Tolerance to self-administration of cocaine in rats: time course and dose-response determination using a multi-dose method

M. W. Emmett-Oglesby, R. L. Peltier, R. Y. Depoortere, C. L. Pickering, M. L. Hooper, Y. H. Gong, J. D. Lane

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9 Scopus citations


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 doseresponse 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.

Original languageEnglish
Pages (from-to)247-256
Number of pages10
JournalDrug and Alcohol Dependence
Issue number3
StatePublished - May 1993


  • cocaine
  • multi-dose
  • rat
  • self-administration
  • tolerance


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