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

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 med iated by somatodendritic 5-hydroxytryptamine (5-HT)(1A) autoreceptors. The current study examined the ability of pindolol to restore the single-unit a ctivity of serotonergic dorsal raphe nucleus neurons in awake cats after ac ute treatment with the SSRI fluoxetine. The effects of pindolol were compar ed with those of N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridi nyl) cyclohexanecarboxamide (WAY-100635), a selective 5-HT1A receptor antag onist. Systemic administration of fluoxetine (0.5 and 5 mg/kg i.v.) decreas ed neuronal firing rates to similar to 50 and 1%, respectively, of baseline levels. The subsequent administration of cumulative doses of (+/-)-pindolo l (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 ne uronal activity in animals pretreated with the low dose of fluoxetine. The active enantiomer, (-)-pindolol (1 mg/kg i.v.), also was ineffective in res toring neuronal activity after fluoxetine. In contrast, systemic administra tion of WAY-100635 completely reversed the effect of fluoxetine (5 mg/kg) a t low doses (0.025 mg/kg i.v.), and further elevated the firing rate of the se neurons above prefluoxetine baseline levels. Overall, these results indi cate that pindolol, unlike WAY-100635, lacks appreciable antagonist activit y at 5-HT1A autoreceptors. Thus, the clinical efficacy of pindolol in augme nting the antidepressant response to SSRIs, such as fluoxetine, may be unre lated to a restoration of serotonergic neuronal activity.