Role of dopamine D1 receptors in morphine withdrawal

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DESCRIPTION (provided by applicant): Opiate dependence in humans is characterized by an abstinence syndrome that includes dysphoria and depression. Alleviation of these aversive withdrawal symptoms is thought to be a primary motivation for continued drug taking. The mesolimbic dopamine system, which includes the nucleus accumbens (NAc), plays an important role in both the rewarding and aversive effects of opiates such as morphine. The purpose of this NRSA proposal is to examine how activation of dopamine D1 receptors in the NAc affects molecular processes and behavior in morphine-dependent rats. D1 receptor stimulation in the NAc activates the transcription factor cAMP response element binding protein (CREB), which has been associated with aversive states. One aim of this proposal is to determine the effect of D1 receptor stimulation on CREB activation in the NAc of rats during morphine withdrawal. CREB regulation in the NAc may contribute to aversive states associated with morphine withdrawal. A second aim is to determine how activation of D1 receptors specifically in the NAc affects morphine withdrawal-induced conditioned place aversions in rats. A final aim is to determine how activation of D1 receptors in the NAc of morphine-dependent rats affects intracranial self-stimulation, an operant behavior sensitive to rewarding and aversive states. Together, these studies may lead to an increased understanding of the mechanisms underlying opiate dependence. This work may lead to new pharmacotherapies that can alleviate aversive and dysphoric states associated with opiate withdrawal and perhaps reduce relapse to drug taking.