The dorsal striatum expressing adenylyl cyclase-5 controls behavioral sensitivity of the righting reflex to high-dose ethanol.
High-dose ethanol inflicts sedation and loss of righting reflex (LORR). Recently, it was reported that AC5 knockout (AC5(-/-)) mice consumed more ethanol and showed reduced sensitivity to high-dose ethanol compared to wild-type mice. As an extension of the previous study, in the present study we examined the signaling mechanism regulating altered behavioral sensitivity of LORR in AC5(-/-) mice. AC5(-/-) mice had enhanced phosphorylation of the NR2B subunit of NMDA receptors in the dorsal striatum and a partial reduction of MK801 (NMDA receptor antagonist)/ethanol-induced LORR. AC5(-/-) mice showed increased levels of phospho-CaMKIIα, phospho-CREB, and BDNF in the dorsal striatum. CaMKIIα(+/-) or BDNF(+/-) mice displayed enhanced LORR, a behavioral phenotype opposite to that displayed by AC5(-/-) mice. Consistently with these results, stereotaxic infusion of KN62 (CaMKII inhibitor), siRNA-CaMKIIα, or siRNA-BDNF, within the dorsal striatum was sufficient to prolong LORR. These results suggest that neural mechanism is important for regulating behavioral sensitivity of LORR and that the signaling pathway(s) interplayed by AC5, CaMKIIα and BDNF within the dorsal striatum is important for regulating the duration of ethanol-induced LORR.
Laboratory Animal Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
Kyoung-Shim
KS
Kim
Hannah
H
Kim
Sun-Kyu
SK
Park
Pyung-Lim
PL
Han
D000262:Adenylyl Cyclases / Q000235:genetics* / Q000378:metabolism; D000428:Alcohol Drinking / Q000235:genetics / Q000503:physiopathology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012018:Reflex / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D019208:Brain-Derived Neurotrophic Factor; D002492:Central Nervous System Depressants; D000431:Ethanol; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D000262:Adenylyl Cyclases; C419510:adenylyl cyclase type V