Central CRF2 receptor antagonism reduces anxiety states during amphetamine withdrawal

Increased depressive and anxiety-like behaviors are exhibited by rats and humans during withdrawal from psychostimulants. Anxiety-like behaviors observed during amphetamine withdrawal are mediated by increased expression and activity of corticotropin releasing factor type 2 (CRF2) receptors in the dorsal raphe nucleus (dRN). Anxiety-like behavior of rats during withdrawal can be reversed by CRF2 receptor antagonism in the dRN, but the efficacy of global central CRF2 receptor antagonism is unknown. Rats were treated with amphetamine (2.5 mg/kg, ip.) or saline daily for 2 weeks, and were tested for anxiety-like behaviors during withdrawal. Rats undergoing withdrawal showed increased anxiety-like behavior, which was reduced by ventricular infusion of the CRF2 antagonist antisauvagine-30 (ASV 2 μg/2 μl). Surprisingly, ventricular ASV increased anxiety-like behavior in rats pre-treated with saline, but had an anxiolytic effect in un-treated rats. Western blots were performed to determine whether differences in CRF receptor densities could explain ASV-induced behavioral results. Saline pre-treated rats showed reduced CRF1 receptor expression in the lateral septum compared to amphetamine pre-treated and un-treated rats. Overall, these results suggest that central CRF2 antagonism reduces anxiety states during amphetamine withdrawal, and that behavioral effects may be dependent upon the balance of CRF1 and CRF2 receptor activity in anxiety-related regions.