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-HT(2)) 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-HT(2) receptor agonists DOI ((+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride) and DOB ((+/-)-2,5-dimethoxy-4-bromoamphetamine hydrobromide), caused a dose-related (10-100 micro g kg(-1) i.v.) inhibition of 5-HT neuronal activity, with the highest dose reducing firing rates by >80%. 3. Pretreatment with the 5-HT(2) 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. 4. Pretreatment with the peripherally acting 5-HT(2) 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-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-HT(2) receptors are not located on 5-HT neurones, postsynaptic 5-HT feedback mechanisms are implicated.
Boothman
L J
LJ
University Department of Pharmacology, Mansfield Road, Oxford OX1 3QT.
Allers
K A
KA
Rasmussen
K
K
Sharp
T
T
D000530:Alfaxalone Alfadolone Mixture; D000818:Animals; D002697:Chloral Hydrate; D004305:Dose-Response Relationship, Drug; D008297:Male; D011903:Raphe Nuclei / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000502:physiology*; D044403:Receptor, Serotonin, 5-HT2B / Q000502:physiology*; D044405:Receptor, Serotonin, 5-HT2C / Q000502:physiology*; D012701:Serotonin / Q000502:physiology; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists; D012701:Serotonin; D002697:Chloral Hydrate; D000530:Alfaxalone Alfadolone Mixture