Alcohol and Alcoholism Advance Access originally published online on October 10, 2005
Alcohol and Alcoholism 2006 41(1):24-32; doi:10.1093/alcalc/agh217
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PHARMACOLOGICAL MANIPULATION OF CB1 RECEPTOR FUNCTION ALTERS DEVELOPMENT OF TOLERANCE TO ALCOHOL
1 New York State Psychiatric Institute, New York, NY, USA, 2 Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA and 3 College of Physicians and Surgeons, Colombia University, New York, NY, USA
* Author to whom correspondence should be addressed at: Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA. Tel: +1 845 398 5452; Fax: +1 845 398 5451; E-mail: hungund{at}nki.rfmh.org
(Received 11 July 2005; first review notified 18 August 2005; accepted in revised form 30 August 2005; accepted 9 September 2005)
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.