ELECTROPHYSIOLOGICAL CHARACTERIZATION OF THE EFFECT OF LONG-TERM DULOXETINE ADMINISTRATION ON THE RAT SEROTONERGIC AND NORADRENERGIC SYSTEMS

Duloxetine is a dual serotonin (5-HT)/norepinephrine (NE) reuptake blo cker with antidepressant potential. In the present in vivo electrophys iological study, the changes in the function of the rat 5-HT and NE sy stems after 2- and 21-day administration of duloxetine (20 mg/kg/day) were assessed in the dorsal hippocampus and the dorsal raphe nucleus ( DRN). The firing rate of DRN neurons was decreased after 2 days of dul oxetine, but returned to the control level after 21-day administration . This recovery of firing rate was presumably due to the desensitizati on of the DRN somatodendritic 5-HT1A,, autoreceptors found after long- term duloxetine administration. Overall serotonergic tone was assessed by examining the ability of the 5-HT1A antagonist WAY 100635 to alter hippocampal firing. WAY 100635 increased hippocampal firing rates in 21-day treated rats to a greater extent than in 2-day treated or contr ol rats, suggesting that long-term administration induced an increase in endogenous levels of 5-HT in postsynaptic regions. This increase in 5-HT levels was accompanied by selective changes in the 5-HT and NE s ystems induced by long-term duloxetine administration. i.e., the desen sitization of the alpha-2 adrenergic heteroreceptor on 5-HT terminals and the continued blockade of the 5-HT transporters. In contrast, the sensitivity of the alpha-2 adrenergic and terminal 5-HT1B,, autorecept ors, as well as that of the postsynaptic 5-HT1A,, receptor after 21-da y treatment was unchanged, Therefore, this study demonstrates that dul oxetine increases serotonergic tone in a limbic forebrain structure an d may therefore be effective in the treatment of depression.