Involvement of the AMPA receptor GluR-C subunit in alcohol-seeking behavior and relapse.
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.
Sanchis-Segura
Carles
C
Department of Psychopharmacology, Central Institute of Mental Health, University of Heidelberg, 68072 Mannheim, Germany. segura@zi-mannheim.de
Borchardt
Thilo
T
Vengeliene
Valentina
V
Zghoul
Tarek
T
Bachteler
Daniel
D
Gass
Peter
P
Sprengel
Rolf
R
Spanagel
Rainer
R
D000437:Alcoholism / Q000188:drug therapy / Q000503:physiopathology*; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology / Q000627:therapeutic use; D003216:Conditioning, Operant / Q000502:physiology; D003463:Cues; D000431:Ethanol / Q000633:toxicity; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D021122:Protein Subunits; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D012008:Recurrence; D013045:Species Specificity; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology
D018691:Excitatory Amino Acid Antagonists; D021122:Protein Subunits; D018091:Receptors, AMPA; C104724:glutamate receptor ionotropic, AMPA 4; C061950:GYKI 52466; D001569:Benzodiazepines; D000431:Ethanol