Over the past 17 years, misuse of prescription opiates (primarily oxycodone) and overdose due to opioids, including heroin, have soared, now reaching three deaths per hour in the United States. Central to the neurobiology underlying the development of addictive diseases is the endogenous opioid system, both the mu opioid receptor system involved in “reward” and the kappa opioid receptor system involved in countermodulation of “reward.” Our Laboratory has undertaken studies of the effects of self-administration of oxycodone in adolescent and adult mice. Many genes whose mRNA levels are changed significantly by oxycodone self-administration in mice also have SNPs that have been shown to be significantly associated with opiate addiction in humans. We developed methadone maintenance treatment for heroin addiction over 50 years ago, and numerous studies have shown that 60-80% of unselected opioid addicted persons respond to this long-term treatment. Currently, over 1.3 million persons worldwide are in methadone maintenance treatment. Buprenorophine-naloxone, developed in the late 1980s, has also been shown to be an effective treatment for opiate addiction. Since we have shown that dynorphin acting at kappa receptors significantly lowers dopaminergic tone in rodents, we are now conducting translational work focused on the kappa opioid receptor as a possible biological target for novel pharmacotherapies for cocaine addiction, for which there is no pharmacotherapy, and alcoholism, for which naltrexone and nalmefene are the only available treatments and are effective in only around 30% of unselected alcoholics. Our ongoing human molecular genetics work has identified over 100 SNPs associated with opiate addiction, many of which have been replicated by other groups. A large number of these SNPs are in genes of the opioid, stress-responsive, and dopaminergic systems, which we have been demonstrated to be of central importance for the development of specific addictive diseases.

Addictive diseases: Molecular neurobiology, behavior, human genetics, and treatments

254th National Meeting (2017)

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