3-(2-hydroxy-4-(1-1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol and Seizures

Administration of the muscarinic agonist pilocarpine is commonly used to induce seizures in rodents for the study of epilepsy. Activation of muscarinic receptors has been previously shown to increase the production of endocannabinoids in the brain. Endocannabinoids act at the cannabinoid CB1 receptors to reduce neurotransmitter release and the severity of seizures in several models of epilepsy. In this study, we determined the effect of CB1 receptor activity on the induction in mice of seizures by pilocarpine. We found that decreased activation of the CB1 receptor, either through genetic deletion of the receptor or treatment with a CB1 antagonist, increased pilocarpine seizure severity without modifying seizure-induced cell proliferation and cell death. These results indicate that endocannabinoids act at the CB1 receptor to modulate the severity of pilocarpine-induced seizures. Administration of a CB1 agonist produced characteristic CB1-dependent behavioral responses, but did not affect pilocarpine seizure severity. A possible explanation for the lack of effect of CB1 agonist administration on pilocarpine seizures, despite the effects of CB1 antagonist administration and CB1 gene deletion, is that muscarinic receptor-stimulated endocannabinoid production is acting maximally at CB1 receptors to modulate sensitivity to pilocarpine seizures.

Topics: Animals; Cyclohexanols; Male; Mice; Mice, Knockout; Muscarinic Agonists; Pilocarpine; Proliferating Cell Nuclear Antigen; Receptor, Cannabinoid, CB1; Seizures

Based on the previously reported co-localization and relationship between cannabinoid and dopamine receptors, the effects of cannabinoid receptor agonists against cocaine-induced toxic behavioural symptoms, including convulsive seizures, were examined in mice. The anticonvulsant effect of several cannabimimetics against seizures induced by other convulsants was also compared. The cannabinoid receptor agonists CP 55940 ((-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)-cyclohexanol) and WIN 55212-2 ((R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone), and the endogenous cannabinoid anandamide were co-administered intraperitoneally with cocaine (75 mg kg(-1)) or other convulsants such as bicuculline, methyl 6,7-dimethoxy-4-ethyl-beta-carboline-carboxylate (DMCM), L-glutamic acid and N-methyl-D-aspartate (NMDA). CP 55940 (2.5 mg kg(-1)) and anandamide (15 mg kg(-1)) significantly antagonized cocaine-induced lethality, and CP 55940 and WIN 55212-2 (2.5 mg kg(-1)) significantly attenuated the severity of cocaine-induced convulsive seizures. Furthermore, ataxic hyperactivity, which was observed only in the cocaine-treated group of mice and could be evaluated by their activity counts, was also depressed in the groups of mice co-treated with each of the three cannabinoid agonists. However, none of these agonists protected against bicuculline- or DMCM-induced lethality or convulsive seizures. In contrast, all of the cannabinoid agonists, most notably anandamide, antagonized both L-glutamic acid (2 g kg(-1))- and NMDA (200 mg kg(-1))-induced convulsive seizures. These data support the previously reported close correlation between dopamine and cannabinoid receptors, and between cannabinoid agonists, especially anandamide, and glutamate (NMDA) receptors. Furthermore, these results suggest a potential therapeutic role for cannabinoid agonists against cocaine- and other-convulsant-induced toxicities.

Topics: Animals; Arachidonic Acids; Behavior, Animal; Benzoxazines; Cocaine; Convulsants; Cyclohexanols; Dopamine Uptake Inhibitors; Drug Interactions; Endocannabinoids; Male; Mice; Mice, Inbred ICR; Morpholines; Naphthalenes; Polyunsaturated Alkamides; Receptors, Cannabinoid; Receptors, Drug; Seizures; Survival Rate

The effects of the endogenous cannabinoid (CB) anandamide (AEA) and its analogs on cocaine (COCA)-induced toxic symptoms such as lethality, convulsive seizures and hyperactivity were examined in mice. In addition to AEA, the effects of the AEA analogs arachidonyl-2-chloroethylamide (ACEA), arachidonylcyclopropylamide (ACPA) and R-(+)-methanandamide (METH) were compared to the selective and strong CB1 agonist CP 55940 (CP). Intraperitoneal (i.p.) coadministrations of these drugs with COCA (75 mg/kg) demonstrated that AEA (10 and 15 mg/kg), ACEA (5 mg/kg), ACPA (5 mg/kg), METH (5, 10 and 15 mg/kg) and CP (2.5 and 5 mg/kg) all antagonized the COCA-induced lethality, and that ACEA (5 and 10 mg/kg), ACPA (5 and 10 mg/kg), METH (5, 10 and 15 mg/kg) and CP (1, 2.5 and 5 mg/kg) antagonized the COCA-induced convulsive seizures. When alterations in the COCA-induced toxic behaviors were also evaluated by an activity counting instrument, antidotal effects against the COCA-induced hyperactivity were also observed using the above doses. The effects against hyperactivity were stronger in the groups of mice cotreated with CP or ACEA than in the groups of mice cotreated with AEA or METH. However, the antidotal effects against the lethality and convulsive seizures were stronger in the METH-treated group than in the AEA-, ACEA- or ACPA-treated groups, although the selectivity of METH for brain CB1 receptors was lower than for ACEA or ACPA. The correlation with other brain receptors and/or peripheral CB receptors seemed to contribute to the strong antidotal effects of METH, which were not exceeded even by CP.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Cocaine; Cyclohexanols; Drug Interactions; Drug Therapy, Combination; Endocannabinoids; Hyperkinesis; Ligands; Mice; Mice, Inbred ICR; Polyunsaturated Alkamides; Receptors, Cannabinoid; Receptors, Drug; Seizures