title: 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.
authors.affiliation: Division of Nano Sciences and Brain Disease Research Institute, Ewha Womans University, Seoul, Korea.
authors.forename: Kyoung-Shim
authors.initials: KS
authors.lastname: Kim
authors.forename: Ko-Woon
authors.initials: KW
authors.lastname: Lee
authors.forename: In-Sun
authors.initials: IS
authors.lastname: Baek
authors.forename: Chae-Moon
authors.initials: CM
authors.lastname: Lim
authors.forename: Vaishnav
authors.initials: V
authors.lastname: Krishnan
authors.forename: Ja-Kyeong
authors.initials: JK
authors.lastname: Lee
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
authors.forename: Pyung-Lim
authors.initials: PL
authors.lastname: Han
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics*; D000818:Animals; D001008:Anxiety Disorders / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D001552:Benzazepines / Q000494:pharmacology; D002766:Cholecystokinin / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D015536:Down-Regulation / Q000235:genetics; D004745:Enkephalins / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D007527:Isoenzymes / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009292:Narcotic Antagonists / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000201:enzymology* / Q000503:physiopathology; D010617:Phenanthridines / Q000494:pharmacology; D011498:Protein Precursors / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors / Q000378:metabolism; D012844:Sincalide / Q000494:pharmacology; D015854:Up-Regulation / Q000235:genetics
chemical_list: D001552:Benzazepines; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D004745:Enkephalins; D007527:Isoenzymes; D009292:Narcotic Antagonists; D010617:Phenanthridines; D011498:Protein Precursors; D034741:RNA, Small Interfering; D017447:Receptors, Dopamine D1; D017473:Receptors, Opioid, kappa; C061532:dihydrexidine; D002766:Cholecystokinin; C033660:preproenkephalin; D000262:Adenylyl Cyclases; C419510:adenylyl cyclase type V; D012844:Sincalide; D004298:Dopamine