Endogenous κ opioid receptor systems modulate the responsiveness of mesoaccumbal dopamine neurons to ethanol

Background: Endogenous kappa-opioid receptor (KOPR) systems modulate the actions of several drugs of abuse. Their role in modulating the effects of ethanol is unknown. An increase in nucleus accumbens extracellular dopamine (DA) has been implicated in mediating the rewarding and locomotor-activating effects of ethanol and virtually all drugs of abuse. The present microdialysis studies were conducted to determine whether the lack of KOPR alters ethanol-evoked DA levels in the nucleus accumbens of naive mice and whether a similar effect is observed in mice repeatedly exposed to ethanol. Methods: Gene deletion techniques were used in conjunction with in vivo microdialysis to examine the influence of lack of KOPR on ethanol-evoked DA in the nucleus accumbens. To determine whether pharmacological inactivation of KOPR produces similar effects in naive mice and those repeatedly exposed to ethanol, the KOPR antagonist norbinaltorphimine (n-BNI) was administered in wild-type mice before repeated air or ethanol vapor inhalation. Microdialysis was conducted 24 hours later. Results: Acute ethanol administration increased DA levels in the nucleus accumbens of wild-type mice. In littermates lacking the KOPR gene, ethanol-evoked DA levels were enhanced. Prior ethanol exposure reduced ethanol-evoked DA levels in vehicle-treated and n-BNI-treated mice. Statistical analysis, however, revealed a significant main effect of n-BNI, indicating that KOPR blockade increased ethanol-evoked DA levels in naive mice and repeated ethanol exposure attenuated. but did not abolish, this effect. Conclusions: These findings demonstrate that inhibition of KOPR leads to increased sensitivity to the DA-releasing effects of ethanol in the nucleus accumbens.