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 continuous administration of either 0, 5, 10, 20, or 40 mg/kg/day cocaine. All subjects were then withdrawn from the pretreatment regimen for 7 days.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 doses induced significant tolerance to the 15.0 mg/kg cocaine challenge, relative to the control group. Furthermore, the 5.0 mg/kg/day group exhibited significantly less tolerance than the 40.0 mg/kg/day group. In experiment 2, the subjects were challenged 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 0.125 mg/kg quinpirole challenge enhanced behavior. The results further suggested that the inhibition of behavior was greater in the cocaine-pretreated subjects than in the saline control group. In experiment 3, the subjects were 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 hyperactivity. The results suggest that the induction of tolerance by continuous cocaine administration is dose-dependent. Continuous cocaine administration did induce dopamine autoreceptor supersensitivity. However, different continuous cocaine doses did not induce differential degrees of dopamine autoreceptor supersensitivity.
King
G R
GR
Department of Psychiatry, Duke University Medical Center, Durham, NC 27710, USA. gking@hsc.unt.edu
Xiong
Z
Z
Douglas
S
S
Lee
T H
TH
Ellinwood
E H
EH
D000818:Animals; D002352:Carrier Proteins / Q000187:drug effects*; D003042:Cocaine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018491:Dopamine Agonists / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004361:Drug Tolerance / Q000502:physiology*; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins; D019257:Quinpirole / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D002352:Carrier Proteins; D018491:Dopamine Agonists; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D019257:Quinpirole; D003042:Cocaine