Role of opioid systems in the addictive actions of ethanol
Interactions between ethanol and opioid systems have been an important focus of neurobiological research on alcohol addiction. Evidence for participation of opioid systems in modulation of ethanol-related behaviors comes from studies of opioid antagonist effects in animal models of ethanol seeking. Both nonselective opioid receptor antagonists and antagonists selective for µ- or 
-opioid receptors (MORs and DORs) reduce ethanol consumption and reinforced responding (for review, see Herz, 1997
; Gianoulakis, 2001). Recent data from MOR KO mice favor a role of this receptor in ethanol reward because ethanol consumption, ethanol-reinforced operant responses, and ethanol-stimulated locomotion are decreased (Roberts et al., 2000; Hall et al., 2001). Ethanol self-administration is increased in DOR KO mice (Roberts et al., 2001), yet these mice exhibit an increased anxious-like phenotype, but reduced anxiety-like behavior is seen after ethanol self-administration. Thus, reversal of anxiety-like behavior is what may have led to the increased ethanol preference in these mice.
As for ethanol reinforcement, participation of opioid systems is not fully understood, but interactions with NAc DA transmission and DA-independent effects via opioid systems are implicated. Ethanol increases extracellular endorphins in the NAc, suggesting that attenuation of the reinforcing properties of ethanol by opioid antagonists may be related to inhibition of endogenous endorphin actions in the NAc (Olive et al., 2001). Reductions in voluntary drinking by intra-NAc administration of an opioid receptor antagonist (Heyser et al., 1999) or MOR antisense oligonucleotide (Myers and Robinson, 1999) suggest that these inhibitory effects may occur within the NAc. However, such effects may also be dependent on interactions with DA mechanisms. Both systemic (Benjamin et al., 1993) and focal (Acquas et al., 1993) administration of opioid receptor antagonists blunt ethanol-induced DA release within the NAc, implicating this effect in the suppression of ethanol intake by opioid antagonists (Gonzales and Weiss, 1998). On the other hand, selective lesions of DA terminals in the NAc do not alter ethanol self-administration in rats, but naltrexone reduced ethanol consumption in the same animals (Koistinen et al., 2001). Thus, mechanisms other than interference with DA transmission contribute to the suppressive effects of opiate antagonists on ethanol intake. Although the exact mechanisms by which ethanol increases NAc endorphin levels and by which opioid receptor antagonists exert suppressant effects on drinking have yet to be identified, these results indicate new directions for understanding the effectiveness of opioid receptor antagonists as pharmacological therapies for alcoholism.
On the basis of findings from animal models, naltrexone was tested and found to be effective as a treatment for alcoholism, in terms of both reducing ethanol consumption and preventing relapse (O'Malley et al., 1992; Volpicelli et al., 1992; Anton et al., 1999). However, a recent report (Krystal et al., 2001) cast doubt on the effectiveness of naltrexone. In this large multicenter, double-blind, placebo-controlled evaluation, naltrexone neither prevented nor delayed relapse, nor did it affect other outcome measures. Although this study questions the use of naltrexone, differences between this study and previous positive reports (mostly older men, and more severe alcoholism) likely account for the absence of positive effects. Understanding the neurobiological basis of the actions of naltrexone in human alcoholics, perhaps with new imaging technologies, as well as in animal models that consider the interactions of opioid systems with each stage of ethanol use and abuse, is key.
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