P.1.016 Effects of endocannabinoid neurotransmission enhancers in the intracranial self-stimulation paradigm and the reinforcing actions of cocaine

Abstract

Dibenzopyran (Δ9-tetrahydrocannabinol) and aminoalkylindole [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrolol[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl) methanone mesylate; (WIN55,212-2)] cannabinoids suppress vomiting produced by cisplatin via cannabinoid CB1 receptors. This study investigates the antiemetic potential of the “nonclassical” cannabinoid CP55,940 [1α,2β-(R)-5α]-(−)-5-(1,1-dimethyl)-2-[5-hydroxy-2-(3-hydroxypropyl) cyclohexyl-phenol] against cisplatin-induced vomiting and assesses the presence and functionality of cannabinoid CB1 receptors in the least shrew (Cryptotis parva) brain. CP55,940 (0.025–0.3 mg/kg) reduced both the frequency of cisplatin-induced emesis (ID50=0.025 mg/kg) and the percentage of shrews vomiting (ID50=0.09 mg/kg). CP55,940 also suppressed shrew motor behaviors (ID50=0.06– 0.21 mg/kg) at such doses. The antiemetic and motor-suppressant actions of CP55,940 were countered by SR141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide], indicating both effects are cannabinoid CB1 receptor-mediated. Autoradiographic studies with [3H]-SR141716A and [35S]-GTPγS binding revealed that the distribution of the cannabinoid CB1 receptor and its activation pattern are similar to rodent brain and significant levels are present in brain loci (e.g., nucleus tractus solitarius (NTS)) that control emesis. The affinity rank order of structurally diverse cannabinoid ligands for cannabinoid CB1 receptor in shrew brain is similar to rodent brain: HU-210=CP55,940=SR141716A≥WIN55,212-2≥delta-9-tetrahydrocannabinol>methanandamide=HU-211=cannabidiol=2-arachidonoylglycerol. This affinity order is also similar and is highly correlated to the cannabinoid EC50 potency rank order for GTPγS stimulation except WIN55,212-2 and delta-9-tetrahydrocannabinol potency order were reversed. The affinity and the potency rank order of tested cannabinoids were significantly correlated with their antiemetic ID50 potency order against cisplatin-induced vomiting (CP55,940>WIN55,212-2=delta-9-tetrahydrocannabinol) as well as emesis produced by 2-arachidonoylglycerol or SR141716A (CP55,940>WIN55,212-2>delta-9-tetrahydrocannabinol).