Previous work has shown that repeated desipramine treatment causes 
downregulation of the norepinephrine transporter (NET) and persistent 
antidepressant-like effects on behavior, ie effects observed 2 days after 
discontinuation of drug treatment when acute effects are minimized. The present 
study examined whether this mechanism generalizes to other antidepressants and 
also is evident for the serotonin transporter (SERT). Treatment of rats for 14 
days with 20 mg/kg per day protriptyline or 7.5 mg/kg per day sertraline reduced 
NET and SERT expression, respectively, in cerebral cortex and hippocampus; these 
treatments also induced a persistent antidepressant-like effect on forced-swim 
behavior. Increased serotonergic neurotransmission likely mediated the 
behavioral effect of sertraline, as it was blocked by inhibition of serotonin 
synthesis with p-chlorophenylalanine; a parallel effect was observed previously 
for desipramine and noradrenergic neurotransmission. Treatment with 20 mg/kg per 
day reboxetine for 42, but not 14, days reduced NET expression; 
antidepressant-like effects on behavior were observed for both treatment 
durations. Treatment for 14 days with 70 mg/kg per day venlafaxine, which 
inhibits both the NET and SERT, or 10 mg/kg per day phenelzine, a monoamine 
oxidase inhibitor, produced antidepressant-like effects on behavior without 
altering NET or SERT expression. For all drugs tested, reductions of NET and 
SERT protein were not accompanied by reduced NET or SERT mRNA in locus coeruleus 
or dorsal raphe nucleus, respectively. Overall, the present results suggest an 
important, though not universal, role for NET and SERT regulation in the 
long-term behavioral effects of antidepressants. Understanding the mechanisms 
underlying transporter regulation in vivo may suggest novel targets for the 
development of antidepressant drugs.