Cocaine's action in the CNS is to limit the uptake of dopamine (DA). Undoubtedly, many of cocaine's behavioral manifestations, including the tendency for repeated, self-administration of cocaine, involve the actions of this neurotransmitter which has been shown to be intimately involved in many complex human behaviors. The prolongation of DA's presence in the synaptic cleft, as well as its potential depletion induced by repeated cocaine administration, is likely to induce changes in CNS DA receptors, as well as in the function of DA uptake sites. Measurement of these alterations may indicate to these receptors are potentially involved in the """"""""drug-seeking"""""""" and withdrawal behaviors associated with cocaine abuse, and may suggest some possible forms of treatment to counteract these changes. This laboratory has developed the methodology to localize and quantitate DA type-l (D1) and DA type-2 (D2) receptors, as well as DA uptake sites in the CNS. We will develop similar methodology for the microscopic localization of (3H)cocaine. These methods will be applied to the analysis of DA receptor subtype and uptake site changes in rats treated with various doses of cocaine for various periods of time. Initial experiments will be performed by receptor binding using striatal membrane homogenates in an effort to determine how the DA receptors and transport sites are affected by acute and chronic exposure to cocaine. Once the peak rime and dose for eliciting changes is established, some animals will be withdrawn from this exposure to see when the system recovers, if there is a rebound effect, or if there is permanent damage. In subsequent groups of animals treated for optimal time at the optimal dose, the microscopic localization of receptor/uptake site changes will be investigated using (3H)SCH 23390 (D1), (3H)sulpiride (D2), (3H)mazindol (uptake sites), as well as with (3H)cocaine itself. Comparison of changes in (3H)mazindol and (3H)cocaine binding will delineate to what extent other neurochemical changes encountered are indeed related to cocaine's action on DA uptake sites. Finally, the biochemical consequences of these receptor alterations will be investigated by studying striatal adenylate cyclase activity in its basal state, as well as in response to D1 or D2 receptor stimulation, in animals exposed to cocaine. DA levels and actual synaptosomal DA uptake will also be examined in treated animals. These studies will provide information on the potential sites of action of cocaine, how the presence of cocaine is translated into receptor effects, and how these changes ultimately alter cellular responsiveness in the treated and withdrawn animals.
Showing the most recent 10 out of 15 publications
