The lack of CB1 receptors prevents neuroadapatations of both NMDA and GABA(A) receptors after chronic ethanol exposure.
As the contribution of cannabinoid (CB1) receptors in the neuroadaptations following chronic alcohol exposure is unknown, we investigated the neuroadaptations induced by chronic alcohol exposure on both NMDA and GABA(A) receptors in CB1-/- mice. Our results show that basal levels of hippocampal [(3)H]MK-801 ((1)-5-methyl-10,11-dihydro-5Hdibenzo[a,d]cyclohepten-5,10-imine) binding sites were decreased in CB1-/- mice and that these mice were also less sensitive to the locomotor effects of MK-801. Basal level of both hippocampal and cerebellar [(3)H]muscimol binding was lower and sensitivity to the hypothermic effects of diazepam and pentobarbital was increased in CB1-/- mice. GABA(A)alpha1, beta2, and gamma2 and NMDA receptor (NR) 1 and 2B subunit mRNA levels were altered in striatum of CB1-/- mice. Our results also showed that [(3)H]MK-801 binding sites were increased in cerebral cortex and hippocampus after chronic ethanol ingestion only in wild-type mice. Chronic ethanol ingestion did not modify the sensitivity to the locomotor effects of MK-801 in both genotypes. Similarly, chronic ethanol ingestion reduced the number of [(3)H]muscimol binding sites in cerebral cortex, but not in cerebellum, only in CB1+/+ mice. We conclude that lifelong deletion of CB1 receptors impairs neuroadaptations of both NMDA and GABA(A) receptors after chronic ethanol exposure and that the endocannabinoid/CB1 receptor system is involved in alcohol dependence.
Warnault
Vincent
V
Equipe Région INSERM 24 (ERI24), Groupe de Recherche sur l'Alcool et les Pharmacodépendances, Université de Picardie Jules Verne, Faculté de Pharmacie, Amiens, France, and IFR 114, Lille, France.
Houchi
Hakim
H
Barbier
Estelle
E
Pierrefiche
Olivier
O
Vilpoux
Catherine
C
Ledent
Catherine
C
Daoust
Martine
M
Naassila
Mickaël
M
D000222:Adaptation, Physiological / Q000235:genetics; D020268:Alcohol-Induced Disorders, Nervous System / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D000437:Alcoholism / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D001923:Brain Chemistry / Q000187:drug effects / Q000235:genetics*; D002908:Chronic Disease; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000009:adverse effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009118:Muscimol / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency / Q000235:genetics*; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*
D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D021122:Protein Subunits; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D009118:Muscimol; D000431:Ethanol