Inhibitors of anandamide breakdown.

-Tetrahydrocannabinol (THC), the psychoactive marijuana plantderived cannabinoid, and numerous synthetic derivatives have been shown to bind to a specific brain receptor, cannabinoid receptor 1 (CB1) (Howlett et al. 1990; Matsuda et al. 1990; Herkenham et al. 1990; Mailleux and Vanderhagen 1992). Arachidonoyl ethanolamide (anandamide), homo--linolenyl ethanolamide, and docosatetraenyl ethanolamide are naturally occurring brain constituents that bind to CB1 and as a class are called the anandamides (Mechoulam et al. 1994; Devane et al. 1992; Hanus et al. 1993; Felder et al. 1993; Devane 1994). Anandamide behaves as a cannabimimetic compound in vitro, stimulating receptor-mediated signal transduction that leads to the inhibition of forskolin-stimulated adenylate cyclase (Vogel et al. 1993; Childers et al. 1993)1. In a neuroblastoma cell line, anandamide causes partial inhibition of N-type calcium currents via a pertussis toxin-sensitive guanosine triphosphate binding protein (Gprotein) pathway, independently of cyclic adenosine monophosphate (cAMP) metabolism (Mackie et al. 1993). Using a series of behavioral tests to evaluate cannabinoid analogs, anandamide has been shown to be a cannabinoid receptor agonist exhibiting pharmacological activity in mice parallel to that of other psychotropic cannabinoids (Fride and Mechoulam, 1993; Crawley et al. 1993; Smith et al. 1994; Abadji et al. 1994).