterase 1, for enhancement of memory performance in rats2016In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, no 17, p. 3113-3124Article in journal (Refereed)
    Abstract [en]

    Rationale: Therapeutic agents for memory enhancement in psychiatric disorders, such as schizophrenia, are urgently needed.

    Objective: The aim of this study is to characterize the preclinical profile of ITI-214, a potent inhibitor of phosphodiesterase 1 (PDE1).

    Methods: ITI-214 was assayed for inhibition of PDE1 versus other PDE enzyme families using recombinant human PDE enzymes and for off-target binding to 70 substrates (General SEP II diversity panel; Caliper Life Sciences). Effects of ITI-214 (0.1–10 mg/kg, po) on memory performance were assayed in rats using the novel object recognition (NOR) paradigm, with drug given at specified time points prior to or following exposure to objects in an open field. ITI-214 was evaluated for potential drug-drug interaction with risperidone in rats using conditioned avoidance response (CAR) and pharmacokinetic assessments.

    Results: ITI-214 inhibited PDE1A (Ki = 33 pmol) with >1000-fold selectivity for the nearest other PDE family (PDE4D) and displayed minimal off-target binding interactions in a 70-substrate selectivity profile. By using specific timing of oral ITI-214 administration, it was demonstrated in the NOR that ITI-214 is able to enhance acquisition, consolidation, and retrieval memory processes. All memory effects were in the absence of effects on exploratory behavior. ITI-214 did not disrupt the risperidone pharmacokinetic profile or effects in CAR.

    Conclusions: ITI-214 improved the memory processes of acquisition, consolidation, and retrieval across a broad dose range (0.1–10 mg/kg, po) without disrupting the antipsychotic-like activity of a clinical antipsychotic medication, specifically risperidone. Clinical development of ITI-214 is currently in progress.

  • 57.
    Thorsell, Annika
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Schank, Jesse R.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Singley, Erick
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Hunt, Stephen P
    University College London, UK.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Neurokinin-1 receptors (NK1Rs), alcohol consumption, and alcohol reward in mice2010In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 209, no 1, p. 103-111Article in journal (Refereed)
    Abstract [en]

    RATIONALE: Reduced voluntary alcohol consumption was recently found in neurokinin-1 receptor (NK1R)-deficient (KO) mice. It remains unknown whether this reflects developmental effects or direct regulation of alcohol consumption by NK1R:s, and whether the reduced consumption reflects motivational effects.

    OBJECTIVE: The objective of this study is to obtain an expanded preclinical validation of NK1R antagonism as a candidate therapeutic mechanism in alcohol use disorders.

    METHODS: The NK1R antagonist L-703,606 and NK1R KO mice were used in models that assess alcohol-related behaviors.

    RESULTS: L-703,606 (3-10 mg/kg i.p.) dose-dependently suppressed alcohol intake in WT C57BL/6 mice under two-bottle free choice conditions but was ineffective in NK1R KO:s, demonstrating the receptor specificity of the effect. Alcohol reward, measured as conditioned place preference for alcohol, was reduced by NK1R receptor deletion in a gene dose-dependent manner. In a model where escalation of intake is induced by repeated cycles of deprivation and access, escalation was seen in WT mice, but not in KO mice. Among behavioral phenotypes previously reported for NK1R mice on a mixed background, an analgesic-like phenotype was maintained on the C57BL/6 background used here, while KO:s and WT:s did not differ in anxiety- and depression-related behaviors.

    CONCLUSIONS: Acute blockade of NK1R:s mimics the effects of NKR1 gene deletion on alcohol consumption, supporting a direct rather than developmental role of the receptor in regulation of alcohol intake. Inactivation of NK1R:s critically modulates alcohol reward and escalation, two key characteristics of addiction. These data provide critical support for NK1R antagonism as a candidate mechanism for treatment of alcoholism.

