Influence of sex, estrous cycle, and drug-onset age on cocaine self-administration in rats (Rattus norvegicus).

The influence of sex, phase of the estrous cycle, and age of drug onset on cocaine self-administration was examined. Adult male, adult female, and adolescent male rats (Rattus norvegicus) were evaluated using low fixed-ratio (FR) schedules of drug delivery with a single fixed cocaine unit dose or a range of cocaine unit doses with a single FR schedule. Sex differences in adults were observed for mg/kg consumption of the 3.0-mg/kg unit dose, with consumption being significantly less in estrus females than in males. Over the estrous cycle, mg/kg consumption of this unit dose was significantly less during estrus than during metestrus-diestrus. Differences due to age of drug onset were also observed, with mg/kg consumption of the 3.0-mg/kg unit dose being significantly less in adolescent males than adult males or adult females during metestrus-diestrus. In contrast, these various groups did not have significantly different mg/kg intakes of cocaine unit doses <3.0 mg/kg, nor did they significantly differ in the rates and patterns of responding and number of infusions earned as a function of FR schedule or unit dose of cocaine available. The role of sex, estrus cycle, and drug-onset age on cocaine self-administration appears to be minimal under these experimental conditions. Experimental conditions that favor no sex or age differences in cocaine intake (1.0-mg/kg unit dose and low FR) may be useful for evaluating potential sex or age differences in the consequences of cocaine self-administration more reliably, as cocaine intake would not be an uncontrolled factor.

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 (1h) were conducted on day 3 (vehicle) and day 5 (100 microg 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.