Role of endogenous opioid systems in alcohol reinforcement and dependence mechanisms

Biochemical and behavioral evidence indicate that the dopaminergic mesolimbic system plays a key role in the mechanisms of reinforcement and reward elicited by alcohol (ethanol) and other drugs of abuse. In addition, the dopaminergic activity of the nigrostriatal pathway has been proposed to determine brain sensitivity to ethanol, a process which could be associated to drug addiction. Besides dopamine, several neurotransmitters and neuromodulators are involved in ethanol reinforcement mechanisms, including gamma aminobutyric acid (GABA), glutamate, serotonin, acetylcholine and opioid peptides (enkephalins, endorphins and dynorphins). Ethanol and opioids share several pharmacological properties and exhibit similar behavioral effects in animals and humans. These and other studies suggest that the alcohol reinforcing properties are due, at least in part, to the ethanolinduced activation of endogenous opioidergic systems. This activation could in turn increase the hedonic value and the reinforcing effects of the drug. Thus, ethanol-induced changes in opioidergic transmission could contribute to alcohol intoxication and to the neuroadaptive responses produced by the long-lasting exposure to the drug. Opioidergic transmission may be altered by ethanol at different levels, including biosynthesis, release and inactivation of endogenous opioid peptides, as well as their binding to their receptors. Several studies suggest that mu and delta opioid receptors play a key role in ethanol reinforcement and dependence. Therefore, enkephalins and β-endorphin could physiologically mediate ethanol actions in the brain and play a major role in high drug use behavior. During the last few years, our research group has focused on the role of the endogenous opioid systems in these processes. Evidence obtained in our laboratory suggests that enkephalins and β-endorphin differentially and selectively participate in ethanol reinforcement and dependence.