Evidence that central 5-HT2A and 5-HT2B/C receptors regulate 5-HT cell firing in the dorsal raphe nucleus of the anaesthetised rat

1 Systemic administration of phenethylamine-derived, 5-hydroxytryptamine(2) (5-HT2) receptor agonists inhibits the firing of midbrain 5-HT neurones, but the 5-HT receptors involved are poorly defined, and the contribution of peripheral mechanisms is uncertain. This study addresses these issues using extracellular recordings of 5-HT neurones in the dorsal raphe nucleus of anaesthetised rats. 2 The 5-HT2 receptor agonists DOI ((+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride) and DOB ((+/-)- 2,5-dimethoxy-4-bromoamphetamine hydrobromide), caused a dose-related (10 100 mug kg(-1) i.v.) inhibition of 5-HT neuronal activity, with the highest dose reducing firing rates by >80%. 3 Pretreatment with the 5-HT2 receptor antagonist ritanserin (1 mg kg(-1) i.v.) completely blocked the action of DOI. The 5-HT2A receptor antagonist MDL 100,907 (0.2 mg kg(-1) i.v.) blocked the action of both DOI and DOB. In comparison, the 5-HT2B/C receptor antagonist SB 206553 (0.5 mg kg(-1) i.v.) caused a small, but statistically significant, shift to the right in the dose response to DOI and DOB. 4 Pretreatment with the peripherally acting 5-HT2 receptor antagonist BW 501C67 (0.1 mg kg(-1) i.v.) had no effect on the DOI-induced inhibition of 5-HT cell firing, but completely blocked the DOI-induced rise in mean arterial blood pressure. 5 These data indicate that the inhibition of 5-HT cell firing induced by systemic administration of DOI and DOB is mediated predominantly by the 5-HT2A receptor-subtype, but that 5-HT2B/C receptors also play a minor role. Moreover, central and not peripheral mechanisms are involved. Given evidence that 5-HT2 receptors are not located on 5-HT neurones, postsynaptic 5-HT feedback mechanisms are implicated.