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The Journal of Neuroscience, January 25, 2006, 26(4):1231-1238; doi:10.1523/JNEUROSCI.4237-05.2006

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Behavioral/Systems/Cognitive
Involvement of the AMPA Receptor GluR-C Subunit in Alcohol-Seeking Behavior and Relapse

Carles Sanchis-Segura,¹ Thilo Borchardt,² Valentina Vengeliene,¹ Tarek Zghoul,¹ Daniel Bachteler,¹ Peter Gass,¹ Rolf Sprengel,² and Rainer Spanagel¹

¹Department of Psychopharmacology, Central Institute of Mental Health, University of Heidelberg, 68072 Mannheim, Germany, and ²Department of Molecular Neuroscience, Max Planck Institute for Medical Research, D-69120 Heidelberg, Germany

Correspondence should be addressed to Dr. Carles Sanchis-Segura, Department of Psychopharmacology, Central Institute for Mental Health, University of Heidelberg, J5, D-68159 Mannheim, Germany. Email: segura{at}zi-mannheim.de

Craving and relapse are core symptoms of drug addiction and alcoholism. It is suggested that, after chronic drug consumption, long-lasting neuroplastic changes within the glutamatergic system are important determinants of addictive behavior. Here, we show that the AMPA type glutamate receptor plays a crucial role in alcohol craving and relapse. We observed, in two animal models of alcohol craving and relapse, that the AMPA antagonist GYKI 52466 [1-(4-aminophenyl)-4-methyl-7, 8-methylenedioxy-5H-2, 3-benzodiazepine] dose-dependently reduced cue-induced reinstatement of alcohol-seeking behavior and the alcohol deprivation effect. The involvement of the AMPA receptor in these phenomena was further studied using mice deficient for the GluR-C AMPA subunit [GluR-C knock-out (KO)]. GluR-C KOs displayed a blunted, cue-induced reinstatement response and alcohol deprivation effect, when compared with wild-type controls; however, no differences between genotypes could be observed regarding ethanol self-administration under operant or home cage drinking conditions. These results imply a role for GluR-C in alcohol relapse, although this phenotype could also be attributable to a reduction in the total number of AMPA receptors in specific brain areas. In conclusion, AMPA receptors seem to be involved in the neuroplastic changes underlying alcohol seeking behavior and relapse. Thus, AMPA receptors represent a novel therapeutic target in preventing relapse.

Key words: AMPA; ethanol relapse; alcohol deprivation effect (ADE); reinstatement; GluR-C; addiction

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Received July 4, 2005; revised Nov. 22, 2005; accepted Nov. 22, 2005.

Correspondence should be addressed to Dr. Carles Sanchis-Segura, Department of Psychopharmacology, Central Institute for Mental Health, University of Heidelberg, J5, D-68159 Mannheim, Germany. Email: segura{at}zi-mannheim.de

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