Cocaine effects on mouse incentive-learning and human addiction are linked to alpha2 subunit-containing GABAA receptors.
Because GABA(A) receptors containing alpha2 subunits are highly represented in areas of the brain, such as nucleus accumbens (NAcc), frontal cortex, and amygdala, regions intimately involved in signaling motivation and reward, we hypothesized that manipulations of this receptor subtype would influence processing of rewards. Voltage-clamp recordings from NAcc medium spiny neurons of mice with alpha2 gene deletion showed reduced synaptic GABA(A) receptor-mediated responses. Behaviorally, the deletion abolished cocaine's ability to potentiate behaviors conditioned to rewards (conditioned reinforcement), and to support behavioral sensitization. In mice with a point mutation in the benzodiazepine binding pocket of alpha2-GABA(A) receptors (alpha2H101R), GABAergic neurotransmission in medium spiny neurons was identical to that of WT (i.e., the mutation was silent), but importantly, receptor function was now facilitated by the atypical benzodiazepine Ro 15-4513 (ethyl 8-amido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate). In alpha2H101R, but not WT mice, Ro 15-4513 administered directly into the NAcc-stimulated locomotor activity, and when given systemically and repeatedly, induced behavioral sensitization. These data indicate that activation of alpha2-GABA(A) receptors (most likely in NAcc) is both necessary and sufficient for behavioral sensitization. Consistent with a role of these receptors in addiction, we found specific markers and haplotypes of the GABRA2 gene to be associated with human cocaine addiction.
Dixon
Claire I
CI
Department of Psychology, University of Sussex, Brighton BN1 9QG, United Kingdom.
Morris
Hannah V
HV
Breen
Gerome
G
Desrivieres
Sylvane
S
Jugurnauth
Sarah
S
Steiner
Rebecca C
RC
Vallada
Homero
H
Guindalini
Camila
C
Laranjeira
Ronaldo
R
Messas
Guilherme
G
Rosahl
Thomas W
TW
Atack
John R
JR
Peden
Dianne R
DR
Belelli
Delia
D
Lambert
Jeremy J
JJ
King
Sarah L
SL
Schumann
Gunter
G
Stephens
David N
DN
D000328:Adult; D000818:Animals; D001386:Azides / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology; D001665:Binding Sites / Q000235:genetics; D016022:Case-Control Studies; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000235:genetics / Q000378:metabolism* / Q000523:psychology*; D003213:Conditioning, Psychological; D004298:Dopamine / Q000378:metabolism; D005260:Female; D006801:Humans; D007858:Learning / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism*; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D011963:Receptors, GABA-A / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology*; D012201:Reward; D055815:Young Adult
D001386:Azides; C484841:GABRA2 protein, human; C493920:Gabra2 protein, mouse; D011963:Receptors, GABA-A; D001569:Benzodiazepines; C042957:Ro 15-4513; D003042:Cocaine; D004298:Dopamine