ANTIPSYCHOTICS AND RECEPTOR DESENSITIZATION MACHINERY

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DESCRIPTION: (Adapted from applicant's abstract) Arrestins and G protein-coupled receptor kinases (GRKs) participate in homologous desensitization of hundreds of G protein-coupled receptors (GPCRs). The rate and extent of desensitization of GPCRs is sensitive to the concentration of arrestins and GRKS in the cells. In its turn, the amount of arrestins and/or GRKs can be modulated by activity of GPCRs. Typical antipsychotic drugs are potent antagonists of the D2 dopamine receptor, whereas atypical drugs interact with several GPCRs. Plasticity of several GPCRs is implicated in schizophrenia pathology and actions of antipsychotic drugs. The a[[;ocamts hypothesize that treatment with antipsychotics induces alterations in the concentration of specific arrestins and/or GRKs in selected brain regions, thereby modifying signal transduction via GPCRs in these regions. Exploration of this hypothesis is clinically relevant because molecular mechanisms of the beneficial actions of antipsychotic drugs remain elusive. Mechanism of action of atypical antipsychotics with their higher efficacy against negative symptoms and cognitive deficits is of particular interest. The specific aims designed to test this hypothesis include determination of the repertoire of arrestin and GRK proteins in specific subtypes of output neurons in the striatum and nucleus accumbens, the brain regions that are prime targets of antipsychotics. The second specific aim focuses on comparison of the effects of acute and subchronic treatment with typical antipsychotic haloperidol and atypical drug clozapine on the expression of arrestin and GRK mRNAs and proteins in various brain areas implicated in schizophrenia pathology and action of antipsychotics. The third specific aim is to determine whether alterations in the arrestin and GRK expression are associated with development of tardive dyskinesia induced by chronic treatment with haloperidol. Plasticity of neuronal receptor trafficking system produced by antipsychotic treatment may lead to changes in the concentrations of specific GPCRs and, ultimately, to long-term modulations of neuronal responses to endogenous stimuli and exogenous drugs. Specific modifications in the arrestin/GRK expression may thus be essential for the beneficial or side effects of antipsychotic drugs. We expect that the information gained by examining the response of the key components of the receptor trafficking machinery to antipsychotics will be helpful for targeted design of drugs with improved clinical profile.