Vol. 291, Issue 1, 220-228, October 1999

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-100635¹

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

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

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.