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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 reward1. 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 (α-amino-3-hydroxy-5-methyl-4-isoxazole propionate) glutamate receptors in the nucleus accumbens shell, a brain region that is critically involved in cocaine reward2,3,4,5. 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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Figure 1: Extinction training increases the amount of AMPA receptor subunits in the NAc shell during cocaine withdrawal.
Figure 2: Increases in GluR1 are associated with extinction of cocaine-seeking and resistance to reinstatement.
Figure 3: Transient viral-mediated overexpression of β-galactosidase and GluR1 in NAc in vivo.
Figure 4: Effects of HSV-mediated overexpression of GluR1 and GluR2 on extinction of cocaine and sucrose seeking.
Figure 5: Prolonged effects of extinction training concomitant with overexpression of GluR1 or GluR2 on stress-induced reinstatement.

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Acknowledgements

This work was supported by US Public Health Service grants (NIDA), a postdoctoral National Research Service Award (to C.A.S.) and the Lydia Bryant Test Professorship.

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Correspondence to David W. Self.

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Sutton, M., Schmidt, E., Choi, KH. et al. Extinction-induced upregulation in AMPA receptors reduces cocaine-seeking behaviour. Nature 421, 70–75 (2003). https://doi.org/10.1038/nature01249

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