| Reference | 1. Neuroscience. 1998 Jul;85(2):327-30.<br />
Self-administration of the cannabinoid receptor agonist WIN 55,212-2 in drug-naive mice.<br />
Martellotta MC(1), Cossu G, Fattore L, Gessa GL, Fratta W.<br />
Marijuana is one of the most widely used illicit recreational drugs. However, contrary to the majority of drugs abused by humans, there is a general opinion that rewarding effects are not manifested by animals. We studied a synthetic cannabinoid agonist WIN 55,212-2 using an intravenous self-administration model in drug-naive mice. The results of this study show that WIN 55,212-2 was intravenously self-administered by mice in a concentration-dependent manner according to a bell-shaped curve. Thus, self-administration of WIN 55,212-2 significantly increased, with respect to the vehicle self-administration control group, at concentrations of 0.5 and 0.1 mg/kg per injection. However, at WIN 55,212-2 concentration of 0.5 mg/kg per injection, self-administration significantly decreased. The results obtained show how WIN 55,212-2 is able to elicit both rewarding and aversive effects depending on the concentration used. Pretreatment of mice with the cannabinoid CB1 receptor antagonist SR 141716A (0.25 mg/kg, i.p.) completely prevented WIN 55,212-2 (0.1 mg/kg per injection) self-administration, indicating that WIN 55,212-2 rewarding effects are specifically mediated by cannabinoid CB1 receptors.<br />
2. Br J Pharmacol. 1997 Apr;120(8):1397-8.<br />
Paradoxical action of the cannabinoid WIN 55,212-2 in stimulated and basal cyclic AMP accumulation in rat globus pallidus slices.<br />
Maneuf YP(1), Brotchie JM.<br />
The effects of the synthetic cannabinoid WIN 55,212-2 on forskolin-stimulated and basal adenosine 3/':5/'-cyclic monophosphate (cyclic AMP) accumulation in globus pallidus slices were investigated. WIN 55,212-2 caused a concentration-dependent decrease in forskolin-stimulated cyclic AMP accumulation in globus pallidus slices (maximum inhibition 36% for 30 microM). This effect was blocked by the cannabinoid receptor antagonist SR 141716A (100 microM). WIN 55,212-2 alone caused a concentration-dependent increase in cyclic AMP levels in unstimulated slices (maximum increase 52.6% for 100 microM). This effect was also blocked by SR 141716A (100 microM). In either forskolin-stimulated or unstimulated conditions SR 1417161A (100 microM) did not affect cyclic AMP levels.<br />
3. Br J Pharmacol. 1993 Dec;110(4):1483-90.<br />
Cross-tolerance between delta-9-tetrahydrocannabinol and the cannabimimetic agents, CP 55,940, WIN 55,212-2 and anandamide.<br />
Pertwee RG(1), Stevenson LA, Griffin G.<br />
1. Mice pretreated intraperitoneally for 2 days with delta-9-tetrahydrocannabinol (delta-9-THC) at a dose of 20 mg kg-1 day-1 and then challenged intravenously with this drug, 24 h after the second pretreatment, showed a 6 fold tolerance to the hypothermic effect of delta-9-THC. This pretreatment also induced tolerance to the hypothermic effects of the cannabimimetic agents, CP 55,940 (4.6 fold) and WIN 55,212-2 (4.9 fold), but not to the hypothermic effect of the putative endogenous cannabinoid, anandamide. 2. Vasa deferentia removed from mice pretreated intraperitoneally with delta-9-THC twice at a dose of 20 mg kg-1 day-1 were less sensitive to its inhibitory effect on electrically-evoked contractions than vasa deferentia obtained from control animals. The cannabinoid pretreatment induced a 30 fold parallel rightward shift in the lower part of the concentration-response curve of delta-9-THC and a marked reduction in the maximal inhibitory effect of the drug. It also induced tolerance to the inhibitory effects on the twitch response of CP 55,940 (8.7 fold), WIN 55,212-2 (9.6 fold) and anandamide (12.3 fold). 3. The results confirm that cannabinoid tolerance can be rapid in onset and support the hypothesis that it is mainly pharmacodynamic in nature. The finding that in vivo pretreatment with delta-9-THC can produce tolerance not only to its own inhibitory effect on the vas deferens but also to that of three other cannabimimetic agents, suggests that this tissue would be suitable as an experimental model for investigating the mechanisms responsible for cannabinoid tolerance. 4. Further experiments are required to establish why tolerance to anandamide-induced hypothermia was not produced by a pretreatment with delta-9-THC that did induce tolerance to the hypothermic effects of delta-9-THC, CP 55,940 and WIN 55,212-2 and to the inhibitory effects of delta-9-THC,CP 55,940, WIN 55,212-2 and anandamide on the twitch response of the vas deferens.
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