Adenylyl cyclase-5 activity in the nucleus accumbens regulates anxiety-related behavior.
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.
Kim
Kyoung-Shim
KS
Division of Nano Sciences and Brain Disease Research Institute, Ewha Womans University, Seoul, Korea.
Lee
Ko-Woon
KW
Baek
In-Sun
IS
Lim
Chae-Moon
CM
Krishnan
Vaishnav
V
Lee
Ja-Kyeong
JK
Nestler
Eric J
EJ
Han
Pyung-Lim
PL
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
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