**1.3 Clinical studies with naltrexone**

A number of clinical studies have reported that naltrexone effectively reduces relapse in a subset of alcohol-dependent humans (Anton et al., 1999; Anton et al., 2006; O'Malley et al., 1992; Volpicelli et al., 1992) and is more effective at reducing heavy drinking (Pettinati et al., 2006). Alcohol-dependent patients that have a polymorphism in the OPRM1 gene encoding the mu opioid peptide receptor (MOP-R) with a mutation at A118G (Asn40Asp) have greater euphoric responses to alcohol, increased pain thresholds, greater susceptibility to AUDs and greater responses treatment with naltrexone (Anton et al., 2008; Bart et al., 2005; Oroszi et al., 2009; Oslin et al., 2003). More recently, the use of naltrexone in an extended– release intra-muscular (i.m.) depot formulation (Vivitrol) is more effective in patients who are able to abstain from drinking prior to treatment (O'Malley et al., 2007; Pettinati et al., 2009). Taken together, treatment with naltrexone appears to have the most consistent effects on drinking outcomes in subjects with A118G mutation.

#### **1.4 Pharmacological activity of naltrexone in reducing ethanol-mediated behaviors**

Naltrexone has the highest affinity for the MOP-R, moderate activity at the delta (DOP-R) and kappa (KOP-R) opioid peptide receptors, but without activity at nociceptin (NOP-R) and the sigma (SIG-R) receptors (Ananthan et al., 1999; Goldstein & Naidu, 1989; Takemori & Portoghese, 1984). There is a large body of evidence that suggests that the MOP-R plays a significant role in ethanol-mediated reward behavior (Becker et al., 2002; Ciccocioppo et al., 2002a; Gardell et al., 1996; Hall et al., 2001; Le et al., 1999; Reid & Hunter, 1984; Roberts et al., 2000) (Table 1). Ethanol has been reported to stimulate the activity of the endogenous opioids which target the MOP-R leading to increased basal dopamine release in the mesolimbic pathway Herz, 1997). Naltrexone's mechanism of action has been proposed to result from inhibition of ethanol-induced activity of endogenous opioid peptides and dopamine release *in vivo* (Benjamin et al., 1993; Gonzales & Weiss, 1998; Zalewska-Kaszubska et al., 2006; Zalewska-Kaszubska et al., 2008). In comparison, the roles of the other opioid subtypes on ethanol-mediated behaviors, such as the DOP-R (Krishnan-Sarin et al., 1995a; Roberts et al., 2001; Stromberg et al., 1998a) and KOP-R (Kovacs et al., 2005; Lindholm et al., 2001; Mitchell et al., 2005) are less well-defined.
