The non-selective opioid antagonist, naltrexone, has been previously shown to reduce ethanol consumption in humans (O'Malley et al. 2002; Volpicelli et al. 1992) and animals (Critcher et al. 1983; Ulm et al. 1995; Gardell et al. 1996; Rodefer et al. 1999; Stromberg et al. 2002; Becker et al., 2002; Roberts et al. 2000) and has since been approved and marketed for the treatment of alcohol dependence in humans. However, recent reports have indicated that naltrexone appears to have limited therapeutic success (Swift 1999; Bouza et al. 2004) which may result from compliance issues arising from possible side-effects such as nausea, vomiting or headache, and possible hepatotoxicity with higher doses (Volpicelli et al. 1992; Croop et al. 1997; Hartmann 1997).  Previous studies indicate that mu opioid (MOP), delta opioid (DOP) and kappa opioid (KOP) receptors are involved in different aspects of ethanol-mediated behaviors (Matsuzawa et al. 1999; Hyytia and Kiianmaa 2001; Margolis et al. 2003; Mitchell et al. 2005). Results from many laboratories suggest that the MOP receptor mediates the rewarding properties of ethanol during ethanol consumption and relapse in both rats and mice behaviors (Matsuzawa et al. 1999; Hyytia and Kiianmaa 2001; Margolis et al. 2003; Mitchell et al. 2005). In contrast, data surrounding the DOP and KOP receptors is not as conclusive.

DOP receptor agonists increase ethanol intake in rats and DOP receptor antagonists decrease ethanol intake in rats as well as MOP receptor antagonists (Le et al. 1993; June  et al. 1999; Hyytia and Kiianmaa 2001; Ciccocioppo et al. 2002; Matsuzawa et al. 1999).  In contrast, the DOP receptor knockout mice increase ethanol intake (Roberts et al. 2001).  These conflicting results have been hypothesized by Roberts et al. (2001) to be attributed to an increased anxiety-like behavior in DOP receptor knockout mice (Filliol et al. 2000).  MOP receptor knockout mice display a decrease in anxiety-like behavior (Filliol et al. 2000) and MOP receptor actions in mice have been reported to be anxiolytic (Asakawa et al. 1998).  Thus the first aim of this project is to determine if the DOP receptor is a valid target for the treatment and modulation of ethanol-mediated behaviors.  A similar conflicting set of data exists for the KOP receptor.  KOP receptor agonists decrease ethanol intake in rats and KOP receptor antagonists increase ethanol intake in rats (Sandi et al. 1988; Lindholm et al. 2001; Matsuzawa et al. 1999; Mitchell et al. 2005). In contrast to the KOP receptor antagonist experiments in rats, KOP receptor knockout mice have decreased self-administration of ethanol and saccharin and a higher preference for quinine. It has been suggested that this is in line with previous observations of opioid involvement in maintenance of food intake and that the dynorphin/KOP receptor system might affect orosensory reward through central mechanisms (Kovacs et al. 2005).

Ethanol has been reported to stimulate the activity of the endogenous opioids, b-endorphins and enkephalins, which target the MOP and DOP receptors, respectively (Herz 1997).  Opioidergic excitation of dopamine neurons in the ventral tegmental area involves predominantly MOP receptors (Tanda and Di Chiara 1998) with KOP receptor activation causing inhibition (Margolis, Hjelmstad et al. 2003).  Activation of MOP receptors in the ventral tegmental area subsequently leads to dopamine release in the nucleus accumbens (Leone et al. 1991; Spanagel et al. 1992).  However, modulation of dopamine terminal activity also reportedly involves DOP receptors (Borg and Taylor 1997).  Hence the reduction of ethanol intake by MOP receptor antagonists may involve inhibition of firing of ventral tegmental area dopamine neurons that project to the nucleus accumbens with DOP receptor antagonists possibly causing inhibition of dopamine release from axon terminals in the nucleus accumbens (Herz 1997; Ciccocioppo et al. 2002).