title: 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.
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. (ED(50) = 0.25 mg/kg) and s.c. (ED(50) = 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)cycloh exanecarboxamide (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 beta-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 microg/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-phenylprop anamid e [(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.
authors.affiliation: Program in Neuroscience, Department of Psychology, Princeton University, Princeton, New Jersey, USA. Fornal@princeton.edu
authors.forename: C A
authors.initials: CA
authors.lastname: Fornal
authors.forename: F J
authors.initials: FJ
authors.lastname: Martin
authors.forename: C W
authors.initials: CW
authors.lastname: Metzler
authors.forename: B L
authors.initials: BL
authors.lastname: Jacobs
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002415:Cats; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010869:Pindolol / Q000494:pharmacology*; D011412:Propanolamines / Q000494:pharmacology; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013876:Thiophenes
chemical_list: D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013876:Thiophenes; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C005632:tertatolol; D010869:Pindolol