NORMAL PSYCHOTIC COCAINE BEHAVIOR--NATURAL BASIS FOR CLOZAPINE

City College Of New York, New York NY

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Abstract

Description (Adapted from Application): The behavioral, as well as the biochemical manifestations, of the cocaine and the schizophrenic (psychotic) syndrome are similar; e.g., both increase DA and 5-HT release within mesolimbic brain neuronal pathways. Cocaine binds to presynaptic DA reuptake inhibitory receptors and 5-HT reuptake inhibitory receptors to prevent the removal of previously released DA and 5-HT in the synaptic. Cocaine users can develop full blown psychoses, and drugs used to alleviate psychoses are those that are used to alleviate cocaine dysfunction (Gawin et al., 1989). However, anti- psychotic drugs, which are dopamine antagonists, produce movement disorders and also produce a state of anhedonia (feeling of displeasure). Recently, the literature shows that 5-HT plays a significant interactive role with DA within A10 neural terminals importantly, in facilitating natural behavior as well as being a significant mediator which induces a temporal dysregulation between monoamines and movement in cocaine induced dysfunctional behavior (Broderick and Phelix, 1997). Therefore, clozapine, an atypical anti- psychotic agent, is selected for study because of its dual DA-ergic and 5-HT-ergic properties and because it produces little or no movement disorders or anhedonia (Meltzer, 1989). It has been thought that it is the action through the A10 pathway that is responsible for the lack of movement disorders accompanying this drug. This proposal addresses the real possibility that 5-HT-DA interactions in DA A10 circuits is responsible for clozapine's effects in psychotic behavior. Thus, the effects of clozapine alone and a clozapine-cocaine combination will be studied on DA and 5-HT within seconds of release, within nucleus accumbens of freely moving and behaving male Sprague Dawley rats; this will be done in vivo and in real time with in vivo micro-voltammetry on line and in vivo at the same time as behavioral parameters are monitored in the same animal. This paradigm offers unique spatial and temporal resolution for neurochemistry and correlated behavior. Preliminary data show that clozapine can alter normal and cocaine-induced dysfunctional behavior. The specific aims include a study of the underlying mesolimbic neuronal circuitry responsible for open-field behavior in male Sprague- Dawley rats, as these normal neural mechanisms relate directly to normal behavior; the studies are extended to clozapine's effects on cocaine behavior. Finally, DA1, DA2, DA4, and 5-HT2 receptor studies will be performed to study clozapine's mechanisms which can reset abnormal neuronal circuitry to regain normal movement.