Addiction – Drug Addiction and Reward

Drug abuse and addiction are tremendously costly public health problems that have profound medical consequences to individuals, as well as serious social and economic impacts on our society. Unfortunately, recidivism rates are high and treatment outcomes remain poor, in part due to our incomplete understanding of the complex nature of this debilitating disease. The progression from initial drug exposure to regular drug use and ultimately to compulsive habitual behavior and loss of inhibitory control involves a series of cellular and molecular adaptations in the cortico-basal ganglia circuit. In addition to regulating motivation and reward, this system is involved in cognitive and motor processes. In order to investigate the neural circuits that contribute to the development of drug addiction, Dr. Susan Ferguson’s laboratory employs a novel chemical-genetic approach that uses viral vectors to express artificial, engineered G-protein coupled receptors (known as DREADD receptors) in discrete neuronal cell populations in rodents (e.g. striatonigral ‘direct’ pathway neurons, striatopallidal ‘indirect’ pathway neurons, populations of cortical neurons). Activation of DREADD receptors by the otherwise inert synthetic ligand clozapine-N-oxide will lead to transient alterations in neuronal signaling (either increasing or decreasing cell signaling depending on which G-protein coupled DREADD receptor is expressed) of the targeted cell populations. This modulation of specific populations of neurons in cortico-basal ganglia circuits is paired with specific phases of the behaviors that we study, including psychostimulant-induced behavioral sensitization and drug self-administration.

Dr. John Welsh’s laboratory is examining the effect of rhesus monkeys’ long-term self-administration of ethanol on the electrical properties of the primate brain, as a model for translational research on human alcohol addiction.  We have found that primates’ chronic (i.e. 18 month) ethanol intoxication produces long-term changes in brain electrophysiology characterized by homeostatic changes in ionic channel function that persist despite long-term abstinence, and which may drive alcohol seeking behavior.  Homeostatic modifications in ionic channel function with ethanol drinking modulate brain rhythmogenesis by altering the activities of the low-threshold calcium channel (Cav3.1) and hyperpolarization-activated cation channel (HCN).  Cav3.1 and HCN channel function are regulated in a bidirectional fashion to allow brain function to be maintained in the face of high brain levels of ethanol, and are subsequently downregulated below their normal levels following long-term abstinence.  The latter may underlie long-term cognitive and motor consequences of chronic alcoholism and be a substrate for therapy.

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