Extrapyramidal effects of methanandamide, an analog of anandamide, the endogenous CB1 receptor ligand

Recent evidence has demonstrated that arachidonylethanolamide (''anandamide'', AEA), the major endogenous ligand of CB1 receptors, inhibits motor behavior in rats, as does (-)Delta(9)-tetrahydrocannabinol (THC), the prototypical tricyclic cannabinoid derived from Cannabis sativa preparations. However, its effects were of shorter duration, as compared to THC, likely due to its rapid breakdown by an amidase activity. The present work has been designed to examine the motor effects of AM356 (R-methanandamide), an analog of AEA that possesses higher metabolic stability to amidase hydrolysis. We have studied the dose-response and time-course effects of R-methanandamide, i.p. administered, on ambulatory activity, frequency of stereotypy and time spent in inactivity measured in an open-field test. Results were as follows. R-Methanandamide, as THC and AEA, inhibited motor behavior. Thus, it decreased ambulation and stereotypy and increased the time spent in inactivity, usually in a dose-related manner, 10 min after administration. However, the motor deficit caused by the highest dose of R-methanandamide was usually more pronounced than that caused by a similar dose of AEA. These inhibitory effects persisted 30 min after the administration of R-methanandamide, as occurred with AEA and THC. Interestingly, at 60 min after administration, the effects of AEA disappeared, likely because of its breakdown to arachidonic acid and ethanolamine, but this did not occur with R-methanandamide whose effects persisted even until 180 min after treatment as occurred with THC. In summary, R-methanandamide inhibits motor behavior in a manner (its effects were persistent) that resembles the effects of THC rather than the effects of AEA (its effects were of rapid onset but shorter duration). This fact supports the use of R-methanandamide as a valuable tool for studying the physiological roles of the anandamidergic system.