Extinction-induced upregulation in AMPA receptors reduces cocaine- seeking behaviour
ABSTRACT Cocaine addiction is thought to involve persistent neurobiological changes that facilitate relapse to drug use despite efforts to abstain. But the propensity for relapse may be reduced by extinction training--a form of inhibitory learning that progressively reduces cocaine-seeking behaviour in the absence of cocaine reward. Here we show that extinction training during withdrawal from chronic cocaine self-administration induces experience-dependent increases in the GluR1 and GluR2/3 subunits of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) glutamate receptors in the nucleus accumbens shell, a brain region that is critically involved in cocaine reward. Increases in the GluR1 subunit are positively associated with the level of extinction achieved during training, suggesting that GluR1 may promote extinction of cocaine seeking. Indeed, viral-mediated overexpression of both GluR1 and GluR2 in nucleus accumbens shell neurons facilitates extinction of cocaine- but not sucrose-seeking responses. A single extinction training session, when conducted during GluR subunit overexpression, attenuates stress-induced relapse to cocaine seeking even after GluR overexpression declines. Our findings indicate that extinction-induced plasticity in AMPA receptors may facilitate control over cocaine seeking by restoring glutamatergic tone in the nucleus accumbens, and may reduce the propensity for relapse under stressful situations in prolonged abstinence.
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ABSTRACT: Cocaine produces multiple neuroadaptations with chronic repeated use. Many of these neuroadaptations can be reversed or normalized by extinction training during withdrawal from chronic cocaine self-administration in rats. This article reviews our past and present studies on extinction-induced modulation of the neuroadaptive response to chronic cocaine in the mesolimbic dopamine system, and the role of this modulation in addictive behavior in rats. Extinction training normalizes tyrosine hydroxylase levels in the nucleus accumbens (NAc) shell, an effect that could help ameliorate dysphoria and depression associated with withdrawal from chronic cocaine use. Extinction training also increases levels of GluR1 and GluR2/3 AMPA receptor subunits, while normalizing deficits in NR1 NMDA receptor subunits, in a manner consistent with long-term potentiation of excitatory synapses in the NAc shell. Our results suggest that extinction-induced increases in AMPA and NMDA receptors may restore deficits in cortico-accumbal neurotransmission in the NAc shell and facilitate inhibitory control over cocaine-seeking behavior. Other changes identified by gene expression profiling, including up-regulation in the AMPA receptor aggregating protein Narp, suggest that extinction training induces extensive synaptic reorganization. These studies highlight potential benefits for extinction training procedures in the treatment of drug addiction.Learning & Memory 09/2004; 11(5):648-57. DOI:10.1101/lm.81404 · 4.38 Impact Factor
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ABSTRACT: The modulation of the mesolimbic and nigrostriatal dopamine pathways by CXCL12 and CXCR4
Article: Copyright[Show abstract] [Hide abstract]
ABSTRACT: "Copyright is the branch of Intellectual Property Law that governs works of expression such as books, paintings and songs, and the expressive aspects of computer programs. Intellectual products such as these have a partially public goods character: they are largely inexhaustible and nonexcludable. Intellectual Property Law responds to inexcludability by giving producers legal rights to exclude nonpayers from certain usages of their intellectual products. The goal is to provide incentives for new production at fairly low transaction costs. However, the copyright owner will charge a price above marginal cost and this, coupled with the inexhaustibility of most copyrighted products, creates deadweight loss. Various copyright doctrines (such as the idea/expression dichotomy, the limited duration of the copyright ownership term and the doctrine of 'fair use') work to reduce deadweight loss and other costs within a larger structure that creates incentives. Copyright Law, unlike Patent Law, gives owners rights only against those who actually copy the work. This limitation, too, may serve to reduce both transaction costs and deadweight loss. Empirically it is unclear how successful copyright has been in creating incentives for production, reducing transaction costs and keeping deadweight costs low."