Neuroimaging and 5-HT_2C Receptor Polymorphism: A HMPAO-SPECT Study in Healthy Male Probands Using mCPP-Challenge of the 5-HT_2C Receptor

Background: The human 5-HT_2C receptor gene has been localized on the X chromosome and is expressed in two genetic variants. Whereas previous investigations have suggested that the 5-HT_2C receptor gene polymorphism is critically involved in the pathogenesis of affective and eating disorders, as yet the functional consequences being associated with the rare serine variant of the 5-HT_2C receptor in humans are unclear. Methods: We explored by HMPAO-SPECT if a challenge with the serotonin agonist mCPP, that interacts mainly with the 5-HT_2C receptor, provokes different patterns of regional cerebral bloodflow (rCBF) as a function of the genetic variant of the receptor. Thus we studied its action in 16 healthy male volunteers carrying the common 5-HT_2C-cys-23 receptor gene and 16 healthy male volunteers carrying the less frequent 5-HT_2C-ser-23 receptor gene. Results: We found significant differences in rCBF between the two genotypes after mCPP infusion compared to placebo: In the cysteine group rCBF was increased in the left medial prefrontal cortex and decreased in the left anterior cingulate and right medio-temporal cortex, whereas the serine group showed an increase of rCBF in the left medio- and superior-temporal cortex and in cerebellum and a reduced rCBF in the right medial prefrontal cortex. In addition, there was a significant disordinal interaction of the genotype factors and challenge with an increase of rCBF in the serine group and a decrease in the cysteine group in the left motor cortex and calcarine cortex. Additionally, a decrease of rCBF in the serine-group and a simultaneous increase in the cysteine group was found in the right anterior and the left posterior cingulate cortex. Conclusion: These findings suggest that differences in the 5-HT_2C receptor gene polymorphism has functional consequences due to a different responsiveness of the expressed 5-HT_2C receptor variants.

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