Involvement of the lateral orbitofrontal cortex in drug context-induced reinstatement of cocaine-seeking behavior in rats.

Drug addiction manifests as a chronic relapsing disorder characterized by compulsive drug seeking and drug craving that can be precipitated by exposure to drug-associated explicit cues or environments even after prolonged abstinence (Rohsenow et al., 1990; Ehrman et al., 1992; Foltin & Haney, 2000; Volkow & Fowler, 2000). The transition from recreational drug use to drug addiction may be related to either neural sensitivity predisposing one to drug addiction or neural plasticity resulting from drug exposure (Volkow et al., 1992; Franklin et al., 2002; Volkow et al., 2002). In particular, structural, physiological, and functional abnormalities in the frontal cortex may facilitate addictive behavior. Cocaine users exhibit abnormalities in frontal cortical regions, including decreased gray matter density in the orbitofrontal cortex and anterior cingulate, diminished baseline blood glucose metabolism in the frontal cortex, and enhanced cue-evoked activation of the orbitofrontal cortex, some of which are proportional to drug use (Volkow et al., 1991; London et al., 2000; Volkow & Fowler, 2000; Franklin et al., 2002; Bolla et al., 2003; Matochik et al., 2003). Thus, from an addiction-treatment perspective, it is important to understand whether frontal cortical mechanisms contribute to loss of control over drug seeking. In the reinstatement model of drug relapse, lOFC lesions greatly potentiate cocaine-primed reinstatement to cocaine seeking in rats during a reinstatement test session held in the previously cocaine-paired operant chamber (Fuchs et al., 2004b). Interestingly, however, lOFC functional inactivation decreases, while lesions fail to enhance, reinstatement elicited by an explicit, response-contingent conditioned stimulus (CS) (Fuchs et al., 2004b). However, the negative effects of lOFC lesions on CS-induced reinstatement may stem from ceiling effects related to steady cocaine-seeking behavior in the sham control group in response to conditioned reinforcement. Thus, it remains to be investigated whether lOFC lesions augment the incentive motivational effects of cocaine-paired stimuli in the absence of conditioned reinforcement. To test this hypothesis, the present study investigated the effects of bilateral lOFC functional inactivation (experiment 1), pre-training lOFC lesions (experiment 2), and post-training lOFC lesions (experiment 3) on the reinstatement of cocaine-seeking behavior upon re-exposure to a distinct cocaine-paired environmental context after extinction training in a different context. Response-contingent stimuli were not presented to the subjects during training or testing to eliminate the influence of conditioned reinforcement on drug-seeking behavior. Based on our previous study (Fuchs et al., 2004b), we hypothesized that lOFC functional inactivation would attenuate context-induced cocaine seeking, but that pre-training lOFC lesions would enhance this behavior due to lesion-induced compensatory neuroadaptations. Furthermore, we predicted that post-training lOFC lesions would either A) produce similar effects as lOFC functional inactivation if loss of lOFC output during self-administration training critically underlies the effects of pre-training lOFC lesions or B) have similar effects as pre-training lOFC lesions if lesion-induced neuroadaptations are sufficient to enhance context-induced motivation for cocaine.