Abuse of cocaine has been linked to the development of psychiatric disorders and seizures. These effects are probably not simply due to overdose, but instead may be related to the repetitive abuse of the drug. Repetitive, intermittent administration of cocaine produces progressive changes in behavior and/or augmentation of the acute behavioral effects of cocaine in several species including rats and monkeys. An augmented response to cocaine can be elicited at least a month after the last cocaine injection and may even be permanent. Thus, this long-lasting alteration in sensitivity to cocaine implies changes in neurochemical and neurophysiological substrates subserving these behaviors. There is reason to believe that these changes may be important in the development of psychiatric symptomatology associated with chronic cocaine abuse and many investigators believe that sensitization to psychomotor stimulants such as cocaine has relevance as a model for the development of endogenous psychiatric diseases such as anxiety/panic disorder, depression and paranoid schizophrenia. It may also be relevant to cocaine """"""""addiction"""""""" and """"""""craving"""""""" which undoubtedly play a role in its pattern of abuse. We propose to test the hypothesis that behavioral sensitization in the rat is mediated by alterations in dopaminergic neurotransmission or by neuronal influences directly involved in its regulation. We also propose that these alterations will be reflected in systems modulated by dopaminergic output. We will use a combination of in vivo and in vitro techniques to answer questions concerning dopamine synthesis, metabolism, release, and reuptake in three primary projection fields: 1) striatum, 2) nucleus accumbens, and 3) prefrontal cortex. These studies will also include the cell body areas for the nigrostriatal and mesolimbic/mesocortical systems. These studies will also determine the effects of cocaine sensitization on systems such as the striatal cholinergic and nigral GABAergic interneurons which are modified by dopaminergic activity.
