Further pharmacological characterization of 5‐HT 2C receptor agonist‐induced inhibition of 5‐HT neuronal activity in the dorsal raphe nucleus in vivo

Background and purpose:  Recent experiments using non‐selective 5‐hydroxytryptamine (5‐HT) 2C receptor agonists including WAY 161503 suggested that midbrain 5‐HT neurones are under the inhibitory control of 5‐HT 2C receptors, acting via neighbouring gamma‐aminobutyric acid (GABA) neurones. The present study extended this pharmacological characterization by comparing the actions of WAY 161503 with the 5‐HT 2C receptor agonists, Ro 60‐0275 and 1‐(3‐chlorophenyl) piperazine (mCPP), as well as the non‐selective 5‐HT agonist lysergic acid diethylamide (LSD) and the 5‐HT releasing agent 3,4‐methylenedioxymethamphetamine (MDMA). Experimental approach:  5‐HT neuronal activity was measured in the dorsal raphe nucleus (DRN) using extracellular recordings in anaesthetized rats. The activity of DRN GABA neurones was assessed using double‐label immunohistochemical measurements of Fos and glutamate decarboxylase (GAD). Key results:  Ro 60‐0175, like WAY 161503, inhibited 5‐HT neurone firing, and the 5‐HT 2C antagonist SB 242084 reversed this effect. mCPP also inhibited 5‐HT neurone firing (∼60% neurones) in a SB 242084‐reversible manner. LSD inhibited 5‐HT neurone firing; however, this effect was not altered by either SB 242084 or the 5‐HT 2A/C receptor antagonist ritanserin but was reversed by the 5‐HT 1A receptor antagonist WAY 100635. Similarly, MDMA inhibited 5‐HT neurone firing in a manner reversible by WAY 100635, but not SB 242084 or ritanserin. Finally, both Ro 60‐0275 and mCPP, like WAY 161503, increased Fos expression in GAD‐positive DRN neurones. Conclusions and implications:  These data strengthen the hypothesis that midbrain 5‐HT neurones are under the inhibitory control of 5‐HT 2C receptors, and suggest that the 5‐HT 2C agonists Ro 60‐0175, mCPP and WAY 161503, but not LSD or MDMA, are useful probes of the mechanism(s) involved.