FUNCTIONAL-ROLE OF HIGH-AFFINITY ANANDAMIDE TRANSPORT, AS REVEALED BYSELECTIVE-INHIBITION

Anandamide, an endogenous ligand for central cannabinoid receptors, is released from neurons on depolarization and rapidly inactivated. Anan damide inactivation is not completely understood, but it may occur by transport into cells or by enzymatic hydrolysis. The compound N-(4-hyd roxyphenyl)arachidonylamide (AM404) was shown to inhibit high-affinity anandamide accumulation in rat neurons and astrocytes in vitro, an in dication that this accumulation resulted from carrier-mediated transpo rt. Although AM404 did not activate cannabinoid receptors or inhibit a nandamide hydrolysis, it enhanced receptor-mediated anandamide respons es in vitro and in vivo, The data indicate that carrier-mediated trans port may be essential for termination of,the biological effects of ana ndamide, and may represent a potential drug target.