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The anandamide transport inhibitor AM404 reduces ethanol self-administration.
Eur J Neurosci 2007; 26(2):476-86EJ

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.

Authors+Show Affiliations

Fundación IMABIS (The European TARGALC Consortium), Hospital Carlos Haya, Avenida Carlos Haya s/n, 7 Planta, Pabellón A, 29010 Málaga, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17650118

Citation

Cippitelli, Andrea, et al. "The Anandamide Transport Inhibitor AM404 Reduces Ethanol Self-administration." The European Journal of Neuroscience, vol. 26, no. 2, 2007, pp. 476-86.
Cippitelli A, Bilbao A, Gorriti MA, et al. The anandamide transport inhibitor AM404 reduces ethanol self-administration. Eur J Neurosci. 2007;26(2):476-86.
Cippitelli, A., Bilbao, A., Gorriti, M. A., Navarro, M., Massi, M., Piomelli, D., ... Rodríguez de Fonseca, F. (2007). The anandamide transport inhibitor AM404 reduces ethanol self-administration. The European Journal of Neuroscience, 26(2), pp. 476-86.
Cippitelli A, et al. The Anandamide Transport Inhibitor AM404 Reduces Ethanol Self-administration. Eur J Neurosci. 2007;26(2):476-86. PubMed PMID: 17650118.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The anandamide transport inhibitor AM404 reduces ethanol self-administration. AU - Cippitelli,Andrea, AU - Bilbao,Ainhoa, AU - Gorriti,Miguel Angel, AU - Navarro,Miguel, AU - Massi,Maurizio, AU - Piomelli,Daniele, AU - Ciccocioppo,Roberto, AU - Rodríguez de Fonseca,Fernando, PY - 2007/7/26/pubmed PY - 2007/10/27/medline PY - 2007/7/26/entrez SP - 476 EP - 86 JF - The European journal of neuroscience JO - Eur. J. Neurosci. VL - 26 IS - 2 N2 - 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. SN - 0953-816X UR - https://www.unboundmedicine.com/medline/citation/17650118/The_anandamide_transport_inhibitor_AM404_reduces_ethanol_self_administration_ L2 - https://doi.org/10.1111/j.1460-9568.2007.05665.x DB - PRIME DP - Unbound Medicine ER -