**1. Introduction**

204 Neuroscience – Dealing with Frontiers

Zalewska-Kaszubska J, Gorska D, Dyr W, Czarneck E (2006) Effect of acute administration

Zalewska-Kaszubska J, Gorska D, Dyr W, Czarnecka E (2008) Effect of chronic acamprosate

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of ethanol on beta-endorphin plasma level in ethanol preferring and non-preferring rats chronically treated with naltrexone. *Pharmacology Biochemistry and Behavior*,

treatment on voluntary alcohol intake and β-endorphin levels in rats selectively bred for high alcohol preference. *Neurosci Lett*, Vol. 431, pp. 221-5, 0304-3940.

> There are few effective medications available for the treatment of alcohol use disorders (AUDs). To date, the opioid antagonist, naltrexone, is the most effective in reducing alcohol consumption in combination with behavioral therapy. Naltrexone has high affinity for the mu opioid peptide receptor (MOP-R) with moderate activity at the delta opioid peptide receptor (DOP-R) and kappa opioid peptide receptor (KOP-R). Preclinical studies suggest that the MOP-R plays a significant role in ethanol-mediated behaviors, however, there is evidence suggesting the DOP-R may be a better therapeutic target for treating AUDs. This chapter will review studies investigating the role of the opioid receptors in ethanol-mediated behaviors with the view of identifying improved therapeutics for the treatment of AUDs.

#### **1.1 Current therapeutics for the treatment of alcohol use disorders**

AUDs are a major public health problem; currently the National Institute on Alcohol Abuse and Alcoholism, reports there are 17.6 million people in the United States either abuse alcohol or are alcohol dependent. There have been three medications approved by the U.S. Food and Drug Administration: disulfiram (Antabuse), acamprosate (Campral), and naltrexone (ReVia, Vivitrol) - all of which suffer from limited effectiveness due to sideeffects and compliance issues (Bouza et al., 2004; Mark et al., 2003a; Mark et al., 2003b; Pettinati et al., 2000). The aldehyde dehydrogenase blocker, disulfiram has not been very effective for treating AUDs (Johnson, 2008; O'Shea, 2000) primarily because of patient compliance (Johnson, 2008; O'Shea, 2000). Disulfiram is reportedly only clinically effective in patients who were fully compliant with taking their medication and were under supervision (Fuller et al., 1986). Acamprosate has been shown to be effective for alcohol dependence in European trials, but not in U.S. trials, and has a low incidence of side-effects (Anton et al., 2006; Bouza et al., 2004; Whitworth et al., 1996). To date, the opioid antagonist, naltrexone, appears to be the most effective medication for alcohol dependence (Anton et al., 2006; O'Malley et al., 1992; Volpicelli et al., 1992).

The Role of Delta Opioid Receptors in Ethanol Consumption

**2.1 Ethanol consumption in MOP-R knockout mice** 

models of ethanol consumption employed.

**2.2 MOP-R activation and ethanol consumption** 

**consumption and seeking** 

and Seeking: Implications for New Treatments for Alcohol Use Disorders 207

Mice with a genetic deletion of the MOP-R have reduced levels of ethanol intake and seeking in comparison to wild-type mice with a mixed C57/129sv background (Becker et al., 2002; Hall et al., 2001; Roberts et al., 2001; Roberts et al., 2000) (Table 1). Although one study using purebred C57BL/6 mice failed to show any difference in ethanol intake (van Rijn & Whistler, 2009), the differences in these studies may reflect the varying degrees of ethanol intake in mice with different genetic backgrounds (Yoneyama et al., 2008) and also the

The opioid receptor agonist, morphine increases ethanol (3-26%) intake in solutions containing sucrose (Hubbell et al., 1986; Reid & Hunter, 1984) suggesting an involvement of the opioid system in the reinforcing properties of ethanol (Table 1). Furthermore, microinjections of morphine into the rat nucleus accumbens (NAc), a brain region involved in the reinforcement pathway, increases ethanol and food intake (Barson et al., 2009). The selective MOP-R agonist, DAMGO, into the NAc increases intake of saccharin, salt, fat and ethanol (de Wet et al., 2001). Since morphine has the highest affinity for the MOP-R but also activity at KOP-R and DOP-R (Goldstein & Naidu, 1989), this may explain some of the nonselective effects on consummatory behavior. It cannot be ruled out that the effects of morphine on food and ethanol consumption may be related to morphine's rewarding effects (Gaiardi et al., 1991; Shippenberg et al., 2009; Shippenberg et al., 1996). Taken together, this

The MOP-R has been proposed to be primarily responsible for the action of naltrexone in reducing ethanol consumption and seeking (Stromberg et al., 1998a). Although naltrexone has consistently been shown to reduce ethanol consumption and seeking, the effects of opioid antagonists with higher selectivity for the MOP-R have been shown to produce mixed results (Ciccocioppo et al., 2002a; Hyytia & Kiianmaa, 2001; Marinelli et al., 2009) (Table 1). The selective MOP-R antagonist, CTOP (D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2), reduces operant ethanol responding in rats when administered into either the cerebroventricles or into the amygdala, but not when administered into the NAc or ventral tegmental area (VTA) (Hyytia & Kiianmaa, 2001). In rats trained to self-administer ethanol and subsequently extinguished from responding, CTOP had no effect of light/tone cueinduced reinstatement and only short-lasting reductions on context-induced reinstatement of ethanol-seeking (Marinelli et al., 2009). Furthermore, in a model of cue-induced reinstatement using visual and olfactory discriminative stimuli, the MOP-R1-selective antagonist, naloxonazine, reduced reinstatement but also produced some nonselective behavioral suppression (Ciccocioppo et al., 2002a). In the same study, naltrexone selectively inhibited cue-induced reinstatement of ethanol-seeking (Ciccocioppo et al., 2002a). The irreversible MOP-R-selective antagonist, clocinnamox, did not reduce responding for oral

data suggests that the MOP-R plays a more general role in ingestive behaviors.

**2.3 MOP-R antagonists and ethanol consumption and seeking** 

**2. The role of the Mu Opioid Peptide Receptor (MOP-R) in ethanol** 

#### **1.2 Preclinical studies with naltrexone**

Naltrexone has been shown to effectively reduce ethanol consumption and seeking in a large number of studies (Ciccocioppo et al., 2002a; Critcher et al., 1983; Franck et al., 1998; Gardell et al., 1996; Le et al., 1999; Nielsen et al., 2008; Simms et al., 2008; Stromberg et al., 1998a; Walker & Koob, 2008). Furthermore, intramuscular injections of naltrexone reduce intravenous (i.v.) or oral self-administration of ethanol in rhesus monkeys (Altshuler et al., 1980; Williams et al., 2001). Naltrexone reduces ethanol consumption in both low ethanol consuming rats (Stromberg et al., 1998a) and high ethanol consuming rats (Nielsen et al., 2008; Simms et al., 2008). However, the effects of naltrexone on ethanol consumption are non-selective as fat, sucrose and water intake are also reduced (Corwin & Wojnicki, 2009; Nielsen et al., 2008; Rao et al., 2008; Simms et al., 2008; Wong et al., 2009). Also, naltrexone reduces alcohol- and cueinduced reinstatement, but not foot-shock stress-induced reinstatement of ethanol-seeking in rodents (Ciccocioppo et al., 2002a; Le et al., 1999; Liu & Weiss, 2002).
