Tolerance and cross-tolerance to cannabinoids in mice: schedule-controlled responding and hypothermia.
BACKGROUND
Cannabinoid CB(1) receptor agonists vary in efficacy in vitro; however, relationships between efficacy and behavioral effects are unclear.


OBJECTIVE
This study examined the relationship between apparent CB(1) agonist efficacy and in vivo effects.


METHODS
Male C57BL/6J mice responded for food under a fixed ratio 30 schedule; rectal temperature was measured. Sensitivity of the mice to cannabinoid agonists (rank order efficacy in vitro reported to be CP 55940 > anandamide > Δ(9)-tetrahydrocannabinol; Δ(9)-THC) and a non-cannabinoid (the benzodiazepine midazolam) was determined before, during, and after discontinuation of daily Δ(9)-THC treatment (32 mg/kg/day, i.p.). Rimonabant was combined with cannabinoids to examine whether CB(1) receptors mediated effects on response rate.


RESULTS
Δ(9)-THC, CP 55940, anandamide, and midazolam decreased responding at doses smaller than those producing hypothermia. Rimonabant antagonized the rate-decreasing effects of Δ(9)-THC and CP 55940, but not those of anandamide. Δ(9)-THC treatment produced tolerance for both rate-decreasing and hypothermic effects. Δ(9)-THC treatment did not change sensitivity to the rate-decreasing effects of CP 55940, but produced cross-tolerance to CP 55940 for hypothermic effects. Δ(9)-THC treatment did not modify sensitivity to anandamide and midazolam.


CONCLUSIONS
CB(1) receptors mediate the operant rate-decreasing effects of Δ(9)-THC and CP 55940, but not anandamide, in mice. CB(1) agonist efficacy is an important determinant of in vivo effects, especially with regard to the magnitude of tolerance and cross-tolerance resulting from daily Δ(9)-THC treatment. This applies not only to different cannabinoids when measuring the same effect but also to the same cannabinoid when measuring different effects.
Department of Pharmacology, The University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.
Harinder
H
Singh
David R
DR
Schulze
Lance R
LR
McMahon
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002186:Cannabinoids / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004361:Drug Tolerance; D007035:Hypothermia / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000037:antagonists & inhibitors; D000077285:Rimonabant; D013997:Time Factors
D002186:Cannabinoids; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant
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