Stimulus gated cocaine sensitization: Interoceptive drug cue control of cocaine locomotor sensitization

Repeated cocaine treatments typically generate sensitization effects which are environment specific. In this study, we investigated whether drug treatments with highly selective receptor specificity can also function as contextual cues to control the expression of cocaine sensitization effects. Two experiments were conducted in which separate groups of rats (N = 10) received ten paired or unpaired cocaine (10.0 mg/kg) treatments. In the experiments, autoreceptor preferring low doses of either the 5-HT1A agonist, 8-OHDPAT (8OH) (0.05 mg/kg) or the D1/D2 agonist apomorphine (APO) (0.05 mg/kg) were administered 20 min prior to cocaine administration and test environment placement (paired treatment). Under these conditions, the drug cues generated by the 8OH/APO treatments were associated with the cocaine stimulant effect in the test environment. The unpaired treatment groups received the same drug treatments but the cocaine was administered after testing, in the homecage. Consequently, for these groups, the 8OH/APO drug cues generated by the drug treatments would not become associated with the cocaine stimulant effect in the test environment. Critically, both 8OH and APO pretreatments elicited equivalent unconditioned response effects which were opposite to the cocaine unconditioned response effects; that is, behavioral inhibition vs. behavioral stimulation. Initially, the 8OH and APO pretreatments prevented the locomotor stimulant effects of cocaine; but, these inhibitory effects were reversed in the paired groups with repeated cocaine treatments, consistent with the emergence of cocaine sensitization effects. In the unpaired 8OH and APO pretreatment groups, behavioral suppression persisted throughout the treatment protocol. Subsequently, paired and unpaired groups were compared in four conditioning/sensitization tests. The conditioning tests included: a saline/saline test; and a 8OH/saline test (Experiment 1); and, a saline/saline test and a APO/saline test (Experiment 2). There were no paired/unpaired group differences in these conditioning tests. The sensitization tests included: a saline/cocaine test; and a 8OH/cocaine test (Experiment 1); and, a saline/cocaine test and a APO/cocaine test (Experiment 2). There were no paired/unpaired group differences in the saline/cocaine test for sensitization but paired/unpaired group differences were found in both the 8OH/cocaine and APO/cocaine sensitization tests. In these tests the paired but not the unpaired groups exhibited cocaine locomotor sensitization effects. Critically when, in an additional test, the pretreatments in the cocaine tests were reversed (i.e., 8OH paired group received APO and APO paired group received 8OH prior to cocaine), then there was no evidence for cocaine sensitization. Since the 8OH/APO pretreatments had equivalent inhibitory response effects, it was the stimulus properties of these drugs which controlled the expression of the cocaine locomotor sensitization effects. These findings support the critical role of associative processes in the stimulus-gating of psychostimulant drug sensitization. Importantly, this report incorporates a new methodology in which context can be specified in terms of highly specific brain receptor targets rather than in terms of global environmental situational cues.