Acquisition of cocaine self-administration (0.125, 0.25 or 0.5 mg/kg/infusion) was assessed in rats that had received prior exposure to either saline or amphetamine (2.0 mg/kg). Acquisition of self-administration was dose-dependent, with the highest dose leading to the shortest latency to reliably discriminate between depression of a lever that resulted in drug delivery and an inactive lever. Latency to acquisition of the lever discrimination for rats that had received prior exposure to amphetamine was shorter than for the saline-pretreated counterparts in each cocaine dosage group. This suggests that repeated exposure to this drug prior to self-administration testing sensitized the rats to the reinforcing effects of cocaine. Co-administration of MK-801 (0.25 mg/kg, IP), a non-competitive NMDA antagonist, blocked the ability of chronic exposure to amphetamine to sensitize rats to cocaine. In experienced self-administering rats, acute pretreatment with MK-801 resulted in a loss of discriminative responding. The number of inactive lever responses was consistently higher than the number of active lever responses across all cocaine dosage groups. These data suggest that the NMDA receptor, possibly through interactions with dopamine systems, is critical for both the development and expression of sensitization to cocaine's reinforcing effects produced by intermittent preexposures to amphetamine.

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Previously, we demonstrated that caffeine dose-dependently reinstated extinguished cocaine-taking behavior in rats. In the present study, we determined whether this effect of caffeine would extinguish with repeated exposures. Rats were first trained to self-administered cocaine intravenously. Once reliable self-administration was obtained, the pumps that delivered cocaine were turned off and the lever-pressing behavior was extinguished. Every 4 days the rats were given an injection of caffeine (20.0 mg/kg) and its ability to reinstate responding was measured. Some rats received each of four exposures to caffeine in the previously cocaine-associated environment. Other rats received the first three exposures to caffeine in the home cage and the last exposure to caffeine in the previously cocaine-associated environment. The results indicated that although caffeine was an effective cue for reinstatement of extinguished cocaine taking, the effect was reduced when repeated exposures occurred in the test environment. In addition, when 4 drug-free days were interspersed between self-administration and reinstatement testing, the caffeine effect was greater than when testing was conducted 1 day following the last self-administration session. Thus, extended withdrawal increases the priming effects of caffeine. The results are discussed in terms of the effectiveness of cue exposure as an adjunct to current therapies for cocaine abuse.

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