Effect of a selective 5-hydroxytryptamine reuptake inhibitor on brain extracellular noradrenaline: microdialysis studies using paroxetine

The clinical efficacy of selective serotonin (5-hydroxytryptamine, 5-HT) re uptake inhibitors (SSRIs) is normally attributed to their ability to increa se brain 5-HT function although recent preclinical findings indicate that t heir selectivity for 5-HT over noradrenaline may be less evident in vivo. T he present study investigated the effects of the SSRI, paroxetine, on extra cellular levels of noradrenaline. Microdialysis was carried out in the hippocampus of the awake rat. In rats treated twice daily for 14 days with paroxetine (5 mg/kg s.c.), dialysate l evels of noradrenaline showed a maintained two-fold increase compared to sa line-injected controls. Paroxetine (5 mg/kg s.c.) administered once daily f ur 14 days did not cause a sustained increase in noradrenaline but levels s howed a moderate (+58%) increase in response to a paroxetine challenge. Acu te injection of paroxetine (5 mg/kg s.c.) did not elevate noradrenaline lev els. Paroxetine (5 mg/kg s.c.) elevated dialysate 5-HT after both acute and repeated (twice daily for 14 days) treatment. The paroxetine-induced incre ase in noradrenaline (and 5-HT) was positively correlated with plasma conce ntrations of the: drug, which were around the therapeutic range. In compari son to paroxetine, desipramine (10 mg/kg s.c.) caused a four-fold increase in dialysate noradrenaline (but did not change 5-HT) following repeated (on ce daily for 14 days) treatment and a two-fold increase at for acute treatm ent. In summary, despite its selectivity as a 5-HT reuptake inhibitor, paroxetin e increased extracellular levels of noradrenaline in rat hippocampus follow ing repeated administration. We discuss the possibility that a facilitation of noradrenaline function might be involved in the antidepressant effect o f paroxetine, and possibly other SSRIs. (C) 2000 Elsevier Science B.V. All rights reserved.