Overexpression of 5-HT2C receptors in forebrain leads to elevated anxiety and hypoactivity

The 5-HT2C receptor has been implicated in mood and eating disorders. In general, it is accepted that 5-HT2C receptor agonists increase anxiety behaviours and induce hypophagia. However, pharmacological analysis of the roles of these receptors is hampered by the lack of selective ligands and the complex regulation of receptor isoforms and expression levels. Therefore, the exact role of 5-HT2C receptors in mood disorders remain controversial, some suggesting agonists and others suggesting antagonists may be efficacious antidepressants, while there is general agreement that antagonists are beneficial anxiolytics. In order to test the hypothesis that increased 5-HT2C receptor expression, and thus increased 5-HT2C receptor signalling, is causative in mood disorders, we have undertaken a transgenic approach, directly altering the 5-HT2C receptor number in the forebrain and evaluating the consequences on behaviour. Transgenic mice overexpressing 5-HT2C receptors under the control of the CaMKII alpha promoter (C2CR mice) have elevated 5-HT2C receptor mRNA levels in cerebral cortex and limbic areas (including the hippocampus and amygdala), but normal levels in the hypothalamus, resulting in > 100% increase in the number of 5-HT2C ligand binding sites in the forebrain. The C2CR mice show increased anxiety-like behaviour in the elevated plus-maze, decreased wheel-running behaviour and reduced activity in a novel environment. These behaviours were observed in the C2CR mice without stimulation by exogenous ligands. Our findings support a role for 5-HT2C receptor signalling in anxiety disorders. The C2CR mouse model offers a novel and effective approach for studying disorders associated with 5-HT2C receptors.