Involvement of mu-opiate receptors in ethanol-induced accumbal dopamine response

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Tang, Man Amanda, 1972-

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The goal of this dissertation was to investigate the role of µ-opiate receptors in the regulation of ethanol-induced accumbal dopamine release using µ-opiate receptor knockout mice. Accumbal dopamine response to ethanol (2 g/kg, intraperitoneal injection, i.p.) was characterized in one of the parental strains that the knockout mice were developed on, C57BL/6; two strains of µ-receptor knockout mice (C57BL/6 x 129SvEv, C57BL/6 background); and the mixed genetic background mice pretreated with µ1-receptor antagonist, naloxonazine. Ethanol increases accumbal dopamine release in both male and female C57BL/6 mice. Thus, the C57BL/6 strain is a justifiable model system for studying the mechanisms involved in ethanol regulation of mesolimbic dopamine activity. Habituation to the i.p. procedure is required to detect a significant increase in accumbal dopamine response compared with saline controls in males. Therefore, it was routinely used for the remaining experiments. Accumbal dopamine response to ethanol was abolished in female, not in male knockout mice (C57BL/6 x 129SvEv). Similar results were obtained in the mixed genetic background mice that were pretreated with naloxonazine. The similarity of the results from the naloxonazine study to that of the knockout model suggests the absence of neurochemical compensations due to gene deletion. Finally, a decrease in accumbal dopamine release induced by ethanol was observed in both male and female knockout mice (C57BL/6). The gender difference seen in the mixed genetic background knockout mice may be due to the influence of one of the parental strains, 129SvEv, on the hybrid strain of the knockout mice. The results with both gene deletion and pharmacological blockade of the µ- opiate receptor support the hypothesis that µ-opiate receptors are a critical component of the mechanism by which ethanol stimulates accumbal dopamine release.



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