title: Sensitization of ethanol-induced place preference as a result of up-regulation of type 1 inositol 1,4,5-trisphosphate receptors in mouse nucleus accumbens.
abstract: This study involved mice that received 4 days of ethanol (EtOH) vapor inhalation and then were assessed for type 1 inositol 1,4,5-trisphosphate receptor (IP3 Rs-1) expression and the development of EtOH-induced place preference at various time points in withdrawal. IP3 R-1 protein was found to be significantly increased in the nucleus accumbens (NAcc) of mice immediately after 4-day EtOH vapor inhalation, while it significantly reduced to the control level during the next 3 days of withdrawal from EtOH inhalation. EtOH (2 g/kg, i.p.)-induced place preference after 3 days of withdrawal from EtOH vapor inhalation increased dose dependently for 4 days, which was significantly inhibited by 2-aminophenoxyethane-borate, an antagonist for IP3 Rs. EtOH conditioning significantly increased, compared to alcohol-naïve control mice, both IP3 R-1 protein and the release of dopamine in the NAcc of mice after 3 days of withdrawal from EtOH vapor inhaled for 4 days, and this increase of IP3 R-1 protein was completely abolished by intracerebroventricular injection of FK506, an inhibitor for calcineurin. These results indicate that the sensitization of EtOH-induced place preference is due to up-regulated IP3 R-1 via calcineurin-mediated pathway after enhanced release of dopamine in the NAcc on EtOH administration during EtOH conditioning. We revealed signal transduction pathways that may promote sensitization of ethanol (EtOH)-induced place preference. EtOH facilitated the release of dopamine (DA) in the Nucleus accumbens (NAcc), enhancing calcineurin function via dopamine D1-like and D2-like receptor activation, which in turn resulted in increased NFATc4 expression. Increase in NFATc4 may further facilitate transcription factor binding to IP3 R-1 promoter domain to stimulate IP3 R-1 synthesis. Such increased IP3 R-1 elevates intracellular Ca(2+) concentration via facilitated mobilization of Ca(2+) from the intracellular Ca(2+) stores to the cytosol.
authors.affiliation: Department of Pharmacology, Kawasaki Medical School, Kurashiki, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kurokawa
authors.forename: Koji
authors.initials: K
authors.lastname: Mizuno
authors.forename: Seitaro
authors.initials: S
authors.lastname: Ohkuma
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D003213:Conditioning, Psychological / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D000431:Ethanol; D002118:Calcium; D004298:Dopamine
keywords: 2-APB; FK506; conditioned place preference; ethanol; nucleus accumbens; type 1 inositol 1,4,5-trisphosphate receptors