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The Relation between Serotonergic Biomarkers and Behaviour: – studies on human primates, non-human primates and transgenic mice
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Rationale: The serotonergic system is involved in the modulation of emotion and plays an important role for personality and vulnerability for psychiatric disorders. In the papers included in this thesis, we investigate three biological factors that have been studied in relation to psychiatric symptoms: Platelet monoamine oxidase B (MAO-B) activity, and variations in the MAO-A and the serotonin transporter (5HTT) genes. We also study intensity dependent auditory evoked potentials (IAEP) as an intermediate phenotype for serotonergic capacity. Platelet MAO-B has been shown to be a biological marker for the properties of monoamine systems, with low activity being associated with vulnerability for high scores of sensation seeking, monotony avoidance, and impulsiveness, as well as for susceptibility for alcoholism. Functional polymorphisms in the promoter of the genes encoding MAO-A and the serotonin transporter result in high- or low- activity alleles that have been associated with numerous psychiatric symptoms. One hypothesis for the shaping of personality is that these genotype variants have prenatal effects on the wiring of the brain. Thus, exploring how the development of the brain is affected by different prenatal serotonin levels is relevant in this context.

Observations: (i) Platelet MAOB activity was associated with monoamine metabolites in cerebrospinal fluid from cisterna magna in monkeys, as well as with voluntary alcohol intake, alcohol-induced aggression, and alcohol sensitivity. (ii) The long 5HTTLPR allele was associated with increased IAEP. (iii) The functional MAOA and 5HTT polymorphisms were associated with symptoms of ADHD-related traits in a population based sample of Swedish adolescents. Associations of these candidate genes with ADHD scores were strenghtened when the platelet MAOB activity was combined with genotype. (iv) Our pilot data showed that treatment of pregnant mice with 5HTT blocking antidepressives resulted in more serotonergic cellbodies in lateral wings of dorsal raphe in the offspring, when compared to saline treatment.

Conclusions: Our studies support the notion that platelet MAOB activity and IAEP are endophenotypes for monoaminergic capacity and related behaviours. The functional candidate polymorphisms in MAOA and 5HTT were linked to behaviour, however, the cause-relationship is unclear and the explanation for the associations need to be further investigated, possibly with focus on prenatal effects of the polymorphisms.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2011. , 57 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 676
Keyword [en]
Serotonin, MAO-A, 5-HTT, MAO-B, alcohol, ADHD
National Category
Medical and Health Sciences
Research subject
Medicine; Neuroscience
Identifiers
URN: urn:nbn:se:uu:diva-151870ISBN: 978-91-554-8091-2OAI: oai:DiVA.org:uu-151870DiVA: diva2:412282
Public defence
2011-06-11, Auditorium Minus, Gustavianum, Akademigatan 3, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2011-05-20 Created: 2011-04-18 Last updated: 2011-07-01Bibliographically approved
List of papers
1. Platelet monoamine oxidase activity predicts alcohol sensitivity and voluntary alcohol intake in rhesus monkeys.
Open this publication in new window or tab >>Platelet monoamine oxidase activity predicts alcohol sensitivity and voluntary alcohol intake in rhesus monkeys.
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2010 (English)In: Uppsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 115, no 1, 49-55 p.Article in journal (Refereed) Published
Abstract [en]

Platelet monoamine oxidase B (MAO-B) has been proposed to be a biological marker for the properties of monoamine systems, with low activity being associated with vulnerability for high scores on personality traits such as sensation seeking, monotony avoidance, and impulsiveness, as well as for vulnerability for alcoholism. In the present study, platelet MAO-B activity was analysed in 78 rhesus macaques, and its relation to voluntary alcohol intake and behaviours after intravenous alcohol administration was observed. Monkeys with low platelet MAO-B activity had low levels of 5-hydroxyindole acetic acid in cerebrospinal fluid and showed excessive aggression after alcohol administration. A novel finding was that animals with low platelet MAO-B activity showed less intoxication following alcohol administration. As we have shown previously, they also voluntarily consumed more alcohol. We here replicate results from studies on both humans and non-human primates, showing the utility of platelet MAO as a marker for risk behaviours and alcohol abuse. Furthermore, we link platelet MAO activity to alcohol sensitivity.

Keyword
Aggressiveness, alchol sensitivity, MAO-B, platelet, rhesus macaque
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-136945 (URN)10.3109/03009731003605813 (DOI)000275061700007 ()20187848 (PubMedID)
Available from: 2010-12-15 Created: 2010-12-14 Last updated: 2011-05-30Bibliographically approved
2. Further evidence for an association of 5-HTTLPR with intensity dependence of auditory-evoked potentials
Open this publication in new window or tab >>Further evidence for an association of 5-HTTLPR with intensity dependence of auditory-evoked potentials
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2006 (English)In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1470-634X, Vol. 31, no 9, 2047-2054 p.Article in journal (Refereed) Published
Abstract [en]

Intensity dependence of auditory-evoked potentials (IAEP) has been suggested as an indicator of central serotonergic neurotransmission. Two recent studies investigated a possible association of IAEP with a functional polymorphism in the transcriptional control region of the serotonin transporter gene (5-HTTLPR) that has a short (s) and a long (l) variant. Although both studies found an association between 5-HTTLPR and IAEP, Gallinat et al found l/l individuals to exhibit lower IAEP, whereas Strobel et al observed stronger IAEP in l/l individuals. These conflicting results require further evaluation and more attention needs to be paid to variables that are known to be confounded with the effects of IAEP and 5-HTTLPR. Using a paradigm comparable to Strobel et al, the present study analyzes the effect of 5-HTTLPR on IAEP in a healthy male student sample (N=91; age=23 years, SD=1.9) that was homogenous for most significant confounding variables. A stronger IAEP was shown in l/l individuals, irrespective of the method of IAEP parametrization. This also held at retest after 3 weeks in a subsample (N=18). Given the successful replication of Strobel et al, several possible reasons for conflicting results with regard to Gallinat et al are discussed. It is argued that the most significant difference between Gallinat et al on the one hand, and Strobel et al and this study on the other, is that different intensity ranges are used which impact IAEP. Therefore, this study encourages further analysis of dose dependence of results.

