TY - JOUR T1 - Pindolol, a Putative 5-Hydroxytryptamine<sub>1A</sub>Antagonist, Does Not Reverse the Inhibition of Serotonergic Neuronal Activity Induced by Fluoxetine in Awake Cats: Comparison to WAY-100635 JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 220 LP - 228 VL - 291 IS - 1 AU - Casimir A. Fornal AU - Francisco J. Martin AU - Christine W. Metzler AU - Barry L. Jacobs Y1 - 1999/10/01 UR - http://jpet.aspetjournals.org/content/291/1/220.abstract N2 - 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 ofN-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY-100635), a selective 5-HT1A 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-HT1Aautoreceptors. 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. The American Society for Pharmacology and Experimental Therapeutics ER -