Tolerance to self-administration of cocaine in rats: time course and dose-response determination using a multi-dose method.
To assess tolerance to cocaine in a self-administration paradigm, rats were trained to self-administer cocaine (0.25 mg/injection) on a fixed-ratio 2 (FR2) schedule of reinforcement. The development of tolerance was studied during chronic administration of cocaine (20 mg/kg per 8 h for 10 days), given either contingently (self-administered by the rats) or non-contingently (infused by the experimenter). Both contingent and non-contingent administration of cocaine produced comparable tolerance, as indicated by a faster rate of cocaine self-administration (the average inter-reinforcer time, ISRT, decreased significantly). Tolerance developed by day 2 of the chronic regimen and reached a floor value (60% of baseline) from day 4 through day 10. Termination of chronic cocaine then resulted in recovery from tolerance, with ISRTs returning to baseline within 6 days of termination. A second set of experiments determined whether tolerance could be studied using a multi-dose method to obtain dose-response data in a single session. A system of multiple pumps allowed testing of three doses of cocaine during a single experimental session. Cocaine dose-response curves obtained from the multi-dose method: (i) did not differ from that obtained from a single-dose method; (ii) were reproducible; and (iii) were shifted to the right by Schering 23390. Rats were then subjected to a 7-day chronic regimen of infused cocaine (20 mg/kg per 8 h) or infused saline. At the end of this chronic cocaine period, they were tested with the multi-dose method. Chronic cocaine, as compared to chronic saline, shifted the cocaine dose-response curve to the right, indicating that the multi-dose method can be successfully applied to demonstrate tolerance to the effects of cocaine in a self-administration paradigm.
Emmett-Oglesby
M W
MW
Department of Pharmacology, Texas College of Osteopathic Medicine, Fort Worth 76107-2699.
Peltier
R L
RL
Depoortere
R Y
RY
Pickering
C L
CL
Hooper
M L
ML
Gong
Y H
YH
Lane
J D
JD
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004361:Drug Tolerance; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D012055:Reinforcement Schedule; D012646:Self Administration; D019966:Substance-Related Disorders / Q000523:psychology*
D001552:Benzazepines; D003042:Cocaine