There has been extensive progress on elucidating the function of the opioid family of peptides and receptors. Understandably, much of the emphasis to date has been on the mu opioid (MOP) receptor, since it is the target of the powerful analgesic and addictive effects of morphine and it congeners. However, our extensive knowledge of the central actions of MOP has not led to new strategies for the treatment of drug addiction. Kappa opioid (KOP) receptors have a wide distribution throughout the CNS that largely parallels that of MOP receptors including subcortical structures associated with motivation and reward. KOP receptor agonists have powerful behavioral effects, which are typically opposed to the behavioral effects of MOPs. For example, while the MOP receptor agonist DAMGO produces conditioned place preference in rats, the KOP receptor agonist U69593 produces conditioned place aversion. Moreover, KOP receptor agonists clearly alter behaviors associated with drugs of abuse and the gene for the KOP receptor has been linked to addictive behaviors. KOP receptors appear to play a regulatory role in reward circuitry, making them an inviting target for the treatment of addiction. Finally, the KOP system is highly plastic: both KOP receptors and its endogenous ligand, dynorphin are altered following exposure to drugs of abuse. In fact, the plasticity of this system provides a plausible mechanism for the development of addiction. This evidence suggests that a complete understanding of opioid actions in reward circuitry depends upon elucidating the action of dynorphin and KOP receptors in reward circuitry. Despite its medical significance, both as an underlying mechanism as well as being a possible target for the treatment of addiction, much remains to be understood about the KOP receptor's basic functions as well as how those functions are modified by drugs of abuse. This proposal aims to examine the regulation of kappa opioid receptor function in the nucleus accumbens (NAc) shell following exposure to psychostimulants. Specifically, we propose to test the hypothesis that psychostimulant exposure produces a dopamine dependent increase in dynorphin release in the NAc, which causes a down-regulation of the KOP receptor-mediated inhibition of glutamate release.
Specific aims will test both the extracellular and intracellular mechanisms underlying this effect, as well as testing the specificity of the effect on glutamate release.
