Addiction, a disease of compulsion and drive: Involvement of the orbitofrontal cortex

Understanding the changes in the brain which occur in the transition from n ormal to addictive behavior has major implications in public health. Here w e postulate that while reward circuits (nucleus accumbens, amygdala), which have been central to theories of drug addiction, may be crucial to initiat e drug self-administration, the addictive state also involves disruption of circuits involved with compulsive behaviors and with drive. We postulate t hat intermittent dopaminergic activation of reward circuits secondary to dr ug self-administration leads to dysfunction of the orbitofrontal cortex via the striato-thalamo-orbitofrontal circuit. This is supported by imaging st udies showing that in drug abusers studied during protracted withdrawal, th e orbitofrontal cortex is hypoactive in proportion to the levels of dopamin e D2 receptors in the striatum. In contrast, when drug abusers are tested s hortly after last cocaine use or during drug-induced craving, the orbitofro ntal cortex is hypermetabolic in proportion to the intensity of the craving . Because the orbitofrontal cortex is involved with drive and with compulsi ve repetitive behaviors, its abnormal activation in the addicted subject co uld explain why compulsive drug self-administration occurs even with tolera nce to the pleasurable drug effects and in the presence of adverse reaction s. This model implies that pleasure per se is not enough to maintain compul sive drug administration in the drug-addicted subject and that drugs that c ould interfere with the activation of the striato-thalamo-orbitofrontal cir cuit could be beneficial in the treatment of drug addiction.