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

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 (IP3Rs‐1) expression and the development of EtOH‐induced place preference at various time points in withdrawal. IP3R‐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 IP3Rs. EtOH conditioning significantly increased, compared to alcohol‐naïve control mice, both IP3R‐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 IP3R‐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 IP3R‐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 IP3R‐1 promoter domain to stimulate IP3R‐1 synthesis. Such increased IP3R‐1 elevates intracellular Ca2+ concentration via facilitated mobilization of Ca2+ from the intracellular Ca2+ stores to the cytosol. 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 IP3R‐1 promoter domain to stimulate IP3R‐1 synthesis. Such increased IP3R‐1 elevates intracellular Ca2+ concentration via facilitated mobil