  • 58. Tiihonen Möller, Anna
    et al.
    Bäckström, Torbjörn
    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.
    Sondergaard, Hans Peter
    Helström, Lotti
    Women with PTSD have a changed sensitivity to GABA-A receptor active substances2016In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, no 11, p. 2025-2033Article in journal (Refereed)
    Abstract [en]

    The use of benzodiazepines in treating anxiety symptoms in patients with posttraumatic stress disorder (PTSD) has been debated. Studies on other anxiety disorders have indicated changed sensitivity to GABA-A receptor active substances. In the present study, we investigated the GABA receptor sensitivity in PTSD patients. Injections of allopreganolone, diazepam, and flumazenil were carried out, each on separate occasions, in 10 drug na < ve patients with PTSD compared to 10 healthy controls. Effects were measured in saccadic eye velocity (SEV) and in subjective ratings of sedation. The PTSD patients were less sensitive to allopregnanolone compared with healthy controls. This was seen as a significant difference in SEV between the groups (p = 0.047). Further, the patients were less sensitive to diazepam, with a significant less increase in sedation compared to controls (p = 0.027). After flumazenil injection, both patients and controls had a significant agonistic effect on SEV, leading to decreased SEV after injection. The patients also responded with an increase in sedation after flumazenil injection, while this was not seen in the controls. Patients with PTSD have a changed sensitivity to GABA-A receptor active substances. As a consequence of this, benzodiazepines and other GABA-A receptor active compounds such as sleeping pills will be less useful for this group of patients.

  • 59.
    Timby, Erika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Balgård, Matts
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Spigset, Olav
    Andersson, Agneta
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Porankiewicz-Asplund, Joanna
    Purdy, Robert H
    Zhu, Di
    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.
    Poromaa, Inger Sundström
    Pharmacokinetic and behavioral effects of allopregnanolone in healthy women2006In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 186, no 3, p. 414-424Article in journal (Refereed)
    Abstract [en]

    Rationale  The behavioral effects of allopregnanolone (3α-hydroxy-5α-pregnan-20-one) in women are not known. Objective  Allopregnanolone, a neuroactive steroid secreted by the mammalian ovary, exerts its anesthetic, anxiolytic, and sedative/hypnotic effects through potentiation of GABAA receptors. The purpose of this study was to evaluate the behavioral effects of allopregnanolone in healthy women. Methods  Ten healthy women were given three increasing intravenous doses of allopregnanolone in the follicular phase of the menstrual cycle. Saccadic eye movement parameters and visual analogue scales of sedation were used to evaluate the behavioral response of allopregnanolone. Repeated blood samples for analyses of allopregnanolone were drawn throughout the study day. Results  Exogenously administered allopregnanolone decreases saccadic eye movement parameters and increases subjective ratings of sedation that correlate with increased serum concentrations of this neuroactive steroid. Conclusion  The behavioral effects of allopregnanolone are similar to that of its 5β-stereoisomer, pregnanolone (3α-hydroxy-5β-pregnan-20-one). Apart from fatigue and mild nausea, allopregnanolone given in a cumulative dose of 0.09 mg/kg did not have any adverse effects.

  • 60.
    Timby, Erika
    et al.
    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.
    Nyberg, Sigrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Stenlund, Hans
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Wihlbäck, Anna-Carin N
    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.
    Women with premenstrual dysphoric disorder have altered sensitivity to allopregnanolone over the menstrual cycle compared to controls — a pilot study2016In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, no 11, p. 2109-2117Article in journal (Refereed)
    Abstract [en]

    In premenstrual dysphoric disorder (PMDD), a condition that afflicts 3-8 % of women in fertile ages, the cyclic recurrence of debilitating mood symptoms is restricted to the luteal phase of the menstrual cycle. The progesterone metabolite allopregnanolone is produced by the corpus luteum, and circulating levels are reflected in the brain. Allopregnanolone is a modulator of the GABA(A) receptor, enhancing the effect of gamma-aminobutyric acid (GABA). Previous studies have demonstrated different sensitivity to other GABA(A) receptor agonists, i.e., benzodiazepines, alcohol, and pregnanolone, in PMDD patients compared to controls.

    This study aimed to investigate the sensitivity to intravenous allopregnanolone over the menstrual cycle in PMDD patients.

