The proposed studies aim to characterize the site and mechanism of action of kappa-opioid receptor agonists in preventing the sensitization or """"""""reverse-tolerance"""""""" which develops to the rewarding effects of cocaine following its repeated administration. Our objectives are to determine whether: 1) activation of kappa-opioid receptors located in regions comprising the mesocorticolimbic dopamine (DA) system, is sufficient to prevent the sensitization which develops to the rewarding effects of cocaine; 2) the modulatory effects of systemically and intracerebrally administered kappa-agonists upon sensitization are correlated with a suppression of cocaine-induced increases in extracellular DA levels within the nucleus accumbens (NAC), a projection site of mesocorticolimbic neurons and 3) inactivation of kappa-opioid receptors exacerbates the development of the sensitization process. The conditioned place preference and intravenous self-administration paradigms, will be used to map the site of action of kappa-agonists in modulating the development of sensitization and to examine whether microinjection of a kappa-opioid receptor antagonists exacerbate the development of sensitization. The technique of microdialysis will be used to monitor extracellular DA levels within the NAC in response to the administration of cocaine and kappa-opioid receptor ligands. We hypothesize that exogenously applied kappa-opioid agonists prevent sensitization to the rewarding effects of cocaine by activating opioid receptors located within the NAC and thereby suppressing cocaine-induced increases in extracellular DA levels within this specific brain region. These studies will provide important information regarding the site of action of kappa-opioid agonists in modulating adaptive behavioral responses which occur in response to repeated cocaine administration and may contribute to the development of an effective pharmacological treatment for cocaine addiction.
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