The overall goal of the proposed research is the study of the effects of cocaine on dissociated mouse hippocampal neurons (HN) in cell cultures. The techniques used will be electrophysiological, biochemical, pharmacological, and autoradiographic. Cocaine will be shown to bind specifically to intact living HN. The acute effects (within minutes) of cocaine and cocaine analogues on HN active and chemosensitive membrane properties and HN synaptic connections will be established using intracellular micropipette recordings. The effects of chronic (hours to days) cocaine and cocaine analogue exposure to HN in culture on membrane and synaptic properties and 3H-cocaine binding will be determined. This prolonged exposure will elucidate changes in neuronal function which underlie psychological dependence and """"""""pharmacologic kindling"""""""". The proposed research represents a most direct way to study the actions of cocaine on the input/output relations of neurons in a brain region known to be particularly sensitive to psychoactive drugs. Cell tissue cultures allow for cellular mechanistic answers to fundamental aspects of neural signalling. The results should elucidate the primary action of cocaine on neurons, distinguish between these actions and chronic effects which form the basis of psychological dependence and seizure generation, and determine the role cocaine plays at the level of the single neuron. This knowledge will ultimately help develop the most rational therapy in cocaine dependence and ultimately help separate therapeutic actions from untoward side effects in clinical use.
