In vivo evidence that 5-HT2C receptors inhibit 5-HT neuronal activity via a GABAergic mechanism

Background and purpose: Recent evidence suggests that 5-HT2C receptor activation may inhibit midbrain 5-HT neurones by activating neighbouring GABA neurones. This hypothesis was tested using the putative selective 5-HT2C receptor agonist, WAY 161503. Experimental approach: The effect of WAY 161503 on 5-HT cell firing in the dorsal raphe nucleus (DRN) was investigated in anaesthetised rats using single unit extracellular recordings. The effect of WAY 161503 on DRN GABA neurones was investigated using double label immunohistochemical measurements of Fos, glutamate decarboxylase (GAD) and 5-HT2C receptors. Finally, drug occupancy at 5-HT2A receptors was investigated using rat positron emission tomography and ex vivo binding studies with the 5-HT2A receptor radioligand [C-11]MDL 100907. Key results: WAY 161503 caused a dose-related inhibition of 5-HT cell firing which was reversed by the 5-HT2 receptor antagonist ritanserin and the 5-HT2C receptor antagonist SB 242084 but not by the 5-HT1A receptor antagonist WAY 100635. SB 242084 pretreatment also prevented the response to WAY 161503. The blocking effects of SB 242084 likely involved 5-HT2C receptors because the drug did not demonstrate 5-HT2A receptor occupancy in vivo or ex vivo. The inhibition of 5-HT cell firing induced by WAY 161503 was partially reversed by the GABA(A) receptor antagonist picrotoxin. Also, WAY 161503 increased Fos expression in GAD positive DRN neurones and DRN GAD positive neurones expressed 5-HT2C receptor immunoreactivity. Conclusions and implications: These findings indicate that WAY 161503 inhibits 5-HT cell firing in the DRN in vivo, and support a mechanism involving 5-HT2C receptor-mediated activation of DRN GABA neurones.