Type 5 adenylyl cyclase (AC5) is highly concentrated in the dorsal striatum and nucleus accumbens (NAc), two brain areas which have been implicated in motor function, reward, and emotion. Here we demonstrate that mice lacking AC5 (AC5)/)) display strong reductions in anxiety-like behavior in several paradigms. This anxiolytic behavior in AC5)/) mice was reduced by the D 1 receptor antagonist SCH23390 and enhanced by the D 1 dopamine receptor agonist, dihydrexidine (DHX). DHX-stimulated c-fos induction in AC5)/) mice was blunted in the dorso-lateral striatum, but it was overactivated in the dorso-medial striatum and NAc. The siRNA-mediated inhibition of AC5 levels within the NAc was sufficient to produce an anxiolytic-like response. Microarray and RT-PCR analyses revealed an up-regulation of prodynorphin and down-regulation of cholecystokinin (CCK) in the NAc of AC5)/) mice. Administration of nor-binaltorphimine (a kappa opioid receptor antagonist) or CCK-8s (a CCK receptor agonist) reversed the anxiolytic-like behavior exhibited by AC5)/) mutants. Taken together, these results suggest an essential role of AC5 in the NAc for maintaining normal levels of anxiety.

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