The effect of ethanol consumption on dopamine and ethanol concentrations in the nucleus accumbens during the development of reinforcement and the involvement of the k-Opioid receptor in the modulation of dopamine activity during ethanol self-administration

textA key process associated with the development of reinforcement is the release of dopamine in the nucleus accumbens from mesolimbic cells of the ventral tegmental area. There is evidence that accumbal dopamine activity increases during operant ethanol self-administration, but it is unknown whether this effect is related to appetitive or consummatory aspects of behavior. Neuroadaptations in the mesolimbic system during the development of ethanol reinforcement are also unclear. Studies were undertaken to address these issues, all of which measured dopamine and ethanol concentrations in the nucleus accumbens of rats using a procedure in which a fixed number of operant responses was followed by 20 min of ethanol availability. An initial exposure to 5 or 10% ethanol (with sucrose) resulted in reduced intake levels compared to controls and no alterations in dopamine concentrations during consumption. In contrast, during limited self-administration (about 7 days) of 10% ethanol (with sucrose) or long term self-administration (over 40 days) of 10% ethanol, a brief rise in dopamine levels occurred within 5 min of access that corresponded to consumption. During the period in which the dopamine response occurred, brain ethanol concentrations were low but increased progressively thereafter, indicating a rapid dissociation between the two time courses. Together these results suggest that the dopamine response was due to factors other than the pharmacological properties of ethanol, such as the stimulus cues of the solution during acquisition. These data also suggest that a dopamine response to ethanol occurs after the development of motivated ethanol drinking. Furthermore, accumbal dopamine activity during ethanol self-administration may be under the regulation of the endogenous κ-opioid system, acting to suppress dopamine activity and ethanol intake. We tested this hypothesis by blocking the κ-opioid receptor with nor binaltorphimine during ethanol self-administration. Nor-binaltorphimine treatment resulted in a brief increase in dopamine concentration 20 min after ethanol drinking commenced. The latent rise in dopamine levels correlated positively with accumbal ethanol concentration, suggesting that kappa blockade uncovered a pharmacological stimulation of dopamine activity by ethanol.Pharmac