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Effects of withdrawal from chronic escalating-dose binge cocaine on conditioned place preference to cocaine and striatal preproenkephalin mRNA in C57BL/6J mice.

ABSTRACT: Relapse is a serious problem for the effective treatment of cocaine addiction.Examining cocaine re-exposure-induced behavioral and neurobiological alterations following chronic escalating-dose binge cocaine administration and withdrawal may provide insight into the neurobiological basis of cocaine relapse.Our goal was to determine how exposure to chronic escalating-dose cocaine affects development of subsequent cocaine-induced conditioned place preference (CPP) and changes in endogenous opioid systems.Mice were injected with either escalating-dose binge cocaine (15-30 mg/kg/injection × 3/day) or saline for 14-days and conditioned with 15 mg/kg of cocaine or saline (once per day for 10-days), starting either 1 or 14-days after the last day of binge injections.Mice exposed to chronic escalating cocaine did not develop CPP to cocaine when conditioning commenced on the first day of withdrawal (CPP test on day 10 of withdrawal). By contrast, mice did develop CPP to cocaine when conditioning started on the 14th day of withdrawal (CPP test on day 24 of withdrawal). Furthermore, preproenkephalin (Penk) mRNA levels in caudate putamen were significantly higher in mice that received 14-day withdrawal from escalating-dose binge cocaine before the CPP procedure (tested 24 days post-binge) than those that received 1-day withdrawal (tested 10 days post-binge).The rewarding effect of cocaine was blunted in early withdrawal from chronic escalating exposure, but recovered in more prolonged withdrawal. Time-dependent elevations in Penk mRNA levels may be part of the underlying mechanisms of this effect.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC3979702 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Effects of withdrawal from chronic escalating-dose binge cocaine on conditioned place preference to cocaine and striatal preproenkephalin mRNA in C57BL/6J mice.

Zhang Yong Y Schlussman Stefan D SD Butelman Eduardo R ER Ho Ann A Kreek Mary Jeanne MJ

Neuropharmacology 20120404 2

<h4>Unlabelled</h4>Relapse is a serious problem for the effective treatment of cocaine addiction.<h4>Rationale</h4>Examining cocaine re-exposure-induced behavioral and neurobiological alterations following chronic escalating-dose binge cocaine administration and withdrawal may provide insight into the neurobiological basis of cocaine relapse.<h4>Objectives</h4>Our goal was to determine how exposure to chronic escalating-dose cocaine affects development of subsequent cocaine-induced conditioned p ...[more]

PMID: 22504589

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Project description:We previously identified a region on chromosome 1 that harbor quantitative trait loci (QTLs) with large effects on alcohol withdrawal risk using both chronic and acute models in mice. Here, using newly created and existing QTL interval-specific congenic (ISC) models, we report the first evidence that this region harbors two distinct alcohol withdrawal QTLs (Alcw11and Alcw12), which underlie 13% and 3-6%, respectively, of the genetic variance in alcohol withdrawal severity measured using the handling-induced convulsion. Our results also precisely localize Alcw11 and Alcw12 to discreet chromosome regions (syntenic with human 1q23.1-23.3) that encompass a limited number of genes with validated genotype-dependent transcript expression and/or non-synonymous sequence variation that may underlie QTL phenotypic effects. ISC analyses also implicate Alcw11and Alcw12 in withdrawal-induced anxiety-like behavior, representing the first evidence for their broader roles in alcohol withdrawal beyond convulsions; but detect no evidence for Alcw12 involvement in ethanol conditioned place preference (CPP) or consumption. Our data point to high-quality candidates for Alcw12, including genes involved in mitochondrial respiration, spatial buffering, and neural plasticity, and to Kcnj9 as a high-quality candidate for Alcw11. Our studies are the first to show, using two null mutant models on different genetic backgrounds, that Kcnj9-/- mice demonstrate significantly less severe alcohol withdrawal than wildtype littermates using acute and repeated exposure paradigms. We also demonstrate that Kcnj9-/- voluntarily consume significantly more alcohol (20%, two-bottle choice) than wildtype littermates. Taken together with evidence implicating Kcnj9 in ethanol CPP, our results support a broad role for this locus in ethanol reward and withdrawal phenotypes. In summary, our results demonstrate two distinct chromosome 1 QTLs that significantly affect risk for ethanol withdrawal, and point to their distinct unique roles in alcohol reward phenotypes.

Dataset Information

Effects of withdrawal from chronic escalating-dose binge cocaine on conditioned place preference to cocaine and striatal preproenkephalin mRNA in C57BL/6J mice.

Publications

Effects of withdrawal from chronic escalating-dose binge cocaine on conditioned place preference to cocaine and striatal preproenkephalin mRNA in C57BL/6J mice.

Similar Datasets

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