Research articleEffects of sex, age, and aggressive traits in man on brain serotonin 5-HT1A receptor binding potential measured by PET using [C-11]WAY-100635
Introduction
Serotonin (5-HT) neurons, arise from the dorsal and median raphe nuclei and innervate virtually all regions of the brain [45]. 5-HT1A 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-HT1A antagonist with high affinity and selectivity for 5-HT1A receptors (KD=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-HT1A binding in females compared to males [4]. Additionally, there are several reports of a relationship between aggression and 5-HT1A receptors [12], [13], [14]. We have previously demonstrated that compartmental modeling is the best method for quantification of 5-HT1A 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-HT1A receptors could be reproduced in vivo, (c) the severity of life-time aggression was correlated with brain 5-HT1A binding. The results would have implications for the design and interpretation of results of studies in clinical populations.
Section snippets
Subjects
Twelve healthy females and 13 healthy males who did not meet criteria for any Axis I diagnosis based on the Structured Clinical Interview for DSM IV (SCID I) [44], including substance abuse or dependence, and were medically well based on history, review of systems, physical examination, routine blood tests, pregnancy test, and urine toxicology, were studied after giving written informed consent. All subjects were off all medications (prescription, over the counter, or herbal) for at least 2
Results
Males and females did not differ in age, the injected dose, injected mass, or clearance of the [C-11]WAY-100635 compound (Table 1). The amount of [C-11]WAY-100635 available to bind to 5-HT1A receptors is dependent on the free fraction of [11C]WAY-100635 (the percentage of [C-11]WAY-100635 not bound to plasma proteins). There was no statistically significant difference in the free fraction between females (9.2±2.7%) and males (9.7±2.0%). There was also no age effect on the free fraction in the
Discussion
We have previously reported [42] that compartmental modeling of [C-11]WAY-100635 in healthy volunteers is preferable for quantifying 5-HT1A binding in vivo. Females have higher 5-HT1A binding potential in all brain regions, and a higher cerebellar VT. There is no age effect on binding potential in either males or females or the group as a whole. There is a significant inverse correlation between binding potential in several brain regions and severity of lifetime aggression as measured by the
Acknowledgements
This work was supported by US PHS grants NIMH P30 MH46745, MH40695 and NIMH K02-MH01603 and NARSAD. The authors would like to thank the staff of the Kreitchman PET Center and Department of Neuroscience Brain Imaging Division, Julie Arcement, Cristina Battistuzzi, and Thomas Cooper.
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