Role of Endogenous Cannabinoids in Synaptic Signaling

• Published in: Physiological reviews Vol. 83; no. 3; pp. 1017 - 1066
• Main Authors: FREUND, TAMAS F, KATONA, ISTVAN, PIOMELLI, DANIELE
• Format: Journal Article
• Language: English
• Published: United States Am Physiological Soc 01-07-2003; American Physiological Society
• Subjects: Animals; Brain; Cannabinoid Receptor Modulators; Cannabinoids; Cannabinoids - analysis; Cannabinoids - metabolism; Cannabinoids - pharmacology; Cellular biology; Central Nervous System - cytology; Central Nervous System - drug effects; Central Nervous System - metabolism; Humans; Neurology; Neurons; Neurotransmitters; Receptors, Cannabinoid; Receptors, Drug - analysis; Receptors, Drug - metabolism; Signal Transduction - drug effects; Synapses - drug effects
• ISSN: 0031-9333; 1522-1210
• DOI: 10.1152/physrev.00004.2003

Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary; Department of Clinical Neurobiology, University Hospital of Neurology, Heidelberg, Germany; and Department of Pharmacology, University of California Irvine, Irvine, California
Freund, Tamás F., István Katona, and Daniele Piomelli.
Role of Endogenous Cannabinoids in Synaptic Signaling. Physiol Rev
83: 1017–1066, 2003; 10.1152/physrev.00004.2003.—Research of cannabinoid actions was boosted in the 1990s by remarkable discoveries including identification of endogenous compounds with cannabimimetic activity (endocannabinoids) and the cloning of their molecular targets, the CB 1 and CB 2 receptors. Although the existence of an endogenous cannabinoid signaling system has been established for a decade, its physiological roles have just begun to unfold. In addition, the behavioral effects of exogenous cannabinoids such as delta-9-tetrahydrocannabinol, the major active compound of hashish and marijuana, await explanation at the cellular and network levels. Recent physiological, pharmacological, and high-resolution anatomical studies provided evidence that the major physiological effect of cannabinoids is the regulation of neurotransmitter release via activation of presynaptic CB 1 receptors located on distinct types of axon terminals throughout the brain. Subsequent discoveries shed light on the functional consequences of this localization by demonstrating the involvement of endocannabinoids in retrograde signaling at GABAergic and glutamatergic synapses. In this review, we aim to synthesize recent progress in our understanding of the physiological roles of endocannabinoids in the brain. First, the synthetic pathways of endocannabinoids are discussed, along with the putative mechanisms of their release, uptake, and degradation. The fine-grain anatomical distribution of the neuronal cannabinoid receptor CB 1 is described in most brain areas, emphasizing its general presynaptic localization and role in controlling neurotransmitter release. Finally, the possible functions of endocannabinoids as retrograde synaptic signal molecules are discussed in relation to synaptic plasticity and network activity patterns.
Address for reprint requests and other correspondence: T. F. Freund, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest 8, Szigony u.43, H-1083 Hungary (E-mail: freund{at}koki.hu ).