The effects of continuous cocaine dose on the induction of behavioral tolerance and dopamine autoreceptor function

The current experiment evaluated the dose-dependent nature of the induction of behavioral tolerance, and changes in dopamine autoreceptor function, by continuously administering different doses of cocaine. For all experiments , rats were exposed to a 14-day pretreatment regimen involving the continuo us administration of either 0, 5, 10, 20, or 40 mg/kg/day cocaine. All subj ects were then withdrawn from the pretreatment regimen for 7 days. The subj ects were placed in activity monitors, and ambulation measured. In experime nt 1, the subjects were challenged with 0.0, 7.5, or 15.0 mg/kg i.p. cocain e on day 7 of withdrawal from the continuous cocaine administration regimen . The results indicated that all continuous cocaine doses induced significa nt tolerance to the 15.0 mg/kg cocaine challenge, relative to the control g roup. Furthermore, the 5.0 mg/kg/day group exhibited significantly less tol erance than the 40.0 mg/kg/day group. In experiment 2, the subjects were ch allenged with 0.0, 0.063, or 0.125 mg/kg quinpirole. The results indicated that the 0.063-mg/kg quinpirole challenge inhibited activity, while the 0.1 25 mg/kg quinpirole challenge enhanced behavior. The results further sugges ted that the inhibition of behavior was greater in the cocaine-pretreated s ubjects than in the saline control group. In experiment 3, the subjects wer e challenged with the same doses of quinpirole in combination with 15 mg/kg i.p. cocaine. The low quinpirole challenge dose inhibited cocaine-induced hyperactivity, while the higher challenge dose enhanced cocaine-induced hyp eractivity. The results suggest that the induction of tolerance by continuo us cocaine administration is dose-dependent. Continuous cocaine administrat ion did induce dopamine autoreceptor supersensitivity. However, different c ontinuous cocaine doses did not induce differential degrees of dopamine aut oreceptor supersensitivity. (C) 1999 Elsevier Science B.V. All rights reser ved.