Alcohol exerts numerous pharmacological effects through its interaction with various neurotransmitters and neuromodulators. Among the latter, endogenous opioids play a key role in the rewarding (addictive) properties of ethanol.
Three types of opioid receptors (mu, delta, and kappa) represent the respective targets of the major opioid peptides (beta-endorphin, enkephalins, and dynorphins, respectively). The rewarding (reinforcing) properties of the mu and delta receptor ligands are caused by activation of the mesolimbic dopamine system, which ascends from the ventral tegmentum of the midbrain (VTA) to rostral structures; of these, the nucleus accumbens (NAC) is of particular importance in drug addiction.
Dysphoria, on the other hand, results from activation of kappa receptors. The neurochemical manifestations of these opposing effects are an increase or decrease in dopamine release in the NAC.
Several lines of evidence suggest that alcohol interferes with endogenous opioid mechanisms closely associated with dopamine transmission in the mesolimbic pathway. The view that condensation products of dopamine and alcohol-derived aldehyde (tetrahydroisoquinolines) play a role remains controversial. However, there is much information on the direct (acute and chronic) effects of alcohol on the binding properties of opioid receptors and on the modulation of opioid peptide synthesis and secretion (e.g., a proposed increase in beta-endorphin release).
With regard to the reinforcing properties of alcohol, it is important to consider behavioral studies involving self-administration of alcohol in rodents and primates. Low doses of morphine have been found to increase alcohol consumption and higher doses of the opiate to decrease it. Conversely, opioid antagonists such as naloxone and naltrexone (which bind to nonselective opioid receptors) have been shown to decrease alcohol consumption under various experimental conditions. Similar results have been reported when selective mu or delta receptor antagonists are administered.
Results obtained in genetic models of high alcohol preference also support the view that alcohol consumption depends on the activity of the endogenous opioid reward system and that alcohol consumption may serve to compensate for inherent deficits in this system.
One hypothetical model proposes that reward results from activation of mu opioid receptors in the VTA and/or delta receptor in the NAC; these two nuclei are targets of endogenous beta-endorphin. It is proposed that alcohol interferes with this reward pathway either directly or indirectly.
The available experimental data are in good agreement with those from clinical trials in which opioid antagonists have been used to prevent relapse in alcoholics. This review also discusses conceptual considerations regarding the commonalities between different forms of addictions.
Psychopharmacology (Berl). 1997 Jan;129(2):99-111. : Endogenous opioid systems and alcohol addiction
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