The dopamine system is a major neurotransmitter system in the mammalian brain. It regulates numerous physiological responses and is implicated in the pathophysiology of several disorders, in particular drug addiction, Parkinson's disease and schizophrenia. Until recently, dopamine was thought to interact with only two receptors, the D1 and D2 dopamine receptors. This two receptors-concept began to change when it was shown, two years ago, that there exist two different forms of D2 receptor and when, last year, a distinct and unexpected dopamine receptor was cloned, the D3 receptor. This concept is going to evolve even further with our discovery of another new dopamine receptor, the D4 receptor. The D4 receptor is especially interesting because of its potential involvement in the pathogenesis of schizophrenia. Until now, it was the D2 receptor which was specifically involved in the etiology of schizophrenia, since most neuroleptics are D2 receptor antagonists. However several observations about the D4 receptor suggest that it might have a predominant role in that disease. First, preliminary studies show that the D4 receptor is present in brain tissues expected to be involved in the etiology of schizophrenia. Second, its pharmacological profile indicates that it is also the target of common neuroleptics. Third, most interestingly, it has the highest affinity of all the dopamine receptors for clozapine, a particular antipsychotic drug which does not produce the extrapyramidal side effects that plague most neuroleptics directed at the D2 receptor. By using the D4 receptor clone, we propose to investigate several aspects of this hypothesis. First, in situ hybridization and immunocytochemical techniques will be used to locate neurons expressing D4 receptors, a task that our preliminary Northern blot analysis could not achieve, and determine whether the D4 receptor is present in the neuronal pathways expected to be important in the etiology of schizophrenia. Second, the D4 receptor's abilities to induce second messenger systems will be tested in a variety of cellular environments. These experiments will determine which intracellular changes are caused by D4 receptor stimulation and might differentiate it from the D2 receptor at the biological level. The hallmark of the D4 receptor is its ability to recognize clozapine. In contrast to D2 receptor, D4 receptor blockade seems to not produce locomotor side effects. It is therefore important to determine which D4- specific structural features allow for clozapine binding. These will be defined by site-directed mutagenesis. Finally, the diversity of the responses mediated by the dopamine system suggests the possible existence of other dopamine receptors. By using a low-stringency screening approach, we have already been able to isolate a gene fragment which codes for a putative D4-related receptor. In addition, the possible existence of D4-related receptors will be checked in a battery of tissues. Our last aim is to characterize these putative D4-related receptors by defining their pharmacological profile, biological activities and tissue distribution.
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