Vol. 291, Issue 1, 229-238, October 1999

Pindolol Suppresses Serotonergic Neuronal Activity and Does Not Block the Inhibition of Serotonergic Neurons Produced by 8-Hydroxy-2-(di-n-propylamino)tetralin in Awake Cats¹

Casimir A. Fornal, Francisco J. Martin², Christine W. Metzler and Barry L. Jacobs

Program in Neuroscience, Department of Psychology, Princeton University, Princeton, New Jersey

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 of N-[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 -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.