Pharmacological manipulation of CB1 receptor function alters development of tolerance to alcohol.
OBJECTIVE
The current study investigated the efficacy of CB1 receptor-targeted drugs on the development and expression of tolerance to alcohol (EtOH).


METHODS
An EtOH-inhalation model was used to induce tolerance, as measured by EtOH-induced sedation and hypothermia after a 24 h withdrawal period. Two drug treatment procedures, (i) co-treatment with EtOH and (ii) acute drug administration following chronic EtOH treatment, were used to test the efficacy of CB1 receptor manipulations on EtOH tolerance.


RESULTS
The effects of the CB1 receptor agonist CP-55,940 varied depending on paradigm and behavioural measure. Chronic CP-55,940 co-treatment blocked tolerance to EtOH-induced hypothermia but not to the sedative effect (sleep time) in EtOH-exposed mice. However, chronic CP-55,940 administration alone resulted in tolerance to the sedative effect of a challenge dose of EtOH in control mice. Acute CP-55,940 administration after chronic alcoholization blocked the development of tolerance to EtOH-induced sedation compared to the EtOH alone exposed group, but induced tolerance to the hypothermic effects of EtOH in control mice. Chronic blockade of CB1 receptor function by SR141716A resulted in tolerance to both the sedative and hypothermic effects of EtOH in control mice, but had no effect on EtOH-exposed mice.


CONCLUSIONS
The data support a role for the endocannabinoid (EC) system in EtOH tolerance/dependence and suggest that drugs targeted against EC system could be therapeutically useful in treating alcohol-related disorders.
Nowak
Karen L
KL
New York State Psychiatric Institute, New York, NY, USA.
Vinod
K Yaragudri
KY
Hungund
Basalingappa L
BL
D000437:Alcoholism / Q000235:genetics*; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D003511:Cyclohexanols / Q000008:administration & dosage / Q000494:pharmacology*; D004361:Drug Tolerance / Q000235:genetics*; D000431:Ethanol / Q000008:administration & dosage / Q000009:adverse effects*; D007035:Hypothermia / Q000139:chemically induced; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D000077285:Rimonabant
D003511:Cyclohexanols; D007166:Immunosuppressive Agents; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000431:Ethanol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000077285:Rimonabant