Protective effects of cannabinoid receptor ligands analogous to anandamide against cocaine toxicity

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.