Research is proposed to investigate jointly the behavioral and neurochemical effects of cocaine and related drugs in non-human primates. Quantitative studies will be conducted to determine the actions of cocaine, cocaine analogs and metabolites, other psychomotor-stimulant drugs, and selective monoamine transport inhibitors. Correspondence between empirical relations obtained in these coordinated studies will serve as a basis for identification of neural targets mediating the behavioral effects and abuse of cocaine. The efficacy of potential antagonists for cocaine will also be determined quantitatively in behavioral experiments. One major objective will be to determine the effects of full dose ranges of cocaine-related drugs on three types of behavior under schedules control. Stimulant effects of drugs will be assessed in monkeys responding under fixedinterval schedules involving different consequences. Interoceptive effects will be evaluated using drug-discrimination procedures involving cocaine and the selective dopamine transport inhibitor GBR 12909. Abuse liability will be investigated using i.v. drug self-administration techniques. A second objective will be to determine the effects of full concentration ranges of cocaine- related drugs at pharmacologically relevant binding sites for cocaine and uptake sites for dopamine in vitro. High, moderate and low affinity binding sites for 3H-cocaine will be characterized in membranes prepared from monkey caudate-putamen and nucleus accumbens. Parallel studies will be conducted for dopamine uptake by labeling the transporter with 3H-GBR 12935 in membranes and by determining accumulation of 3H-dopamine in slices. Binding sites for 3H-cocaine and 3H-GBR 12935 will be solubilized and evaluated for drug binding profiles, recovery and molecular weight to determine relationships between cocaine binding and dopamine transport sites. A third objective will be to determine the effectiveness of novel dopamine antagonists and adenosine analogs in counteracting the behavioral effects of cocaine. Drugs differing widely in affinity for dopamine D1 and D2 and adenosine Al and A2 receptors will be studied over a range of doses to evaluate their potential as antagonists of the stimulant, interoceptive and reinforcing effects of cocaine.
| 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 |
