Molecular imaging of the serotonin system in human behaviour

Abstract: The serotonin (5-HT) neurotransmission system has a role in essential physiological and psychological functions such as sleep, eating behaviour, sexuality, perception, emotion and cognition. Individual measures of serotonin biomarkers in the living human brain can be obtained using positron emission tomography (PET) imaging, direct measures of. The interindividual variability in these measures can then be related to human behavioural output. In combination with genotyping, this strategy provides an approach to complex chain of events linking the genetic endowment to higher brain functions. The present thesis includes a series of PET studies aimed to increase understanding of the role of serotonin in higher brain functions in man. In study I, fifteen control subjects were examined with PET and [11C]WAY100635, a radioligand that is selective for the serotonin 5-HT1A receptor. Personality traits were assessed with the Temperament and Character Inventory (TCI) self-report questionnaire. Availability of 5-HT1A receptor was found to correlate inversely with scores for self-transcendence, a personality trait covering religious behaviour and attitudes. This finding indicates that the serotonin system may serve as a biological underpinning for spiritual experiences. Interestingly, the observed several-fold variability in 5-HT1A receptor density may partly explain why people vary greatly in spiritual zeal. In study II, twenty-four control subjects were examined with [11C]WAY100635 PET and a battery of tests covering all major cognitive domains. There were no significant correlations between regional 5-HT1A binding and cognitive performance. The results do not provide support for involvement of the 5-HT1A receptor in cognitive functioning in man, thereby questioning the predictive validity of some currently used animal models in translational neuroscience. In study III, seventeen volunteers were examined with [11C]MADAM PET and a battery of cognitive tests. Serotonin transporter (5-HTT) availability in cortical regions correlated significantly with performance in sustained attention. The results support a role for the serotonin system in some but not all cognitive functions in man. In study IV, fifty-four control subjects were examined with [11C]WAY100635 PET and a battery of cognitive tests. Subjects were genotyped for the 5-HTT linked polymorphic region (5-HTTLPR), a functional polymorphism in the promoter region of the 5-HTT gene. The short (S) allele of the 5-HTTLPR has been associated with depression as well as anxiety-related personality traits. Carriers of the S allele of the 5-HTTLPR did not differ from non-carriers with respect to [11C]WAY100635 binding potential in any of the brain regions studied. S-carriers however performed significantly better in the Wisconsin Card Sorting Test. These observations suggest that functional implications of the 5-HTTLPR are not likely to be mediated by differences in 5-HT1A density and that other biomarkers must be considered for future investigations at phenotype level. The present studies of serotonergic biomarkers in man provide new evidence for a role of the serotonin system in complex human behaviour such as cognitive functions and personality traits.