Addiction to heroin (diacetylmorphine) is a major social problem, affecting over a million people in the United States. In the body and brain, heroin is hydrolyzed to morphine, which acts at the mu opioid receptor and results in an euphoric effect, thus conferring the reinforcing properties of the drug and contributing to the development of addiction. Heroin addiction can be managed through treatment, primarily methadone maintenance, but the biological basis of heroin addiction, with respect to the genetic diversity of the mu receptor and the impact of such diversity on receptor function. With the cloning of the human mu opioid receptor, it is possible now to study the sequence variations among different individuals and correlate them with changes in receptor function. The hypothesis for this proposal is that DNA sequence variations in the mu receptor gene exist in humans, and such natural occurring polymorphisms affect the receptor function in response to morphine. To test this hypothesis, blood samples will be collected from heroin addicts and normal volunteers to establish a repository that contains DNA and viable lymphocyte cell lines, storing duplicate samples with one set at Indiana University and one at Rockefeller University. Polymorphisms in these individuals will be determined by amplifying the mu receptor coding sequence using PCR and screening for sequence variations. A correlation between polymorphisms and changes in receptor function will be examined by mutating the mu receptor cDNA to match the polymorphisms. These mutated receptors will be expressed in cultured cells, and tested for their functions in ligand banding, inhibition of adenylyl cyclase activity, and activation of a potassium channel. The time course of morphine effect will be studied upon acute stimulation, chronic exposure, and acute withdrawal. Also, modulation of receptor function by protein kinases will be examined as a molecular mechanism for drug-induced changes in the cell. This is a novel approach for studying the biological significance of narcotic receptors. By using a well-controlled group of subjects. with detailed information on health and drug abuse history, detailed molecular analysis of each subject's mu receptor gene should yield valuable information on the genetic and functional diversity of the mu receptor and provide a direct assessment of its structure-function relationship. Furthermore, this approach can be readily applied to other proteins involved in the physiological pathways of abused drugs, yielding important information regarding the biological mechanisms for these proteins, and provide a broad perspective on the biological basis of drug addiction.
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