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

The current experiment evaluated the duration-dependent nature of the induction of behavioral tolerance and changes in dopamine autoreceptor function by continuously administering cocaine for different durations. For all experiments, rats were exposed to a pretreatment regimen involving the continuous administration of 40 mg/kg/day cocaine. The pretreatment regimen lasted 3, 7, or 14 days. All subjects were then withdrawn from the pretreatment regimen for 7 days. The subjects were placed in activity monitors and ambulation measured. In experiment 1, the subjects were challenged with 0.0, 7.5, or 15.0 mg/kg i.p. cocaine on day 7 of withdrawal from the continuous cocaine administration regimen. The results indicated that all continuous cocaine durations induced significant tolerance to the 7.5 and 15.0 mg/kg cocaine challenge, relative to the control group. However, the magnitude of tolerance was not duration dependent. In experiment 2, the subjects were challenged with 0.063 or 0.125 mg/kg quinpirole. The results indicated that the 0.063 mg/kg quinpirole challenge inhibited activity in both pretreatment groups, while the 0.125 mg/kg quinpirole challenge enhanced behavior in the saline control, but not the cocaine, pretreatment group. In experiment 3, the subjects were challenged with the same doses of quinpirole in combination with 7.5 mg/kg i.p. cocaine. Both quinpirole challenge doses inhibited cocaine-induced hyperactivity. The results suggest that the induction of tolerance by continuous cocaine administration is not duration-dependent. Continuous cocaine administration did induce dopamine autoreceptor supersensitivity. Different continuous cocaine durations may induce differential degrees of dopamine autoreceptor supersensitivity.