Partial 5-HT_1A receptor agonist properties of (–)pindolol in combination with citalopram on serotonergic dorsal raphe cell firing in vivo

Abstract.

Rationale: Pindolol has been reported to shorten the onset of antidepressant action of selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) as well as to increase their efficacy. It has been postulated that pindolol enhances the antidepressant effect of SSRIs by blocking somatodendritic 5-HT_1A autoreceptors, thus antagonizing the SSRI-induced feedback inhibition of midbrain 5-HT cell firing. A recent study, however, found that pindolol suppresses the firing rate of central 5-HT cells, suggesting that the compound possesses agonistic activity at 5-HT_1A autoreceptors. Objectives: The purpose of the present study was to investigate if acute administration of (–)pindolol antagonizes the decrease in firing rate of dorsal raphe 5-HT cells produced by acute treatment with the SSRI citalopram. Methods: Extracellular recordings of single 5-HT neurons in the dorsal raphe nucleus in anaesthetized rats. Results: Administration of 0.25 or 3.0 mg/kg (IV) (–)pindolol alone decreased the firing rate of a majority of the 5-HT cells studied, an effect that was reversed by the 5-HT_1A receptor antagonist WAY100635 (0.1 mg/kg, IV). Neither 0.25 nor 3.0 mg/kg (–)pindolol reversed the citalopram (0.1–0.2 mg/kg, IV)-induced suppression of 5-HT cell activity, but produced a further decrease in firing rate. In contrast, WAY100635 (0.1 mg/kg) completely reversed this effect of citalopram. Yet, pretreatment with 3.0, but not 0.25 mg/kg (–)pindolol significantly attenuated the acute inhibitory effect of citalopram on serotonergic cell firing. Conclusions: The present findings support the previous notion that (–)pindolol possesses prominent agonistic activity at somatodendritic 5-HT_1A autoreceptors, but also indicate that it may possess a weak antagonistic action at these receptors.