• Grandy, David (PI)
  • Civelli, Olivier (PI)

    Project: Research project

    Project Details


    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.
    Effective start/end date5/1/924/30/96


    • National Institutes of Health
    • National Institutes of Health: $188,227.00


    • Medicine(all)

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