Dopamine D1 Receptors Participate in Cocaine-Induced Place Preference via Regulation of Ryanodine Receptor Expression

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Ryanodine receptors (RyRs) with three different isoforms in the brain play a role to facilitate Ca2+ release from the intracellular Ca2+ pool. Although cocaine is a strongly addictive psychostimulant that dramatically affects the central nervous system function, the role of RyRs and regulation of their expression by cocaine-induced place preference have not yet been defined well. The present study investigated the regulation of RyR expression in mice under intermittent cocaine treatment using the place preference procedure. The cocaine-induced place preference was inhibited by intracerebroventricular pretreatment with dantrolene, a RyRs antagonist, in a dose-dependent manner. The levels of RyR-1 and -2 in the limbic forebrain and frontal cortex significantly increased in the cocaine-conditioned mice, whereas that of RyR-3 in these two brain regions showed no changes. Although the up-regulation of RyRs was not affected by blockade of L-type voltage-gated calcium channels, the increase of RyR-1 and -2 in the limbic forebrain and frontal cortex was completely abolished by SCH23390, a selective antagonist of dopamine D1 receptors, but not by sulpiride, a selective antagonist of dopamine D2 receptors. These findings indicate that RyRs play a critical role in the development of cocaine-induced place preference and that the up-regulation of RyRs in the brain of a mouse showing cocaine-induced place preference is regulated by dopamine D1 receptors.