Effect of a selective 5‐HT reuptake inhibitor in combination with 5‐HT1A and 5‐HT1B receptor antagonists on extracellular 5‐HT in rat frontal cortex in vivo

Selective 5‐hydroxytryptamine (5‐HT; serotonin) reuptake inhibitors (SSRIs) cause a greater increase in extracellular 5‐HT in the forebrain when the somatodendritic 5‐HT1A autoreceptor is blocked. Here, we investigated whether blockade of the terminal 5‐HT1B autoreceptor influences a selective 5‐HT reuptake inhibitor in the same way, and whether there is an additional effect of blocking both the 5‐HT1A and 5‐HT1B autoreceptors. Extracellular 5‐HT was measured in frontal cortex of the anaesthetized rat by use of brain microdialysis. In vivo extracellular recordings of 5‐HT neuronal activity in the dorsal raphe nucleus (DRN) were also carried out. The selective 5‐HT reuptake inhibitor, paroxetine (0.8 mg kg−1, i.v.), increased extracellular 5‐HT about 2 fold in rats pretreated with the 5‐HT1A receptor antagonist, WAY100635. When administered alone neither paroxetine (0.8 mg kg−1, i.v.) nor WAY100635 (0.1 mg kg−1, i.v.) altered extracellular 5‐HT levels. Paroxetine (0.8 mg kg−1, i.v.) did not increase 5‐HT in rats pretreated with the 5‐HT1B/D receptor antagonist, GR127935 (1 mg kg−1, i.v.). GR127935 (1 and 5 mg kg−1, i.v.) had no effect on extracellular 5‐HT when administered alone. Interestingly, paroxetine (0.8 mg kg−1, i.v.) caused the greatest increase in 5‐HT (up to 5 fold) when GR127935 (1 or 5 mg kg−1, i.v.) was administered in combination with WAY100635 (0.1 mg kg−1, i.v.). Administration of GR127935 (5 mg kg−1, i.v.) plus WAY100635 (0.1 mg kg−1, i.v.) without paroxetine, had no effect on extracellular 5‐HT in the frontal cortex. Despite the lack of effect of GR127935 on 5‐HT under basal conditions, when 5‐HT output was elevated about 3 fold (by adding 1 μM paroxetine to the perfusion medium), the drug caused a dose‐related (1 and 5 mg kg−1, i.v.) increase in 5‐HT. By itself, GR127935 slightly but significantly decreased 5‐HT cell firing in the DRN at higher doses (2.0–5.0 mg kg−1, i.v.), but did not prevent the inhibition of 5‐HT cell firing induced by paroxetine. In summary, our results suggest that selective 5‐HT reuptake inhibitors may cause a large increase in 5‐HT in the frontal cortex when 5‐HT autoreceptors on both the somatodendrites (5‐HT1A) and nerve terminals (5‐HT1B) are blocked. This increase is greater than when either set of autoreceptors are blocked separately. The failure of a 5‐HT1B receptor antagonist alone to enhance the effect of the selective 5‐HT reuptake inhibitor in our experiments may be related to a lack of tone on the terminal 5‐HT1B autoreceptor due to a continued inhibition of 5‐HT cell firing. These results are discussed in relation to the use of 5‐HT autoreceptor antagonists to augment the antidepressant effect of selective 5‐HT reuptake inhibitors.