Adenylyl cyclase‐5 activity in the nucleus accumbens regulates anxiety‐related behavior

Abstract

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.

Brain-Derived Neurotrophic Factor Controls Cannabinoid CB1 Receptor Function in the Striatum

“…Additional lines of evidence, however, support the idea that BDNF-mediated inhibition of CB 1 R (GABA) function represent a synaptic correlate of the anxious-depressive behavior induced by the activation of BDNF-TrkB signaling in the striatum (Eisch et al, 2003;Berton et al, 2006). Enhancement of cAMP signaling in the striatum has been associated with increased anxious-depressive behavior in mice (Favilla et al, 2008;Kim et al, 2008;Zhang et al, 2008) and confirms the relevance of our findings for the pathophysiology of emotional disorders. CB 1 Rs, in fact, reduce transmitter release by (GABA) in BDNF ϩ/Ϫ mice and increases BDNF levels in the striatum.…”

Structural Basis for the High-Affinity Inhibition of Mammalian Membranous Adenylyl Cyclase by 2′,3′-O-(N-Methylanthraniloyl)-Inosine 5′-Triphosphate

“…However, the usefulness of MANT-ITP per se as starting point for the development of AC isoform-specific inhibitors, particularly AC5 inhibitors for the treatment of heart failure, aging, bone loss, anxiety, and acute and chronic pain (Chester and Watts, 2007;Rottlaender et al, 2007;Kim et al, 2008;Okumura et al, 2009) is limited for several reasons. First, MANT-ITP per se is membrane-impermeant and would have to be delivered as a prodrug (Laux et al, 2004;Hü bner et al, 2011).…”

“…ACs are activated by the G-protein G s via numerous receptors for hormones and neurotransmitters and catalyze the production of the second-messenger cAMP. Studies with AC5(Ϫ/Ϫ) mice indicate that potent and selective AC5 inhibitors may be valuable drugs for the treatment of heart failure, aging, bone loss, anxiety, and acute and chronic pain (Chester and Watts, 2007;Rottlaender et al, 2007;Kim et al, 2008;Okumura et al, 2009).…”

RNA Interference: A New Hope in Understanding and Treatment of Psychiatric Disorders

“…In parallel with this finding, knockdown of CREB in the NAc resulted in decreased depression-like and increased anxiety-like behavior similar to that caused by EE. Interestingly knockdown of adenyl cyclase-5 (AC5), an enzyme that converts ATP into cAMP, in the NAc was reported to have anxiolytic effects (46).…”