There is now compelling evidence for a functional link between cocaine's indirect dopamine (DA) agonist properties and its abuse-related effects in animals and humans. Based on such findings, several DA agonists and antagonists have been proposed as candidate medications to serve either as pharmacological replacements for cocaine or as functional cocaine antagonists. However, no broadly effective pharmacotherapy for cocaine abuse has yet been identified, prompting exploration of alternative treatment strategies. One such strategy involves the use of a relatively new class of DA drugs, the DA partial agonists. Because of their dual agonist-like and antagonist-like properties, DA partial agonists could have important therapeutic advantages over conventional DA antagonists or full agonists, along with less restrictive side-effects and low abuse liability. Research proposed in this application will establish the agonist efficacy of selective DA partial agonists in vitro and in vivo and evaluate their potential utility for treating cocaine abuse and relapse in relevant non-human primate models. In vitro studies will determine the capacity of D/1 and D/2 partial agonists to either stimulate or inhibit adenylyl cyclase activity in squirrel monkey striatal tissue. Corresponding in vivo studies in the same species will: 1) characterize the agonist-like and antagonist-like behavioral effects of D/1 and D/2 partial agonists, 2) establish efficacy relationships by quantifying interactions of these drugs with selective DA antagonists and full agonists and 3) identify potential extrapyramidal and sedative side-effects. Evaluation of D/1 and D/2 partial agonists as pharmacotherapies for cocaine abuse will determine their capacity to modulate the effects of cocaine in: 1) monkeys trained to discriminate different doses of cocaine from vehicle, 2) monkeys trained to self- administer cocaine under a second-order schedule of i.v. drug injection, and 3) monkeys whose drug-seeking behavior is extinguished and subsequently reinstated by cocaine priming and cocaine paired stimuli. Additional studies will determine the selectivity of promising drugs to modulate cocaine-maintained versus food-maintained behavior and the degree to which the cocaine-modulating effect of these drugs are retained as the dose of cocaine is increased. The results will provide relevant information for establishing functional relationships between agonist efficacy and the cocaine-modulating effects of DA partial agonists and for identifying candidate medications to combat cocaine abuse and relapse.
| Park, W-K; Bari, A A; Jey, A R et al. (2002) Cocaine administered into the medial prefrontal cortex reinstates cocaine-seeking behavior by increasing AMPA receptor-mediated glutamate transmission in the nucleus accumbens. J Neurosci 22:2916-25 |
