The role of orbitofrontal cortex in drug addiction: a review of preclinical studies

Abstract

Studies using brain imaging methods have shown that neuronal activity in the orbitofrontal cortex, a brain area thought to promote the ability to control behavior according to likely outcomes or consequences, is altered in drug addicts. These human imaging findings have led to the hypothesis that core features of addiction like compulsive drug use and drug relapse are mediated in part by drug-induced changes in orbitofrontal function. Here, we discuss results from laboratory studies using rats and monkeys on the effect of drug exposure on orbitofrontal-mediated learning tasks and on neuronal structure and activity in orbitofrontal cortex. We also discuss results from studies on the role of the orbitofrontal cortex in drug self-administration and relapse. Our main conclusion is that although there is clear evidence that drug exposure impairs orbitofrontal-dependent learning tasks and alters neuronal activity in orbitofrontal cortex, the precise role these changes play in compulsive drug use and relapse has not yet been established.

Figure 1. Cocaine exposure induces OFC-dependent reversal learning deficits that are of similar magnitude to learning deficits induced by OFC lesions

(A) Effect of OFC lesions on reversal learning. Sham and OFC-lesioned rats were tested on serial reversals of a post-operatively acquired 2-odor go, no-go discrimination. One odor predicted sucrose availability, while a second odor predicted quinine. Rats had to learn to respond for sucrose but withhold responding for quinine; criterion was 90% correct responding in a block of 20 trials. OFC lesions had no effect on retention but impaired reversal learning. (B) Effect of repeated non-contingent cocaine exposure (30 mg/kg/day X 14 days) on reversal learning. Rats were injected with cocaine or saline and were then tested on the same odor discrimination reversal task used in (A) after approximately 1 month of withdrawal from the drug. Cocaine exposure had no effect on retention but impaired reversal learning. (C) Effect of contingent cocaine self-administration (0.75 mg/kg/infusion, 4 h/day X 14 days) on reversal learning. Rats were trained to self-administer cocaine and then tested on the same odor discrimination reversal task used in (A) after approximately 3 months of withdrawal from the drug. Cocaine self-administration had no effect on retention but impaired reversal learning. * Different from the respective controls, p < 0.05. Data in (A), (B), and (C) were adapted from references 49, 64 and 80, respectively.