title: New medications for drug addiction hiding in glutamatergic neuroplasticity.
abstract: The repeated use of drugs that directly or indirectly stimulate dopamine transmission carry addiction liability and produce enduring pathological changes in the brain circuitry that normally regulates adaptive behavioral responding to a changing environment. This circuitry is rich in glutamatergic projections, and addiction-related behaviors in animal models have been linked to impairments in excitatory synaptic plasticity. Among the best-characterized glutamatergic projection in this circuit is the prefrontal efferent to the nucleus accumbens. A variety of molecular adaptations have been identified in the prefrontal glutamate synapses in the accumbens, many of which are induced by different classes of addictive drugs. Based largely on work with cocaine, we hypothesize that the drug-induced adaptations impair synaptic plasticity in the cortico-accumbens projection, and thereby dysregulate the ability of addicts to control their drug-taking habits. Accordingly, we go on to describe the literature implicating the drug-induced changes in protein content or function that impinge upon synaptic plasticity and have been targeted in preclinical models of relapse and, in some cases, in pilot clinical trials. Based upon modeling drug-induced impairments in neuroplasticity in the cortico-accumbens pathway, we argue for a concerted effort to clinically evaluate the hypothesis that targeting glial and neuronal proteins regulating excitatory synaptic plasticity may prove beneficial in treating addiction.
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston National Institute on Drug Abuse, Charleston, SC 29425, USA. kalivasp@musc.edu
authors.forename: P W
authors.initials: PW
authors.lastname: Kalivas
authors.forename: N D
authors.initials: ND
authors.lastname: Volkow
mesh_terms: D000222:Adaptation, Physiological; D016739:Behavior, Addictive / Q000188:drug therapy / Q000378:metabolism; D018683:Excitatory Amino Acid Agents / Q000627:therapeutic use*; D018698:Glutamic Acid / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D009434:Neural Pathways / Q000187:drug effects* / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D019966:Substance-Related Disorders / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D018683:Excitatory Amino Acid Agents; D018698:Glutamic Acid