Effects of chronic treatment with escitalopram or citalopram on extracellular 5‐HT in the prefrontal cortex of rats: role of 5‐HT 1A receptors

Microdialysis was used to study the acute and chronic effects of escitalopram (S‐citalopram; ESCIT) and chronic citalopram (CIT), together with the 5‐HT 1A receptor antagonist WAY100,635 ( N ‐[2‐[methoxyphenyl)‐1‐piperazinyl]ethyl]‐ N ‐(2‐pyridinyl) cyclohexane carboxamide trihydrochloride) and the 5‐HT 1A receptor agonist 8‐hydroxy‐2‐(di‐ n ‐propylamino)tetralin (8‐OH‐DPAT), on extracellular 5‐hydroxytryptamine (5‐HT) levels in the rat prefrontal cortex. Extracellular 5‐HT rose to 234 and 298% of basal values after subcutaneous (s.c.) acute doses of 0.15 and 0.63 mg kg −1 ESCIT. No further increase was observed at 2.5 mg kg −1 ESCIT (290%). The effect of 13‐day s.c. infusion of 10 mg kg −1 day −1 ESCIT on extracellular 5‐HT (422% of baseline) was greater than after 2 days (257% of baseline), whereas exposure to ESCIT was similar. In contrast, the increase in extracellular 5‐HT induced by the infusion of CIT for 2 (306%) and 13 days (302%) was similar. However, brain and plasma levels of S ‐citalopram in rats infused with CIT for 13 days were lower than after 2 days. Acute treatment with 2.5 mg kg −1 ESCIT or 5 mg kg −1 CIT raised extracellular 5‐HT by 243 and 276%, respectively, in rats given chronic vehicle but had no effect in rats given ESCIT (10 mg kg −1 day −1 ) or CIT (20 mg kg −1 day −1 ) for 2 or 13 days, suggesting that the infused doses had maximally increased extracellular 5‐HT. WAY100,635 (0.1 mg kg −1 s.c.) increased extracellular 5‐HT levels by 168, 174 and 169% of prechallenge values in rats infused with vehicle or ESCIT for 2 or 13 days, respectively. WAY100,635 enhanced extracellular 5‐HT levels to 226, 153 and 164% of prechallenge values in rats infused with vehicle or CIT for 2 and 13 days, respectively. 8‐OH‐DPAT (0.025 mg kg −1 ) reduced extracellular 5‐HT by 54% in control rats, but had no effect in those given ESCIT and CIT for 13 days. This series of experiments led to the conclusion that chronic treatment with ESCIT desensitizes the 5‐HT 1A receptors, regulating the release of 5‐HT in the prefrontal cortex and enhances the effect of the drug on extracellular 5‐HT. They also indicate that chronic treatment with ESCIT and CIT did not prevent WAY100,635 from raising extracellular 5‐HT.British Journal of Pharmacology (2004) 142 , 469–478. doi: 10.1038/sj.bjp.0705800