Behavioral sensitization is an enhanced responsiveness to a drug following prior exposure to the drug, and is a common property of many abused substances, including cocaine and amphetamine. The present study is primarily designed to continue our investigation of the mechanisms of sensitization to the locomotor activation and stereotypy induced by cocaine or amphetamine. The studies will involve mainly mice, but rats will also be used in selected studies. Two experimental approaches will be designed to discover mechanisms: First, relatively selective drugs will be tested in vivo to identify CNS effector systems that functionally change with, and are presumably involved in, behavioral sensitization; the involvement of these systems will be assessed in behavioral sensitization by the use of their appropriate agonists and antagonists. In the second approach, selective drugs will be employed to study in vitro the influence of sensitization on synaptic transmission and on neuronal membrane properties. The in vivo approach is predicted on the results of our previous studies that indicate that behavioral sensitization in the nigrostriatal system to amphetamine-induced stereotypy involved the excitatory amino acids (EAA), Ca++, calmodulin and protein synthesis, and that sensitization consists of at least two pharmacologically separable components, induction and expression. In the current proposal these studies will be continued to elucidate the role of EAA systems in the induction and expression of behavioral sensitization to indirect- (cocaine and amphetamine) and direct-acting DA agonists in both the nigrostriatal and mesolimbic pathways, to define intracellular mechanisms involved in behavioral sensitization, and t include the investigation of mechanisms of sensitization to morphine and the cannabinoids. The studies are designed to identify pharmacologically mechanisms that are involved in behavioral sensitization, including pre- and postsynaptic loci of the putative mechanisms. The electrophysiological studies will use corticostriatal brain slices and are designed to investigate the influence of sensitization on the effects of dopamine agonists and EAA agonists and antagonists on synaptic and membrane properties of the striatal neurons. The results of these studies will enhance our understanding of the participating systems in behavioral sensitization in the whole animal, and of the synaptic and neuronal membrane functions in the dopaminergic and glutamatergic systems that are involved in mediating the enhanced response characteristic of sensitized animals.
