The effects of continuous cocaine dose, treatment, and withdrawal duration on the induction of behavioral tolerance and dopamine autoreceptor function.
The present experiment evaluated the interactions between continuous cocaine dose, duration of administration, and duration of withdrawal on the induction of behavioral tolerance and changes in dopamine autoreceptor (DA) function. In the current experiments, rats were exposed to a pretreatment regimen involving the continuous administration of 0, 5, or 20 mg/kg/day cocaine for either 3 or 7 days. All subjects were then withdrawn from the pretreatment regimen for 1 or 7 days. For the experiments examining behavioral tolerance, the subjects received 15.0 mg/kg ip cocaine. For the experiments examining alterations in DA function, the subjects received a 0.063 mg/kg ip quinpirole injection, followed 5 min later by a 15.0 mg/kg ip cocaine injection. For all experiments, the subjects were placed in activity monitors, and ambulation was measured for 60 min. The results indicated that all continuous cocaine durations induced significant changes in cocaine-induced behavior at the 1-day withdrawal period. However, for tolerance to be exhibited on the 7-day withdrawal period, either high-dose or long-duration continuous cocaine had to be administered. This tolerance was associated with an increase in DA sensitivity. However, the change in DAs was dose- or duration-dependently related to tolerance. Overall, the literature suggests that behavioral tolerance following continuous cocaine administration may be mediated by multiple, time-dependent mechanisms that operate in an all-or-none manner.
King
George R
GR
Department of Pharmacology, University of North Texas Health Sciences Center, Fort Worth, TX 76107, USA. g.king@tcu.edu
Hillburn
Craig
C
Pinto
Gail
G
Konen
Jennifer
J
D000818:Animals; D017660:Autoreceptors / Q000502:physiology*; D003042:Cocaine / Q000008:administration & dosage*; D004361:Drug Tolerance / Q000502:physiology; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000502:physiology*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*
D017660:Autoreceptors; D011954:Receptors, Dopamine; D003042:Cocaine