CB1 receptor knockout mice display reduced ethanol-induced conditioned place preference and increased striatal dopamine D2 receptors.
Cannabinoids and ethanol activate the same reward pathways, and recent advances in the understanding of the neurobiological basis of alcoholism suggest that the CB1 receptor system may play a key role in the reinforcing effects of ethanol and in modulating ethanol intake. In the present study, male CB1 receptors knockout mice generated on a CD1 background displayed decreased ethanol-induced conditioned place preference (CPP) compared to wild-type (CB1(+/+)) mice. Ethanol (0.5, 1.0, 1.5, and 2.0 g/kg) induced significant CPP in CB1(+/+) mice at all doses tested, whereas it induced significant CPP only at the highest dose of ethanol (2.0 g/kg) in CB1(-/-) mice. However, there was no genotypic difference in cocaine (20 mg/kg)-induced CPP. There was also no genotypic difference, neither in cocaine (10-50 mg/kg) nor in D-amphetamine (1.2-5 mg/kg)-induced locomotor effects. In addition, mutant and wild-type mice did not differ in sensitivity to the anxiolytic effects of ethanol (1.5 g/kg) when tested using the elevated plus maze. Interestingly, this decrease in ethanol efficacy to induce CPP in CB1(-/-) mice was correlated with an increase in D2/D3 receptors, as determined by [3H]raclopride binding, whereas there was no difference in D1-like receptors, as determined by [3H]SCH23390 binding, measured in the striatum from drug-naive mice. This increase in D2/D3 binding sites observed in CB1 knockout mice was associated with an altered locomotor response to the D2/D3 agonist quinpirole (low doses 0.02-0.1 mg/kg) but not to an alteration of quinpirole (0.1-1.0 mg/kg)-induced CPP compared to wild-type mice. Altogether, the present results indicate that lifelong deletion of CB1 receptors reduced ethanol-induced CPP and that these reduced rewarding effects of ethanol are correlated to an overexpression of striatal dopamine D2 receptors.
Houchi
Hakim
H
Groupe de Recherche sur l'Alcool et les Pharmacodépendances (GRAP), Jeune Equipe, Université de Picardie Jules Verne, Faculté de Pharmacie, 1 rue des Louvels, Amiens, France.
Babovic
Daniela
D
Pierrefiche
Olivier
O
Ledent
Catherine
C
Daoust
Martine
M
Naassila
Mickaël
M
D000428:Alcohol Drinking / Q000235:genetics / Q000523:psychology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001552:Benzazepines / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects*; D003913:Dextroamphetamine / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D019257:Quinpirole / Q000494:pharmacology; D020891:Raclopride / Q000494:pharmacology; D011869:Radioligand Assay; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000502:physiology*; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012201:Reward
D014151:Anti-Anxiety Agents; D001552:Benzazepines; D002492:Central Nervous System Depressants; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D043884:Receptor, Cannabinoid, CB1; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D019257:Quinpirole; D000431:Ethanol; D020891:Raclopride; D003042:Cocaine; D003913:Dextroamphetamine