    Allopregnanolone, 0.05 mg/kg, was administered intravenously once in the mid-follicular and once in the luteal phase of the menstrual cycle to 10 PMDD patients and 10 control subjects. The saccadic eye velocity (SEV) was recorded by electrooculography as a measurement of functional GABA(A) receptor activity, at baseline and repeatedly after the injection. A mixed model was used to analyze data.

    There was a highly significant group x phase interaction in the SEV response to allopregnanolone (F(1,327.489) = 12.747, p < 0.001). In the PMDD group, the SEV response was decreased in the follicular phase compared to the luteal phase (F(1,168) = 7.776, p = 0.006), whereas in the control group, the difference was opposite during the menstrual cycle (F(1,158.45) = 5.70, p = 0.018).

    The effect of exogenous allopregnanolone is associated with menstrual cycle phase in PMDD patients and in controls. The results suggest an altered sensitivity to allopregnanolone in PMDD patients.

  • 61.
    Wallin-Miller, Kathryn G.
    et al.
    Univ Southern Calif, Neurosci Grad Program, Los Angeles, CA 90033 USA.
    Kreutz, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Li, Grace
    Univ Southern Calif, Keck Sch Med, Dept Integrated Anat Sci, 1333 San Pablo St,BMT 401, Los Angeles, CA 90033 USA.
    Wood, Ruth I.
    Univ Southern Calif, Keck Sch Med, Dept Integrated Anat Sci, 1333 San Pablo St,BMT 401, Los Angeles, CA 90033 USA.
    Anabolic-androgenic steroids (AAS) increase sensitivity to uncertainty by inhibition of dopamine D1 and D2 receptors2018In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 235, no 4, p. 959-969Article in journal (Refereed)
    Abstract [en]

    Anabolic-androgenic steroid abuse is implicated in maladaptive behaviors such as impaired cognition in humans. In a rat model, our lab has shown that testosterone decreases preference for a large/uncertain reward in probability discounting. Other studies have shown that androgens decrease dopamine D1 and D2 receptors in the nucleus accumbens shell, a region important for decision-making behavior in probability discounting. Thus, we attempted to restore selection of the large/uncertain reward in testosterone-treated rats by administering the D2 receptor agonist quinpirole or the D1 receptor agonist SKF81297 and testing probability discounting. Adolescent male Long-Evans rats were treated chronically with high-dose testosterone (7.5 mg/kg) or vehicle (13% cyclodextrin in water), and tested for probability discounting after injections of saline, 0.1 and 0.5 mg/kg of quinpirole or SKF81297. Rats chose between a small/certain reward (1 sugar pellet, 100% probability) and a large/uncertain reward (4 pellets, decreasing probability: 100, 75, 50, 25, 0%). Testosterone-treated rats selected the large/uncertain reward significantly less than vehicle-treated controls after saline injection. However, acute injection with 0.1 mg/kg quinpirole increased large/uncertain reward preference in testosterone-treated rats only, indicated by a testosterone x quinpirole interaction. At 0.5 mg/kg, quinpirole increased large/uncertain reward preference in all rats. Acute injection with SKF81297 at 0.1 or 0.5 mg/kg rescued large/uncertain reward preference in testosterone-treated rats by eliminating the difference between groups. It appears that altered probability discounting behavior in testosterone-treated rats is due to both decreased D1 and D2 receptor function.

  • 62. Zheng, Ming
    et al.
    Appel, Lieuwe
    Luo, Feng
    Lane, Roger
    Risinger, Robert
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Cahir, Matthews
    Sanjay, Keswani
    Hayes, Wendy
    Burt, David
    Zubin, Bhagwaragar
    Safety, Pharmacokinetic, and Positron Emission Tomography Evaluation of Serotonin and Dopamine Transporter Occupancy Following Multiple-Dose Administration of the Triple Monoamine Reuptake Inhibitor BMS-8208362015In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 232, no 3, p. 529-540Article in journal (Refereed)
    Abstract [en]

    Rationale

    BMS-820836 is a novel antidepressant that selectively inhibits the reuptake of serotonin, norepinephrine, and dopamine.

