Role of the orbitofrontal cortex and dorsal striatum in regulating the dose-related effects of self-administered cocaine

Little is known regarding which neural systems regulate dose-related changes in responses maintained by self-administered cocaine. This empirical question is important because elucidating neural systems engaged in this process could provide clues for effectively treating cocaine addiction. It has been suggested that different cocaine doses represent reinforcers of differing magnitudes, implicating the dorsal striatum or orbitofrontal cortex as important. Rats were trained to self-administer 1.0 mg/kg cocaine under a fixed-interval based second-order schedule. Next, cocaine unit doses (0.1-3.0 mg/kg) were each non-systematically available for a 5-day block of sessions. Tests (1 h) were conducted on day 3 (vehicle) and day 5 (100 mu g lidocaine) of each block. Lidocaine inactivation of the lateral dorsal striatum had no effect on dose-related responding or cocaine intake. In contrast, when doses along the ascending limb were available for self-administration, lidocaine inactivation of the lateral orbitofrontal cortex caused reductions in responding and cocaine intake, resulting in overall flattening of dose-response curves. This included reductions during the entire 1-h test sessions and during the interval immediately following the first cocaine infusion of test sessions. Lidocaine inactivation of the lateral orbitofrontal cortex did not alter responding during the first cocaine-free interval of test sessions, but increased the latency to the first infusion. Collectively, the findings suggest that when the amount of experience with different cocaine unit doses is limited to a few sessions, the lateral orbitofrontal cortex regulates the dose-related effects of self-administered cocaine, likely by processing information pertaining to the reinforcing value of each unit dose. (C) 2009 Elsevier B.V. All rights reserved.