Abstract
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 CB1 and CB2 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 CB1 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 CB1 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.
Highlights
The cerebellum was one of the areas where depolarization-induced suppression of inhibition (DSI) was discovered [200, 214]. Cannabinoid effects in these two brain regions have been discussed at the cellular level in sections III and IV; here we only focus on implications for DSI/depolarization-induced suppression of excitation (DSE) and, whenever data are available, possible network mechanisms
The aim of this review was to synthesize the currently available data about the life cycle of endocannabinoids; the conditions that result in their release in the brain; the precise sites of their action at the regional, cellular, and subcellular levels; and their physiological effects on neuronal networks
A general view emerging from the synthesis of the available data is that endocannabinoids serve as mediators in neuronal communication that is distinct from synaptic and nonsynaptic transmission in its range and function
Summary
Ancient Indian and Chinese medical writers were even more accurate than their European colleagues in describing the remarkable physiological and psychological effects of this plant (for review, see Ref. 241). We know that these effects, which in humans include a variable combination of euphoria, relaxation, reflex tachycardia, and hypothermia, are primarily produced by the dibenzopyrane derivative, delta-9-tetrahydrocannabinol (delta-9-THC), present in the yellow resin that covers the leaves and flower clusters of the ripe female plant. Cocaine, and other alkaloids of plant origin, delta-9-THC is a highly hydrophobic compound, a property that, curiously enough, has slowed the progress on the mode of action of this compound for nearly three decades. The affinity of delta-9-THC for lipid membranes erroneously suggested, that the drug’s main effect was to modify in a nonselective manner the fluidity of cell membranes rather than to activate a selective cell-surface receptor [157, 207]
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