Cocaine is thought to exert most of its CNS effects by blocking the reuptake of dopamine (DA), resulting in an increase in the concentration DA in the extracellular space (and presumably in the synapse). The agonist that actually interacts with traditional receptor mechanisms in the CNS to produce the final behavioral response is endogenous DA. Using the technique of in vitro microdialysis it is now possible to monitor extracellular levels of both cocaine and dopamine in the behaving animal. In addition, an indication of at lease one post-synaptic response is also accessible the concentration of extracellular cAMP. Access to the concentrations of these intermediates in the CNS makes it possible to address quantitative issues regarding the mediation of the response to cocaine by endogenous DA. We will: 1) characterize the statistical properties of these measurements as they relate to the behavioral response to acute cocaine administration. 2) determine the extent to which quantitative predictions may be made regarding the effect of the DA antagonist, fluphenazine on the behavioral and neurochemical (extracellular cyclic amp) responses to cocaine. This will be accomplished by analyzing the behavior as a classical null pharmacological experiment with extracellular DA as the agonist. Methods for performing this analysis with ordered categorical behavioral data. i.e. rating scales are developed in the proposal. 3) We will make similar determinations regarding the effects of more specific DA antagonists which discriminate between subtypes of the DA receptor. 4) Lastly, we will determine the extent to which the effects of repeated cocaine treatments may be explained in a similar fashion.
| Jaworski, J N; Gonzales, R A; Randall, P K (2001) Effect of dopamine D2/D3 receptor antagonist sulpiride on amphetamine-induced changes in striatal extracellular dopamine. Eur J Pharmacol 418:201-6 |