    Objective

    This Phase I study assessed safety, tolerability, and pharmacokinetics of multiple daily doses of BMS-820836 in healthy subjects. Central serotonin transporter (SERT) and dopamine transporter (DAT) occupancy were assessed using positron emission tomography and [11C]MADAM or [11C]PE2I, respectively.

    Methods

    Fifty-seven healthy volunteers were enrolled in this double-blind, placebo-controlled, ascending multiple-dose study (ClincalTrials.gov identifier: NCT00892840). Eight participants in seven dose cohorts received oral doses of BMS-820836 (0.1–4 mg) or placebo for 14 days to assess safety, tolerability, and pharmacokinetics. Additionally, SERT and DAT occupancies were evaluated in 4–8 subjects per cohort at 8 h post-dose on Day 10 and 24 h post-dose on Day 15 at anticipated steady-state conditions.

    Results

    Most adverse events were mild to moderate; there were no serious safety concerns. Median maximum concentrations of BMS-820836 were observed at 4.0–5.5 h post-dose; estimated elimination half-life was 44–74 h. About 80 % striatal SERT occupancy was achieved after multiple doses of 0.5 mg BMS-820836 at both 8 and 24 h post-dose. Striatal DAT occupancy ranged between 14 % and 35 % at 8 h post-dose with a slight decline at 24 h post-dose.

    Conclusions

    Multiple daily doses of up to 4 mg BMS-820836 appeared to be generally safe and well tolerated in a healthy population. SERT and DAT occupancies were in a range associated with therapeutic efficacy of antidepressants. Together with the pharmacokinetic profile of BMS-820836, the occupancy data support once-daily administration.

  • 63.
    Zhukovsky, Peter
    et al.
    Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England.;Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England..
    Alsiö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England.;Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England..
    Jupp, Bianca
    Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England.;Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England.;Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Parkville, Vic, Australia..
    Xia, Jing
    Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England.;Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England..
    Giuliano, Chiara
    Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England.;Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England..
    Jenner, Lucy
    Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England.;Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England..
    Griffiths, Jessica
    Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England.;Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England..
    Riley, Errin
    Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England.;Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England..
    Ali, Sajeed
    Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England.;Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England..
    Roberts, Angela C.
    Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England.;Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England.;Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge, England..
    Robbins, Trevor W.
    Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England.;Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England..
    Dalley, Jeffrey W.
    Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England.;Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England.;Univ Cambridge, Dept Psychiat, Cambridge, England..
    Perseveration in a spatial-discrimination serial reversal learning task is differentially affected by MAO-A and MAO-B inhibition and associated with reduced anxiety and peripheral serotonin levels2017In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 234, no 9-10, p. 1557-1571Article in journal (Refereed)
    Abstract [en]

    Impairments in behavioral flexibility lie at the core of anxiety and obsessive-compulsive disorders. Few studies, however, have investigated the neural substrates of natural variation in behavioral flexibility and whether inflexible behavior is linked to anxiety and peripheral markers of stress and monoamine function. The objective of the study was to investigate peripheral and central markers associated with perseverative behavior on a spatial-discrimination serial reversal learning task. Rats were trained on a reversal learning task prior to blood sampling, anxiety assessment, and the behavioral evaluation of selective monoamine oxidase-A (MAO-A) and MAO-B inhibitors, which block the degradation of serotonin (5-HT), dopamine (DA), and noradrenaline (NA). Perseveration correlated positively with 5-HT levels in blood plasma and inversely with trait anxiety, as measured on the elevated plus maze. No significant relationships were found between perseveration and the stress hormone corticosterone or the 5-HT precursor tryptophan. Reversal learning was significantly improved by systemic administration of the MAO-A inhibitor moclobemide but not by the MAO-B inhibitor lazabemide. Moclobemide also increased latencies to initiate a new trial following an incorrect response suggesting a possible role in modulating behavioral inhibition to negative feedback. MAO-A but not MAO-B inhibition resulted in pronounced increases in 5-HT and NA content in the orbitofrontal cortex and dorsal raph, nuclei and increased 5-HT and DA content in the basolateral amygdala and dorsomedial striatum. These findings indicate that central and peripheral monoaminergic mechanisms underlie inter-individual variation in behavioral flexibility, which overlaps with trait anxiety and depends on functional MAO-A activity.

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