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

Alcohol Clin Exp Res. 2014 Jan;38(1):195-203. doi: 10.1111/acer.12246. Epub 2013 Aug 27.


Background: While there is a growing body of evidence that the delta opioid receptor (DOR) modulates ethanol (EtOH) 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 EtOH consumption and conditioned place preference (CPP) and the physiological effects of these 2 DOR agonists on GABAergic synaptic transmission in VTA-containing brain slices from Lewis rats.

Results: Neither deltorphin nor DPDPE induced a significant place preference in EtOH-naïve Lewis rats. However, deltorphin (but not DPDPE) induced a significant CPP in EtOH-drinking rats. In contrast to the previous finding that intra-VTA DOR-1 activity inhibits EtOH consumption and that this inhibition correlates with a DPDPE-induced inhibition of GABA release, here we found no effect of DOR-2 activity on EtOH consumption nor was there a correlation between level of drinking and deltorphin-induced change in GABAergic 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.

Keywords: Delta Opioid Receptor; Ethanol; Place Preference; Reward; Self-Administration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Drinking / psychology
  • Analgesics, Opioid / administration & dosage
  • Animals
  • Conditioning, Psychological / drug effects
  • Conditioning, Psychological / physiology
  • Enkephalin, D-Penicillamine (2,5)- / administration & dosage*
  • Ethanol / administration & dosage*
  • Injections, Intraventricular
  • Male
  • Oligopeptides / administration & dosage*
  • Rats
  • Rats, Inbred Lew
  • Receptors, Opioid, delta / agonists*
  • Receptors, Opioid, delta / physiology
  • Reward*
  • Ventral Tegmental Area / drug effects*
  • Ventral Tegmental Area / physiology


  • Analgesics, Opioid
  • Oligopeptides
  • Receptors, Opioid, delta
  • deltorphin
  • Ethanol
  • Enkephalin, D-Penicillamine (2,5)-