FORMATION AND INACTIVATION OF ENDOGENOUS CANNABINOID ANANDAMIDE IN CENTRAL NEURONS

ANANDAMIDE (N-arachidonoyl-ethanolamine) was recently identified as a brain arachidonate derivative that binds to and activates cannabinoid receptors(1-4), yet the mechanisms underlying formation, release and i nactivation of this putative messenger molecule are still unclear. Wer e we report that anandamide is produced in and released from cultured brain neurons in a calcium ion-dependent manner when the neurons are s timulated with membrane-depolarizing agents. Anandamide formation occu rs through phosphodiesterase-mediated cleavage of a novel phospholipid precursor, N-arachidonoyl-phosphatidylethanolamine. A similar mechani sm also governs the formation of a family of anandamide congeners, who se possible roles in neuronal signalling remain unknown. Our results a nd those of others(5,6) indicate therefore that multiple biochemical p athways may participate in anandamide formation in brain tissue. The l ife span of extracellular anandamide is limited by a rapid and selecti ve process of cellular uptake, which is accompanied by hydrolytic degr adation to ethanolamine and arachidonate. Our results thus strongly su pport the proposed role of anandamide as an endogenous neuronal messen ger.