Abstract

Clinical studies have shown that pindolol can enhance the effects of antidepressant drugs, presumably by acting as an antagonist at somatodendritic 5-hydroxytryptamine (5-HT)_1A autoreceptors, which regulate the firing rate of central serotonergic neurons. The current study characterized the action of pindolol on the single-unit activity of serotonergic neurons in the dorsal raphe nucleus of freely moving cats. (±)-Pindolol produced a dose-dependent inhibition of neuronal activity after i.v. (ED₅₀ = 0.25 mg/kg) and s.c. (ED₅₀ = 1.23 mg/kg) administration. The active enantiomer (−)-pindolol (1 mg/kg i.v.) also suppressed neuronal activity (maximal decrease, 88%). Upon p.o. administration, (±)-pindolol (10 mg/kg) produced a marked, long-acting suppression of neuronal activity similar to that observed after s.c. administration. In all cases, the reduction in firing rate produced by pindolol was completely reversed by low doses ofN-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY-100635) (0.1 mg/kg i.v. or 0.2 mg/kg s.c.), a selective 5-HT_1A antagonist. Systemic administration of (−)-tertatolol (1–5 mg/kg i.v.), another β-adrenoceptor blocker/putative 5-HT_1A antagonist, had no significant effect on neuronal activity. The ability of i.v. (±)-pindolol (0.1–1 mg/kg) to reverse the suppression of serotonergic neuronal activity produced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (10 μg/kg i.v.), a selective 5-HT_1A agonist, also was examined. (±)-Pindolol had no appreciable effect on the action of 8-OH-DPAT. In contrast, the 5-HT_1A antagonist drugs WAY-100635 (0.1 mg/kg i.v.), 4-fluoro-N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl benzamide (0.1 mg/kg, i.v.),N-tert-butyl-3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenylpropanamide [(S)-WAY-100135] (0.5 mg/kg i.v.), and (−)-tertatolol (1–5 mg/kg i.v.) reversed the effect of 8-OH-DPAT to varying degrees. Overall, these results indicate that pindolol acts as an agonist rather than an antagonist at 5-HT_1A autoreceptors in awake animals.