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Alcohol and Alcoholism Advance Access published online on October 10, 2005
Alcohol and Alcoholism, doi:10.1093/alcalc/agh217
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© The Author 2005. Published by Oxford University Press on behalf of the Medical Council on Alcohol. All rights reserved
Received July 11, 2005
Revised August 30, 2005
Accepted September 9, 2005

Article

PHARMACOLOGICAL MANIPULATION OF CB1 RECEPTOR FUNCTION ALTERS DEVELOPMENT OF TOLERANCE TO ALCOHOL

KAREN L. NOWAK 1, K. YARAGUDRI VINOD 1, and BASALINGAPPA L. HUNGUND 2*

1 New York State Psychiatric Institute, New York, NY, USA; Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA
2 New York State Psychiatric Institute, New York, NY, USA; Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA; College of Physicians and Surgeons, Colombia University, New York, NY, USA

* To whom correspondence should be addressed.
BASALINGAPPA L. HUNGUND, E-mail: hungund{at}nki.rfmh.org


  Abstract

Aims: 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.


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