Transgenic superoxide dismutase mice: Increased mesolimbic µ-opioid receptors results in greater opioid-induced stimulation and opioid-reinforced behavior.

ABSTRACT

Consequent to the insertion of the human Cu/Zn-superoxide dismutase (SOD) transgene, SOD transgenic mice (SOD-Tg) show higher concentrations of the primary receptor thought to be involved in opioid reinforcement (µ). These increases are observed in areas specifically associated with the primary neurotransmitter thought to be involved in addiction (dopamine), and in neuroanatomical regions thought to mediate substance abuse (mesolimbic). In the present study we have tested the idea that these increases in µ-receptors are associated with parallel changes in µ-mediated behaviors. Baseline and morphine-induced locomotor activity were significantly altered in the SOD-Tg mice. A qualitative change in the nature of acute and chronic morphine-induced locomotor activity was demonstrated by a significant change in the slope of the dose-effect curve. SOD-Tg mice were significantly more sensitive to the locomotor stimulant effects of morphine. Intravenous morphine-reinforced behavior was also altered in the SOD-Tg mice. SOD-Tg mice showed significant dose-related changes in operant lever-press responding maintained by morphine injection and significantly greater amounts of behavior were maintained by the drug than by vehicle under an intermittent schedule of reinforcement. In addition, SOD-Tg mice increased operant responding for the drug when the amount of behavior required to maintain drug intake increased 10-fold under a PR schedule of reinforcement. In contrast, in wild-type mice morphine injections failed to maintain greater amounts of behavior than vehicle, there were no dose-related changes in behavior, and when response requirements increased under the PR schedule, morphine intake decreased significantly. Thus, SOD transgene insertion significantly enhanced the efficacy of morphine as a reinforcer.