Pindolol, a putative 5-hydroxytryptamine(1A) antagonist, does not reverse the inhibition of serotonergic neuronal activity induced by fluoxetine in awake cats: Comparison to WAY-100635

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

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

The ability of pindolol to enhance the clinical antidepressant response to selective serotonin reuptake inhibitors (SSRIs) is generally attributed to a blockade of the feedback inhibition of serotonergic neuronal activity mediated by somatodendritic 5-hydroxytryptamine (5-HT)(1A) autoreceptors. The current study examined the ability of pindolol to restore the single-unit activity of serotonergic dorsal raphe nucleus neurons in awake cats after acute treatment with the SSRI fluoxetine. The effects of pindolol were compared with those of N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2- pyridinyl)cyclohexanecarboxamide (WAY-100635), a selective 5-HT(1A) receptor antagonist. Systemic administration of fluoxetine (0.5 and 5 mg/kg i.v.) decreased neuronal firing rates to ~50 and 1%, respectively, of baseline levels. The subsequent administration of cumulative doses of (±)-pindolol (0.1-5 mg/kg i.v.) failed to reverse the neuronal inhibition produced by either dose of fluoxetine. In addition to lacking efficacy as an antagonist in these experiments, (±)-pindolol produced an additional decrease in neuronal activity in animals pretreated with the low dose of fluoxetine. The active enantiomer, (-)-pindolol (1 mg/kg i.v.), also was ineffective in restoring neuronal activity after fluoxetine. In contrast, systemic administration of WAY-100635 completely reversed the effect of fluoxetine (5 mg/kg) at low doses (0.025 mg/kg i.v.), and further elevated the firing rate of these neurons above prefluoxetine baseline levels. Overall, these results indicate that pindolol, unlike WAY-100635, lacks appreciable antagonist activity at 5-HT(1A) autoreceptors. Thus, the clinical efficacy of pindolol in augmenting the antidepressant response to SSRIs, such as fluoxetine, may be unrelated to a restoration of serotonergic neuronal activity.

Original languageEnglish (US)
Pages (from-to)220-228
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume291
Issue number1
StatePublished - Oct 1999

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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