Tolerance to the disruptive effects of Delta(9)-THC on learning in rats

Pharmacol Biochem Behav. 2002 Dec;74(1):129-40. doi: 10.1016/s0091-3057(02)00966-8.


Tolerance to the effects of the cannabinoid agonist Delta(9)-tetrahydrocannabinol (Delta(9)-THC) was characterized in rats responding under a multiple schedule of repeated acquisition and performance. During the acquisition component, subjects acquired a different three-response sequence each session, whereas in the performance component the sequence was the same each session. Responding was maintained under a second-order fixed-ratio 2 (FR2) schedule of food reinforcement. Acute doses of Delta(9)-THC (1-10 mg/kg) decreased rate and accuracy in both components, whereas doses of the cannabinoid (CB1) receptor antagonist N-(piperidin-1-yn-)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A; 0.32 and 1 mg/kg) were ineffective. While 5.6 mg/kg of Delta(9)-THC disrupted responding when administered acutely, tolerance to the rate-decreasing and error-increasing effects of this dose developed in both components after daily administration. When 1 mg/kg of SR141716A was substituted for Delta(9)-THC during chronic administration, this previously ineffective dose selectively increased within-session errors in the acquisition component of the multiple schedule. During the postchronic phase, subjects were generally less sensitive to the disruptive effects of Delta(9)-THC. In summary, these data demonstrated that tolerance to Delta(9)-THC developed across two different behavioral tasks and that learning was generally more sensitive than performance to the effects of SR141716A during chronic treatment with Delta(9)-THC.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Color Perception / drug effects
  • Conditioning, Operant / drug effects
  • Dose-Response Relationship, Drug
  • Dronabinol / antagonists & inhibitors
  • Dronabinol / pharmacology*
  • Drug Tolerance
  • Hallucinogens / antagonists & inhibitors
  • Hallucinogens / pharmacology*
  • Learning / drug effects*
  • Male
  • Naltrexone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Piperidines / pharmacology
  • Pyrazoles / pharmacology
  • Rats
  • Rats, Long-Evans
  • Reinforcement Schedule
  • Rimonabant


  • Hallucinogens
  • Narcotic Antagonists
  • Piperidines
  • Pyrazoles
  • Naltrexone
  • Dronabinol
  • Rimonabant