Membrane excitability of nucleus accumbens neurons gates the incubation of cocaine craving

A primary behavioral pathology in drug addiction is the overpowering motivational strength and decreased ability to control the desire to obtain drugs. In this review the authors explore how advances in neurobiology are approaching an understanding of the cellular and circuitry underpinnings of addiction, and they describe the novel pharmacotherapeutic targets emerging from this understanding. Findings from neuroimaging of addicts are integrated with cellular studies in animal models of drug seeking. While dopamine is critical for acute reward and initiation of addiction, end-stage addiction results primarily from cellular adaptations in anterior cingulate and orbitofrontal glutamatergic projections to the nucleus accumbens. Pathophysiological plasticity in excitatory transmission reduces the capacity of the prefrontal cortex to initiate behaviors in response to biological rewards and to provide executive control over drug seeking. Simultaneously, the prefrontal cortex is hyperresponsive to stimuli predicting drug availability, resulting in supraphysiological glutamatergic drive in the nucleus accumbens, where excitatory synapses have a reduced capacity to regulate neurotransmission. Cellular adaptations in prefrontal glutamatergic innervation of the accumbens promote the compulsive character of drug seeking in addicts by decreasing the value of natural rewards, diminishing cognitive control (choice), and enhancing glutamatergic drive in response to drug-associated stimuli.

Addiction is associated with neuroplasticity in the corticostriatal brain circuitry that is important for guiding adaptive behaviour. The hierarchy of corticostriatal information processing that normally permits the prefrontal cortex to regulate reinforcement-seeking behaviours is impaired by chronic drug use. A failure of the prefrontal cortex to control drug-seeking behaviours can be linked to an enduring imbalance between synaptic and non-synaptic glutamate, termed glutamate homeostasis. The imbalance in glutamate homeostasis engenders changes in neuroplasticity that impair communication between the prefrontal cortex and the nucleus accumbens. Some of these pathological changes are amenable to new glutamate- and neuroplasticity-based pharmacotherapies for treating addiction.

The nucleus accumbens is a major input structure of the basal ganglia and integrates information from cortical and limbic structures to mediate goal-directed behaviors. Chronic exposure to several classes of drugs of abuse disrupts plasticity in this region, allowing drug-associated cues to engender a pathologic motivation for drug seeking. A number of alterations in glutamatergic transmission occur within the nucleus accumbens after withdrawal from chronic drug exposure. These drug-induced neuroadaptations serve as the molecular basis for relapse vulnerability. In this review, we focus on the role that glutamate signal transduction in the nucleus accumbens plays in addiction-related behaviors. First, we explore the nucleus accumbens, including the cell types and neuronal populations present as well as afferent and efferent connections. Next we discuss rodent models of addiction and assess the viability of these models for testing candidate pharmacotherapies for the prevention of relapse. Then we provide a review of the literature describing how synaptic plasticity in the accumbens is altered after exposure to drugs of abuse and withdrawal and also how pharmacological manipulation of glutamate systems in the accumbens can inhibit drug seeking in the laboratory setting. Finally, we examine results from clinical trials in which pharmacotherapies designed to manipulate glutamate systems have been effective in treating relapse in human patients. Further elucidation of how drugs of abuse alter glutamatergic plasticity within the accumbens will be necessary for the development of new therapeutics for the treatment of addiction across all classes of addictive substances.