Knowledge concerning the pharmacology, biochemical organization and regulation of central dopaminergic neurons is crucial for obtaining a better understanding of the role played by these dopamine systems in normal and abnormal behavior. It is well known that antipsychotic drugs have one property in common, namely an ability to block dopamine receptors and influence the function of central dopaminergic neurons. Although the dopamine receptor blocking properties of antipsychotic drugs have been appreciated for a long time it is still unclear whether this property is related to the therapeutic actions of this class of agents. We plan to continue to investigate the effects of acute and chronic administration of antipsychotic agents (both typical and atypical on central dopaminergic neurons in both rat and primate (Vervet monkey). Since the time course of the effects elicited by chronic administration of antipsychotic drugs on measocortical dopamine neurones appears to parallel the time course of the therapeutic action of these drugs in man we have focussed our studies on this interaction in bvoth rodents and monkeys. Our recent investigations have suggested that the reason the mesocortical dopamine systems do not develop tolerance is because they do not possess dopamine autoreceptors. The absence of autoreceptors has also been suggested to be responsible for the minimal responsiveness of several mesocortical dopamine systems to antipsychotic drugs administered in a single dose and for the unique responsiveness of some mesocortical dopamine systems to mild stress. Our proposed studies will address the question of whether the presence or absence of dopamine autoreceptors on some dopamine systems is responsible for the unique responsiveness of these dopamine systems. In addition, in view of our recent experiments indicating that dopamine autoreceptors may regulate protein carboxymethylase (PCM) activity and the fact that calmodulin is a good substrate for this enzyme, we will investigate whether the mode by which autoreceptors regulate dopamine synthesis and release may involve an autoreceptor mediated methylation of calmodulin. We will also determine whether apomorphine stimulated PCM can be utilized as a biochemical marker for dopamine autoreceptors.
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