Several literature reviews have examined tolerance and sensitization in the extended cocaine abuse withdrawal syndrome, and its relevance for recidivism. However, the potential for manipulating mechanisms underlying tolerance and sensitization for therapeutic purposes remains unclear. Our goal in this project is to examine the mechanisms underlying chronic cocaine tolerance at one week after withdrawal. Our focus is on an examination of the robust presynaptic dopamine autoreceptor mechanisms, along with parallel assessment of changes in dopamine reuptake parameters. Rats made tolerant by continuous cocaine administration will be compared with two control groups: 1) a positive drug control group made supersensitive to the behavioral effects of cocaine by daily intermittent injections of the same daily dose, and 2) saline controls. Our previous studies have established that tolerance extends out to at least seven days of withdrawal and is accompanied by dopamine autoreceptor supersensitivity as measured by several different methods ranging from behavioral, to in vitro HPLC and voltammetric, to antisense ODN probes. We are now proposing a set of experiments that further, and more extensively, characterize dopamine autoreceptor function during withdrawal from continuous or intermittent cocaine administration, using these same methods: 1) Behavior to examine the functional consequences of autoreceptor supersensitivity, 2) Voltammetry, with its ultra-fast temporal and spatial resolution allows for the assessment of both DA release and reuptake parameters in specific, localized brain areas, and 3) Antisense ODN's to reduce messenger RNA transcription of DA D2 receptors, to further assess the ODN effects on autoreceptor control of dopamine synthesis, neuronal firing rates, and dopamine mediated behaviors.
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