Original article Environment and the serotonergic system L. Oreland a , N. Nordquist a, *, J. Hallman a , J. Harro b , K.W. Nilsson c a Department of Neuroscience, Uppsala University, Uppsala, Sweden b Department of Psychology, Estonian Center of Behavioral and Health Sciences, University of Tartu, Tartu, Estonia c Center for Clinical Research Vasteras, Uppsala University, Uppsala, Sweden Based on findings by the groups of Marie A ˚ sberg, Lil Tra ¨ skman, John Mann and others it has been stated that one of the more consistent observations among suicide attempters is low cerebro- spinal fluid (CSF) levels of the serotonin (5-HT) metabolite 5- hydroxyindole acetic acid (5-HIAA), which is formed by the catalytic effect of Monoamine Oxidase A (MAOA), indicating reduced CNS serotonergic activity in these individuals [21]. Besides MAOA, also e.g. activities of the 5-HT reuptake pump (5-HTT) and the rate-limiting enzymes for 5-HT synthesis, tryptophan hydro- xylases (TPH1 and TPH2) have been shown to be of importance for CNS serotonergic activity. Interestingly, great sex differences have been observed with regard to serotonin and behaviour, both acutely and in a long-term perspective. Thus, acutely, it was reported that depletion of tryptophan, the serotonin precursor, in a healthy control sample, made females more cautious together with a lowered mood, while males became more impulsive with no change in mood [20]. With regard to long-term effects, it is reasonable to assume that they are mainly attributable to effects on development of the CNS serotonergic system. Thus, it has been shown that serotonin levels during foetal life and most likely also at early childhood acts as an inhibitor of the CNS 5-HT system, and perhaps also of other systems as well, in a self-regulatory feedback system [10]. Differences in size or capacity of serotonin pathways would then form the constitutional basis for differences in the individual’s interaction with environment for behaviour in a given situation. In the human foetal brain 5-HT neurons are evident at week 5, increases dramatically at week 10 and an anatomical raphe organization is ready at week 15 with cortical projections noticeable at about week 12. Serotonin levels are then increasing until about 5-years of age, where after there is a gradual reduction to about 50% of infant levels until adult age [22]. Functional genetic polymorphisms in the promoter of both the 5-HTT gene (5-HTTLPR) and in the MAOA gene (MAOAVNTR) have been shown to alter the in vitro expression of the respective proteins [16]. Both polymorphisms also exist as orthologous variants in rhesus macaques (RM). In the RM presence of the low expressing allele (5-HTTLPR-s) resulted in lower CSF levels of 5- HIAA in free-living, peer-reared animals, while there was no change in parent-reared animals [2]. A plausible explanation for this result would be that low synaptic reuptake, as a consequence of the low expressing 5-HTT allele, together with an increased serotonin release as a result of early stress, resulted in chronically elevated levels of 5-HT during early childhood. Through negative feedback on the developing serotonergic neuro-circuitry, this resulted in a low-capacity serotonin system with low CSF 5-HIAA as a measurable outcome. Also in this regard there seems to be a sex difference. Thus, female 5-HTTLPR-s infant RM were much more dependent on environment (peer-rearing) than males with regard to ACTH response to stress [1]. In humans, however, literature is conflicting on the matter of 5-HTT genotype interaction with environment for behaviour. One reason for this might be ethnic differences and another that environmental factors may have different meanings in different cultural settings. European Psychiatry 25 (2010) 304–306 ARTICLE INFO Article history: Received 18 December 2009 Accepted 18 December 2009 Keywords: Suicide Serotonin Environment Monoamine oxidase Personality Gene-environment interaction ABSTRACT In summary, genetics, as well as foetal and early life environmental factors shape the size or capacity of our monoamine systems, of which the serotonergic one might play a leading role. Those constitutional properties then form the biological basis for personality traits, such as impulsiveness and ‘‘sensation seeking’’, which interact with psychosocial settings and life events to form a pattern of reactivity to a current life event or psychosocial situation, shown as a high or low order of magnitude of gene- environment interaction. In the present paper emphasis is put on the role of genotypes of the serotonin transporter, of monoamine oxidases A and B, and of platelet monoamine oxidase B activity, which all have been shown to be of importance for behaviour and with obvious effects of interactions with environment. Under unfortunate circumstances constitutional properties might be strong enough to result in vulnerability for suicide, even with a modest influence of environment. ß 2010 Elsevier Masson SAS. All rights reserved. * Corresponding author. E-mail address: niklas.nordquist@neuro.uu.se (N. Nordquist). 0924-9338/$ – see front matter ß 2010 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.eurpsy.2009.12.017