Systemic administration of phenethylamine‐derived, 5‐hydroxytryptamine₂ (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. 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 μg kg⁻¹ i.v.) inhibition of 5‐HT neuronal activity, with the highest dose reducing firing rates by >80%. Pretreatment with the 5‐HT₂ receptor antagonist ritanserin (1 mg kg⁻¹ i.v.) completely blocked the action of DOI. The 5‐HT_2A receptor antagonist MDL 100,907 (0.2 mg kg⁻¹ i.v.) blocked the action of both DOI and DOB. In comparison, the 5‐HT_2B/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. 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. 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‐HT_2A receptor‐subtype, but that 5‐HT_2B/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. British Journal of Pharmacology (2003) 139, 998–1004. doi:10.1038/sj.bjp.0705328

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