This is a Shannon Award providing partial support for the research projects that fall short of the assigned institute's funding range but are in the margin of excellence. The Shannon Award is intended to provide support to test the feasibility of the approach; develop further tests and refine research techniques; perform secondary analysis of available data sets; or conduct discrete projects that can demonstrate the PI's research capabilities or lend additional weight to an already meritorious application. The abstract below is taken from the original document submitted by the principal investigator. Cocaine is a powerful addicting psychostimulant that causes severe toxicities in humans and animal models, particularly after repeated exposure to the drug. One of the major hypothesis pertaining to psychostimulant-induced toxicity is the development of increased sensitivity to the drug with its continued use, a phenomenon termed """"""""sensitization."""""""" In animal models, cocaine-induced sensitization is primarily manifested by increased sensitivity to locomotor stimulation and stereotype (behavior sensitization) and intensified seizure susceptibility (pharmacological kindling). The precise neurochemical pathways underlying the development f such sensitization are not clear. Elucidation of mechanisms responsible for these outcomes may have important implications for understanding cocaine-induced behavioral changes, and drug-related toxicities in humans. The long term goal of this project is to identify neurochemical correlate(s) for the development of sensitization to cocaine. Increasing evidence supports the involvement of excitatory amino acids in psychostimulant-induced sensitization. Particularly, studies suggest a role for N-methyl-D- aspartate (NMDA) type of glutamate receptors in cocaine-induced sensitization, and our recent data imply the involvement of brain nitric oxide synthase (NOS) in the process of cocaine-induced kindling. Our working hypothesis is that cocaine-induced kindling is associated with upregulation of the NMDA receptor; hence, increase in NMDA receptor activity could lead to the stimulation of brain NOS function. Over- production of NO may further confer to the process of sensitization and kindling, by modulating the release of various neurotransmitters. We postulate that the NMDA/NOS pathway may represent one of the neurochemical correlates of sensitization to cocaine. Our first goal is to determine if the regulation of ionotropic glutamate receptors underlies the induction and maintenance of cocaine kindling. The second goal is to investigate if the regulation of ionotropic glutamate receptors underlies the mechanism of sensitization to psychostimulant- induced stereotypy and drug-induced kindling by epileptogenic agents, other than cocaine. These studies will establish if a common determinant underlies the development of sensitization to stereotypy and cocaine kindling. Our third goal is to investigate the role of brain NOS in the mechanism of sensitization to cocaine and to determine if there is a functional relationship between NMDA receptor activation and brain NOS activity in this process. Taken together, the proposed studies should enable us to clarify the role of inotropic glutamate receptors and brain NOS in the induction and maintenance of sensitization to cocaine. Elucidation of neurochemical correlate(s) that correspond to the CNS toxicity of cocaine should advance the development of new therapeutics for the management of patients with cocaine toxicity.
