Intra‐ VTA Deltorphin, But Not DPDPE , Induces Place Preference in Ethanol‐Drinking Rats: Distinct DOR ‐1 and DOR ‐2 Mechanisms Control Ethanol Consumption and Reward

Background While there is a growing body of evidence that the delta opioid receptor ( DOR ) modulates ethanol ( E t OH ) consumption, development of DOR ‐based medications is limited in part because there are 2 pharmacologically distinct DOR subtypes ( DOR ‐1 and DOR ‐2) that can have opposing actions on behavior. Methods We studied the behavioral influence of the DOR ‐1‐selective agonist [D‐Pen 2 ,D‐Pen 5 ]‐Enkephalin ( DPDPE ) and the DOR ‐2‐selective agonist deltorphin microinjected into the ventral tegmental area ( VTA ) on E t OH consumption and conditioned place preference ( CPP ) and the physiological effects of these 2 DOR agonists on GABA ergic synaptic transmission in VTA ‐containing brain slices from L ewis rats. Results Neither deltorphin nor DPDPE induced a significant place preference in E t OH ‐naïve L ewis rats. However, deltorphin (but not DPDPE ) induced a significant CPP in E t OH ‐drinking rats. In contrast to the previous finding that intra‐ VTA DOR ‐1 activity inhibits E t OH consumption and that this inhibition correlates with a DPDPE ‐induced inhibition of GABA release, here we found no effect of DOR ‐2 activity on E t OH consumption nor was there a correlation between level of drinking and deltorphin‐induced change in GABA ergic synaptic transmission. Conclusions These data indicate that the therapeutic potential of DOR agonists for alcohol abuse is through a selective action at the DOR ‐1 form of the receptor.