The proposed experiments, which build on previous work, are directed toward the examination of the interaction of the opiate and dopamine systems in mediating the drug-induced euphoria caused by the abused opiates, e.g. morphine or heroin and the psychomotor stimulants, e.g. cocaine. Various experimental manipulations will be evaluated by changes that they cause in the effects of cocaine or morphine on the threshold for brain-stimulation reward (BSR), a model of drug-induced euphoria, as well as changes in local cerebral metabolic rate of glucose (LCMRglu). Because of the findings that the olfactory tubercle (OT) and the nucleus accumbens (NACC) are probably involved in the rewarding effects of the abused opiates and the psychomotor stimulants, experiments will be carried out to determine if lesions of the OT and the NACC differentially effect the action of morphine and cocaine on BSR. Since morphine not only causes euphoria in humans, but is the prototypic opiate analgesic, its effects on LCMRglu will be compared in animals working to receive rewarding brain stimulation with animals who are specific opiate receptor ligands will be compared. Because three high doses of morphine administered to a rat within a 24 hour period result in a marked oral stereotypy and subsequent re-expression of the stereotypy after the administration of low doses of morphine or dopamine agonist, it will be determined whether the three high doses of morphine will result in the increased sensitivity of the response of the animals to morphine and cocaine's effect on BSR. Also a low challenge dose of morphine or a dopamine agonist administered up to 450 days after the original three dose treatment of morphine results in the re-expression of the oral stereotypy. Experiments will be carried out to determine if these long term effects are identified with alterations in LCMRglu, dopamine release and regulation, as well as changes in dopamine and/or opiate receptors. The proposed experiments have implications for the development of drugs for the treatment of drug abuse and the uncovering of potential long term sequelae of the use of abuse substances.
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