Chronic antidepressant treatments induce a time-dependent up-regulation of AMPA receptor subunit protein levels.

Growing evidence suggests a pivotal role for glutamatergic neurotransmission in the pathophysiology of major depressive disorder and in the action of antidepressants. The main aim of this study was to elucidate the temporal profile of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors expression and their functional regulation in prefrontal/frontal cortex (P/FC) and hippocampus (HC) of rats chronically treated with two different antidepressants: fluoxetine (FLX) and reboxetine (RBX). Rat groups were treated for 1, 2 or 3 weeks with the two drugs and, in additional groups, the treatments were followed by 1 week of drug washout (3+1). We found that both drugs induced strong increases in AMPAR subunit protein expression that were time dependent and subunit specific. Especially in P/FC, FLX had the main effect on GluA2 and GluA4 subunits, reaching a 5-fold increase after the drug washout; RBX mostly affected GluA1 and GluA3, reaching a 4-fold increase at the end of the treatment. Furthermore, in HC, the two drugs induced a time specific increase in subunit protein levels, with GluA3 and GluA4 presenting the main changes, albeit with different kinetics. In addition, our data indicate that antidepressants might alter, though by small changes, the R/G editing levels for GluA2, mostly in P/FC, and in turn may induce fine-tuning of glutamate neurotransmission. Overall, we showed that antidepressant treatments induced marked changes in AMPA receptor subunits expression, with time-dependent effects that are consistent with the onset of therapeutic effect of these drugs. These data confirm the involvement of glutamate neurotransmission in the effects of these drugs and further suggest the targeting of AMPA receptors as a therapeutic approach for the treatment of depression.