The neural basis of addiction: a pathology of motivation and choice.
OBJECTIVE
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.


METHODS
Findings from neuroimaging of addicts are integrated with cellular studies in animal models of drug seeking.


RESULTS
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.


CONCLUSIONS
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.
Kalivas
Peter W
PW
Department of Neurosciences, Medical University of South Carolina, 173 Ashley Ave., BSB-403, Charleston, SC 29425, USA. kalivasp@musc.edu
Volkow
Nora D
ND
D000818:Animals; D016739:Behavior, Addictive / Q000209:etiology / Q000503:physiopathology / Q000523:psychology; D001921:Brain / Q000502:physiology* / Q000503:physiopathology; D002755:Choice Behavior / Q000502:physiology*; D004298:Dopamine / Q000502:physiology; D005917:Globus Pallidus / Q000502:physiology; D006801:Humans; D008959:Models, Neurological; D009042:Motivation; D009434:Neural Pathways / Q000502:physiology; D009714:Nucleus Accumbens / Q000502:physiology; D049268:Positron-Emission Tomography; D017397:Prefrontal Cortex / Q000502:physiology; D012008:Recurrence; D012377:Rodentia; D019966:Substance-Related Disorders / Q000209:etiology* / Q000503:physiopathology / Q000523:psychology
D004298:Dopamine