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

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

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

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

The Role of Delta Opioid Receptors in Ethanol Consumption

**Opioid Receptor** 

MOP-R

DOP-R

Knock -out mice

(1,2,3)

(4,24)

KOP-R (5) (46)

NOP-R (42) No Effect

(21)

(16)

(33,38)

(6,7,8,10,20,18,3 6,47,48) No Effect (10)

(10,14,15,20,24)

No Effect (7,13)

**3.3 Ethanol consumption and seeking with DOP-R antagonists** 

different roles of subtypes of the DOP-R on ethanol-mediated behaviors.

 (6) (18,33) No Effect (22,23)

 (21,24) (22,23,25)

 (19,23) No Effect (22)

(35, 45)

(33,34,35,37,38 ,40,45)

SIG-R - (44) - (43) (31) (44) -

Table 1. The roles of opioid receptors in ethanol consumption and seeking in rats and mice. 1. Roberts et al., 2000; 2. Hall et al., 2001; 3. Becker et al., 2002; 4. Roberts et al., 2001; 5. Kovacs et al., 2005; 6. Critcher et al., 1983; 7. Stromberg et al., 1998a; 8. Gardell et al., 1996; 9. Hyytia & Kiianmaa, 2001; 10. Franck et al., 1998; 11. Ciccocioppo et al., 2002a; 12. June et al., 1999; 13. Ingman et al., 2003; 14. Krishnan-Sarin et al., 1995a; 15. Krishnan-Sarin et al., 1995b; 16. Mitchell et al., 2005; 17. Holter et al., 2000; 18. Reid & Hunter, 1984; 19. Lindholm et al., 2001. 20. Nielsen et al., 2008; 21. Margolis et al., 2008; 22. Barson et al., 2009; 23. Barson et al., 2010; 24. van Rijn & Whistler, 2009; 25. van Rijn et al., 2010; 26. Walker et al., 2011 ; 27. Walker & Koob, 2008; 28. Marinelli et al., 2009; 29. Nielsen et al., 2011; 30. Le et al., 1999; 31. Sabino et al., 2011; 32. Kuzmin et al., 2007; 33. Ciccocioppo et al., 2007; 34. Ciccocioppo et al., 2003; 35. Ciccocioppo et al., 1999; 36. Simms et al., 2008; 37. Economidou et al., 2008; 38. Ciccocioppo et al., 2002b. 39. Martin-Fardon et al., 2000; 40. Cifani et al., 2006 41. Ciccocioppo et al., 2004; 42. Sakoori & Murphy, 2008; 43. Sabino et al., 2009a; 44. Sabino et al., 2009b; 45. Economidou et al., 2006; 46.

Sandi et al., 1990.; 47. Stromberg et al., 2002; 48. Stromberg et al., 1998b.

**Voluntary ethanol consumption Operant responding** 

and Seeking: Implications for New Treatments for Alcohol Use Disorders 209

The administration of DOP-R antagonists decreases ethanol consumption and seeking in rats (Franck et al., 1998; Hyytia & Kiianmaa, 2001; June et al., 1999; Krishnan-Sarin et al., 1995b; Marinelli et al., 2009; Nielsen et al., 2011; Nielsen et al., 2008). However, DOP-R antagonists also have been shown to not affect (Ingman et al., 2003; Stromberg et al., 1998a) or increase ethanol intake (Margolis et al., 2008) (Table 1). Factors likely contributing to these disparities include the length of ethanol exposure, the route of drug administration, different types of drinking models that induce low, moderate and high ethanol consumption, the rodent strains used (such as alcohol-preferring rats) and potential

> **Effects on Ethanol Consumption and Seeking Decreased, Increased, or No Effect (Reference)**

**for ethanol** 


(9, 12) - (11,28,29) -

(26, 27) - No Effect

(32,37,41) No Effect (37)

No Effect (28)

(17)

Antagonists Agonists Antagonists Agonists Antagonists Agonists

(9,27,30.32)


**Reinstatement of ethanol-seeking** 

(32)

(17)

39, 41)


ethanol in rhesus monkeys, except when it was co-administered with naltrexone (Williams & Woods, 1998). These studies suggest that naltrexone's ability to reduce ethanol consumption and seeking may be mediated via a non-MOP-R.
