5-HT1A and 5-HT1B receptors control the firing of serotoninergic neurons in the dorsal raphe nucleus of the mouse: studies in 5-HT1B knock-out mice

The characteristics of the spontaneous firing of serotoninergic neurons in the dorsal raphe nucleus and its control by serotonin (5-hydroxytryptamine, 5-HT) receptors were investigated in wild-type and 5-HT1B knock-out (5-HT1 B-/-) mice of the 129/Sv strain, anaesthetized with chloral hydrate. In bot h groups of mice, 5-HT neurons exhibited a regular activity with an identic al firing rate of 0.5-4.5spikes/s. Intravenous administration of the 5-HT r euptake inhibitor citalopram or the 5-HT1A agonist 8-hydroxy-2-(di-n-propyl amino)tetralin (8-OH-DPAT) induced a dose-dependent inhibition of 5-HT neur onal firing which could be reversed by the selective 5-HT1A antagonist N-[2 -[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexane carbo xamide (WAY 100635). Both strains were equally sensitive to 8-OH-DPAT (ED50 similar to 6.3 mu g/kg i.v,), but the mutants were less sensitive than wil d-type animals to citalopram (ED50 = 0.49 +/- 0.02 and 0.28 +/- 0.01 mg/kg i.v., respectively, P < 0.05). This difference could be reduced by pretreat ment of wild-type mice with the 5-HT1B/1D antagonist 2'-methyl-4'-(5-methyl -[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid [4-methoxy-3-(4-methyl-p iperazine-1-yl)-phenyl]amide (GR 127935), and might be accounted for by the lack of 5-HT1B receptors and a higher density of 5-HT reuptake sites (spec ifically labelled by [H-3]citalopram) in 5-HT1B-/- mice. In wild-type but n ot 5-HT1B-/- mice, the 5-HT1B agonists 3-(1,2,5,6-tetrahydro-4-pyridyl)-5-p ropoxypyrrolo[3,2-b]pyridine (CP 94253, 3 mg/kg i.v.) and 5-methoxy-3-(1,2, 3,6-tetrahydropyridin-4-yl)-1H-indole (RU 24969, 0.6 mg/kg i,v.) increased the firing rate of 5-HT neurons (+22.4 +/- 2.8% and +13.7 +/- 6.0%, respect ively, P < 0.05), and this effect could be prevented by the 5-HT1B antagoni st GR 127935 (1 mg/kg i.v.). Altogether, these data indicate that in the mo use, the firing of 5-HT neurons in the dorsal raphe nucleus is under both a n inhibitory control through 5-HT1A receptors and an excitatory influence t hrough 5-HT1B receptors.