Abstract
The endocannabinoid system mediates in the pharmacological actions of ethanol and genetic studies link endocannabinoid signaling to alcoholism. Drugs activating cannabinoid CB1 receptors have been found to promote alcohol consumption but their effects on self-administration of alcohol are less clear because of the interference with motor performance. To avoid this problem, a novel pharmacological approach to the study of the contribution of the cannabinoid system in alcoholism may be to use drugs that locally amplify the effects of alcohol on endogenous cannabinoids. In the present study we addressed this model by studying the effects of the anandamide transport inhibitor N-(4-hydroxyphenyl) arachidonoyl-ethanolamide (AM404) on both ethanol self-administration and reinstatement of alcohol-seeking behavior in rats. The results show that AM404 significantly reduced ethanol self-administration in a dose-dependent manner but failed to modify reinstatement for lever pressing induced by the stimulus associated with alcohol. This effect was not due to a motor depressant effect and was not related to a decrease in general motivational state, as it was not effective in other reward paradigms such as lever pressing for a saccharin solution. The mechanism of action of AM404 does not involve cannabinoid CB1 receptors as the CB1-selective antagonist SR141716A did not block the reduction of ethanol self-administration induced by the anandamide uptake blocker. Moreover, 3-(1,1-dimethylheptyl)-(-)-11-hydroxy-delta 8-tetrahydrocannabinol (HU-210), a classical cannabinoid receptor agonist, did not affect ethanol self-administration. The effects of AM404 are not mediated by either vanilloid VR1 receptors or cannabinoid CB2 receptors because it is not antagonized by either the VR1 receptor antagonist capsazepine or the CB2 antagonist AM630. These results indicate that AM404 may be considered as an innovative approach to reduce alcohol consumption.
Highlights
Cannabis and alcohol are two of the oldest drugs used by humans
Pre-treatment with the anandamide transport inhibitor N-(4-hydroxyphenyl) arachidonoyl-ethanolamide (AM404) 30 min prior to the ethanol self-administration session significantly reduced the operant response for ethanol in a dose-dependent manner
The effects were selective for ethanol because pre-treatment with AM404 did not modify operant responding for saccharin (0.2%, Fig. 1D)
Summary
Cannabis and alcohol are two of the oldest drugs used by humans Together with nicotine, they represent a relevant health problem because of the clinical consequences of their abuse. The endogenous cannabinoid system [a functional set of lipid transmitters and receptors that is the target of both natural and synthetic cannabinoids (Piomelli, 2003)] has been shown to mediate some of the pharmacological and behavioral aspects of alcohol (Basavarajappa & Hungund, 2002; Rodriguez de Fonseca et al, 2005; Ferrer et al, 2007). Both cannabinoids and alcohol activate the same reward pathways and the cannabinoid CB1 receptor plays an important role in regulating the positive reinforcing effects of alcohol as well as alcohol relapse (Cippitelli et al, 2005; Hungund et al, 2003; Wang et al, 2003).
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