Cerebral Cortex, Vol. 10, No. 3, 318-325,
March 2000
© 2000 Oxford University Press
Addiction, a Disease of Compulsion and Drive: Involvement of the Orbitofrontal Cortex
1 Medical and , 2 Chemistry Departments, Brookhaven National Laboratory, Upton, NY 11973 and , 3 Department of Psychiatry, SUNY-Stony Brook, Stony Brook, NY 11794, USA
Understanding the changes in the brain which occur in the transition from normal to addictive behavior has major implications in public health. Here we postulate that while reward circuits (nucleus accumbens, amygdala), which have been central to theories of drug addiction, may be crucial to initiate drug self-administration, the addictive state also involves disruption of circuits involved with compulsive behaviors and with drive. We postulate that intermittent dopaminergic activation of reward circuits secondary to drug self-administration leads to dysfunction of the orbitofrontal cortex via the striato-thalamo-orbitofrontal circuit. This is supported by imaging studies showing that in drug abusers studied during protracted withdrawal, the orbitofrontal cortex is hypoactive in proportion to the levels of dopamine D2 receptors in the striatum. In contrast, when drug abusers are tested shortly after last cocaine use or during drug-induced craving, the orbitofrontal cortex is hypermetabolic in proportion to the intensity of the craving. Because the orbitofrontal cortex is involved with drive and with compulsive repetitive behaviors, its abnormal activation in the addicted subject could explain why compulsive drug self-administration occurs even with tolerance to the pleasurable drug effects and in the presence of adverse reactions. This model implies that pleasure per se is not enough to maintain compulsive drug administration in the drugaddicted subject and that drugs that could interfere with the activation of the striato-thalamo-orbitofrontal circuit could be beneficial in the treatment of drug addiction.
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