Keyword
serotonin transporter, genetic polymorphism, 5-HTTLPR, endophenotype, auditory-evoked potentials, intensity dependence
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-102700 (URN)10.1038/sj.npp.1301020 (DOI)000239920400021 ()16421513 (PubMedID)
Available from: 2009-05-11 Created: 2009-05-11 Last updated: 2011-05-27Bibliographically approved
3. ADHD and Disruptive Behavior scores - associations with MAO-A and 5-HTT genes and with platelet MAO-B activity in adolescents
Open this publication in new window or tab >>ADHD and Disruptive Behavior scores - associations with MAO-A and 5-HTT genes and with platelet MAO-B activity in adolescents
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2008 (English)In: BMC Psychiatry, ISSN 1471-244X, Vol. 8, 28- p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Pharmacological and genetic studies suggest the importance of the dopaminergic, serotonergic, and noradrenergic systems in the pathogenesis of Attention Deficit Hyperactivity Disorder (ADHD) and Disruptive Behavior Disorder (DBD). We have, in a population-based sample, studied associations between dimensions of the ADHD/DBD phenotype and Monoamine Oxidase B (MAO-B) activity in platelets and polymorphisms in two serotonergic genes: the Monoamine Oxidase A Variable Number of Tandem Repeats (MAO-A VNTR) and the 5-Hydroxytryptamine Transporter gene-Linked Polymorphic Region (5-HTT LPR). METHODS: A population-based sample of twins, with an average age of 16 years, was assessed for ADHD/DBD with a clinical interview; Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL). Blood was drawn from 247 subjects and analyzed for platelet MAO-B activity and polymorphisms in the MAO-A and 5-HTT genes. RESULTS: We found an association in girls between low platelet MAO-B activity and symptoms of Oppositional Defiant Disorder (ODD). In girls, there was also an association between the heterozygote long/short 5-HTT LPR genotype and symptoms of conduct disorder. Furthermore the heterozygote 5-HTT LPR genotype in boys was found to be associated with symptoms of Conduct Disorder (CD). In boys, hemizygosity for the short MAO-A VNTR allele was associated with disruptive behavior. CONCLUSION: Our study suggests that the serotonin system, in addition to the dopamine system, should be further investigated when studying genetic influences on the development of Disruptive Behavior Disorders.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-102686 (URN)10.1186/1471-244X-8-28 (DOI)000256218600001 ()18430257 (PubMedID)
Available from: 2009-05-11 Created: 2009-05-11 Last updated: 2011-05-27Bibliographically approved
4. Associations of MAOA-VNTR or 5HTT-LPR alleles with attention-deficit hyperactivity disorder symptoms are moderated by platelet monoamine oxidase B activity
Open this publication in new window or tab >>Associations of MAOA-VNTR or 5HTT-LPR alleles with attention-deficit hyperactivity disorder symptoms are moderated by platelet monoamine oxidase B activity
2012 (English)In: Psychiatric Genetics, ISSN 0955-8829, E-ISSN 1473-5873, Vol. 22, no 1, 42-45 p.Article in journal (Refereed) Published
Abstract [en]

The monoamine systems have been suggested to play a role in the biological basis of ADHD symptoms. Thus, polymorphisms in e.g. the monoamine oxidase A (MAOA) and the serotonin transporter (5HTT) genes have been associated with ADHD like phenotypes. Furthermore, platelet MAOB activity has frequently been linked to impulsiveness-related traits. In the present paper, we have studied ADHD symptoms with regard to the combination of platelet MAOB activity and MAOAVNTR or 5HTT-LPR genotype.

The study group consisted of 156 adolescent twin pairs, i.e. 312 individuals, who were used in a previous study (Malmberg et al., 2008). ADHD symptoms were scored with a structured clinical interview of both the twin and a parent using Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version. Presence of a short 5HTT-LPR or short MAOA-VNTR allele, in combination with high levels of platelet MAOB enzyme activity was associated with higher scores of ADHD like problems (p<0.001; p<0.01, respectively).

This reexamination of ADHD scores in a non-clinical sample suggests that effects of the MAOA-VNTR and 5HTT-LPR are moderated by platelet MAOB activity.

 

Keyword
ADHD, ODD, conduct disorder, candidate genes, MAO-A, 5HTT, platelet MAO-B
National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-151865 (URN)10.1097/YPG.0b013e328347c1ab (DOI)000298376800005 ()21610556 (PubMedID)
Available from: 2011-04-19 Created: 2011-04-18 Last updated: 2012-01-31Bibliographically approved
5. Effects of prenatal fluoxetine on serotonergic cell number in the dorsal raphe lateral wing
Open this publication in new window or tab >>Effects of prenatal fluoxetine on serotonergic cell number in the dorsal raphe lateral wing
(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:uu:diva-151856 (URN)
Available from: 2011-04-19 Created: 2011-04-18 Last updated: 2016-05-11

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