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 cats

Clinical studies have shown that pindolol can enhance the effects of antide pressant 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 dor sal raphe nucleus of freely moving cats. (+/-)-Pindolol produced a dose-dep endent 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%). U pon 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 pin dolol was completely reversed by low doses of N-[2-[4-(2-methoxyphenyl)-1-p iperazinyl]-ethyl]- N-(2-pyridinyl) cyclohexanecarboxamide (WAY-100635) (0. 1 mg/kg i.v. or 0.2 mg/kg s.c.), a selective 5-HT1A antagonist. Systemic ad ministration of (-)-tertatolol (1-5 mg/kg i.v.), another beta-adrenoceptor blocker/putative 5-HT1A antagonist, had no significant effect on neuronal a ctivity. The ability of i.v. (+/-)-pindolol (0.1-1 mg/kg) to reverse the su ppression of serotonergic neuronal activity produced by 8-hydroxy-2-(di-n-p ropylamino) tetralin (8-OH- DPAT) (10 mu g/kg i.v.), a selective 5-HT1A ago nist, also was examined. (+/-)- Pindolol had no appreciable effect on the a ction of 8-OH-DPAT. In contrast, the 5-HT1A 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-tertbutyl- 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-HT1A autoreceptors in awake animals.