Interaction between a selective 5‐HT1A receptor antagonist and an SSRI in vivo: effects on 5‐HT cell firing and extracellular 5‐HT

1 The acute inhibitory effect of selective 5‐hydroxytryptamine (serotonin) reuptake inhibitors (SSRIs) on 5‐HT neuronal activity may offset their ability to increase synaptic 5‐HT in the forebrain. 2Here, we determined the effects of the SSRI, paroxetine, and a novel selective 5‐HT1A receptor antagonist, WAY 100635, on 5‐HT cell firing in the dorsal raphe nucleus (DRN), and on extracellular 5‐HT in both the DRN and the frontal cortex (FCx). Extracellular electrophysiological recording and brain microdialysis were used in parallel experiments, in anaesthetized rats. 3 Paroxetine dose‐dependently inhibited the firing of 5‐HT neurones in the DRN, with a maximally effective dose of approximately 0.8 mg kg−1, i.v. WAY 100635 (0.1 mg kg−1, i.v.) both reversed the inhibitory effect of paroxetine and, when used as a pretreatment, caused a pronounced shift to the right of the paroxetine dose‐response curve. 4 Paroxetine (0.8 mg kg−1, i.v.), doubled extracellular 5‐HT in the DRN, but did not alter extracellular 5‐HT in the FCx. A higher dose of paroxetine (2.4 mg kg−1, i.v.) did increase extracellular 5‐HT in the FCx, but to a lesser extent than in the DRN. Whereas 0.8 mg kg−1, i.v. paroxetine alone had no effect on extracellular 5‐HT in the FCx, in rats pretreated with WAY 100635 (0.1 mg kg−1), paroxetine (0.8 mg kg−1, i.v.) markedly increased extracellular 5‐HT in the FCx. 5 In conclusion, pretreatment with the selective 5‐HT1A receptor antagonist, WAY 100635, blocked the inhibitory effect of paroxetine on 5‐HT neuronal activity in the DRN and, at the same time, markedly enhanced the effect of paroxetine on extracellular 5‐HT in the FCx. These results may be relevant to recent clinical observations that 5‐HT1A receptor antagonists in combination with SSRIs have a rapid onset of antidepressant effect.