Effects of sex, age, and aggressive traits in man on brain serotonin 5-HT_1A receptor binding potential measured by PET using [C-11]WAY-100635

Abstract

Serotonin (5-HT) 1A receptors have been implicated in a variety of conditions including, depression, suicidal behavior, and aggression. Post-mortem brain studies and in vivo imaging studies report a variety of age and sex effects on brain 5-HT_1A binding. Behavioral data from 5-HT_1A specific pharmacological challenges suggest a role for 5-HT_1A receptors in aggression. The goal of the present study was to determine age, sex, and severity of life-time aggression effects on 5-HT_1A binding potential (BP) in vivo using positron emission tomography (PET) and the high affinity 5-HT_1A antagonist, [carbonyl-C-11]WAY-100635 in 12 healthy females (ages 41.0±15.7 years) and 13 healthy males (ages 39.6±15.5 years). Regions of interest included the dorsal raphe, anterior cingulate cortex, cingulate body, hippocampus, amygdala, medial prefrontal cortex (PFC), and orbital PFC. No significant correlation between age and BP was detected in any brain region. MANOVA of the first three principle components demonstrated a significantly higher BP in females compared with males (P=0.0127). Post-hoc tests confirmed sex differences (P<0.05) in the following regions: dorsal raphe, amygdala, anterior cingulate, cingulate body, medial PFC, and orbital PFC. The cerebellar volume of distribution was also significantly higher in females. There is a significant negative correlation between binding in several regions and lifetime aggression. We have replicated our post-mortem finding of higher 5-HT_1A binding in females compared to males. We did not detect an age dependent decrease in binding in males or females. Lower 5-HT_1A binding in more aggressive individuals is consistent with pharmacological challenge studies. Future studies should determine whether the binding is a state or trait effect.

Introduction

Serotonin (5-HT) neurons, arise from the dorsal and median raphe nuclei and innervate virtually all regions of the brain [45]. 5-HT_1A receptors are somatodendritic autoreceptors in the raphe nuclei and post-synaptic receptors in the neocortex, hippocampus, and other limbic structures [7], [50]. WAY-100635, N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl) cyclohexane carboxamide, is a 5-HT_1A antagonist with high affinity and selectivity for 5-HT_1A receptors (K_D=0.1–0.4 nM) [21], [23]. Previous in vivo imaging studies using the [C-11]WAY-100635 compound have shown an age dependent decrease in the specific to non-specific equilibrium partition coefficient (V₃″) in males only [10], and in a mixed population of both males and females [47]. A larger study in males only did not replicate the age related decline using the same outcome measure [43]. Post mortem studies by our group have demonstrated greater 5-HT_1A binding in females compared to males [4]. Additionally, there are several reports of a relationship between aggression and 5-HT_1A receptors [12], [13], [14]. We have previously demonstrated that compartmental modeling is the best method for quantification of 5-HT_1A binding [42]. In this study we wanted to determine whether: (a) decreases in V₃″ with age could be replicated or if these findings reflected limitations of the method used to model the binding data, (b) post mortem sex differences in 5-HT_1A receptors could be reproduced in vivo, (c) the severity of life-time aggression was correlated with brain 5-HT_1A binding. The results would have implications for the design and interpretation of results of studies in clinical populations.