CLOZAPIN--CHOLINERGIC BASIS OF MESOLIMBIC SPECIFICITY

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The objective of this research is to gain insight into brain mechanisms of action of the clinically atypical antipsychotic drug clozapine. Unique among anti-schizophrenic drugs, clozapine produces virtually no extrapyramidal side effects or tardive dyskinesia, the often-serious neurological side effects common to other antipsychotic drugs which are thought to result from antipsychotic drug-induced dysfunction in the nigrostriatal dopamine (DA) system. A large body of research, both from this laboratory and elsewhere, strongly suggests that clozapine selectively acts as a functional DA antagonist in the mesolimbic DA system while virtually sparing the nigrostriatal system. This site-specificity explanation of clozapine's unique pharmacological profile is attractive on many grounds, not the least of which is the fact that current pharmacological methods for screening potential new antipsychotic drugs (which do not presently distinguish between mesolimbic and nigrostriatal specificities) could be modified to select only compounds having site-specific mesolimbic profiles. To this end, we have developed an adaptation of the electrical intracranial self-stimulation (ICSS) paradigm which is highly accurate in distinguishing clozapine's mesolimbic site-specificity from the more anatomically diffuse DA antagonism of classical neuroleptics. The paradigm used for these studies, and to be used for the present work, is that of chronic neuroleptic-induced functional DA hypersensitivity in both mesolimbic and nigrostriatal DA loci as assessed by the ICSS model. We now seek funds to extend our previous work by addressing the following question - is clozapine's mesolimbic functional stie-specificity a result of clozapine's powerful intrinsic anticholinergic potency? If "yes", development of new antischizophrenic agents with clozapine-like intrinsic anticholinergic potency would appear warranted. If "no", clozapine's unique atypical profile must logically derive from other neuropharmacological mechanisms, possibly including differential action on mesolimbic versus nigrostriatal presynaptic modulatory mechanisms. Also, if "no", the utility of the ICSS paradigm for screening potential new antipsychotic drugs would be immense, since it would not detect "false-positive" drugs merely on the basis of anticholinergic potency. Thus, either outcome would add significantly to our knowledge of atypical antipsychotic drugs, and aid development of new drugs with significantly lessened side effect liability. The health relatednes of such work is clear and straightforward - the development of better drugs for treating mental illness.