The CB1 cannabinoid receptor has attracted much recent interest because of the observation that CB1 receptor antagonists have efficacy in treating metabolic syndrome and obesity. CB1 receptors also mediate most of the psychotropic effects of Δ9-tetrahydrocannabinol (Δ9THC), the principal psychoactive component of cannabis. In addition, they are one component of an interesting and widespread paracrine signaling system, the endocannabinoid system. The endocannabinoid system is comprised of cannabinoid receptors, endogenous cannabinoids, and the metabolic pathways responsible for their synthesis and degradation. The details of the endocannabinoid system have been most thoroughly studied in the brain. Here it has been shown to be intimately involved in several forms of neuronal plasticity. That is, activation of CB1 receptors by endocannabinoids produces either short- or long-term changes in the efficacy of synaptic transmission. The behavioral consequences of these changes are many, but some of the most striking and relevant to the current symposium are those associated with endogenous reward and consumptive behavior.
Cannabinoid receptors are members of the G protein-coupled receptor (GPCR) superfamily of cell surface, heptihelical receptors.1 Thus far, the cloning of two cannabinoid receptors, CB1 and CB2, has been reported. In addition, there is strong pharmacological evidence for additional cannabinoid receptors.2, 3, 4 CB2 receptors are primarily found on immune cells, particularly cells of macrophage lineage.1 As these receptors only indirectly affect neuronal function, they will not be considered further in this review. The CB1 receptor was cloned and identified as a cannabinoid receptor nearly 15 years ago.5 CB1 receptors are members of the Gi/Go-linked GPCR family. Thus, they inhibit voltage-sensitive calcium channels and adenylyl cyclase and activate inwardly rectifying potassium channels and MAP kinase.1 CB1 receptors are among the most abundant GPCRs in the brain, and their levels are comparable to those of ionotropic glutamate receptors.6 This abundance comes about because of the very high levels of CB1 receptor expression in a relatively restricted number of neurons. In the forebrain, CB1 receptors are particularly enriched on axons and presynaptic terminals. In this region of the brain CB1 receptor and the neuropeptide, cholecystokinin (CCK) expression is highly correlated.7, 8 Generally, in the hippocampus, more than 80% of the neurons expressing high levels of CB1 also express CCK, while in cortex the co-expression is about 50%. Similarly, most large diameter CCK containing neurons also express CB1. Although in many forebrain and midbrain structures CB1 receptors are expressed on GABAergic neurons, there is functional evidence for CB1 receptor expression on some glutamatergic neurons in the forebrain.9 In addition, CB1 receptors are abundantly expressed by other glutamatergic neurons such as cerebellar granule cells.1
CB1 receptors inhibit neurotransmitter release
The strong presynaptic localization of CB1 receptors and their inhibition of voltage-dependent calcium channels and adenylyl cyclase suggest that a primary function of CB1 receptors might be to inhibit neurotransmitter release. Indeed, this appears to be the case. Numerous studies with cultured cells, isolated organs, and brain slice preparations have found that activation of presynaptic CB1 receptors leads to an attenuation of neurotransmission. At most synapses, this appears to be primarily because of inhibition of voltage-dependent calcium channels, although at times activation of potassium channels has been suggested.10 At most GABAergic synapses, there appears to be little role for direct inhibition of the vesicular release machinery by CB1 receptors. This coincides with the observation that despite high levels of CB1 expression in presynaptic terminals, they appear to be absent from the active zone of the synapse.11
The presence of a receptor implies the existence of endogenous ligand(s). The cloning of the CB1 receptor intensified the search for such compounds that might mimic Δ9-tetrahydrocannabinol (Δ9THC). Two classes of endogenous cannabinoids (endocannabinoids) have been identified and thoroughly studied.12 The first to be identified was anandamide. This compound is the amide of arachidonic acid and ethanolamine. Anandamide is one member of a rather large family of fatty acid amides. Many, but not all, of these fatty acid amides bind CB1 receptors. The second family of endocannabinoids identified was the glycerol esters, typified by 2-arachidonyl glycerol (2-AG). A striking difference between the endocannabinoids and many classic neurotransmitters is that endocannabinoids appear to be ‘formed on demand’ rather than presynthesized and stored in synaptic vesicles. This has significant implications for the regulation of endocannabinoid signaling. A number of other fatty acid-containing compounds have also been identified as potential endocannabinoids. These include the amino-acid amides, virodhamine, and noladin ether.13 These are discussed in more detail in other reviews in this volume.
Despite the relatively similar structure of the two families of endogenous cannabinoids, substantial differences distinguish the two classes. The first difference is the route of synthesis. The primary pathway of anandamide formation is cleavage of a N-acyl phosphatidyl enthanolamine by a specific phospholipase D. In contrast, 2-AG is typically formed by the sequential action of phospholipase C (forming diacyl glycerol) and of an sn-1 diacyl glycerol lipase, forming 2-AG. The localization and regulation of these enzymes are completely different.14 Thus, the production of anandamide and 2-AG might reasonably be expected to occur at distinct locations and following different stimuli. The actions of 2-AG and anandamide at CB1 receptors are also divergent. Most studies have found 2-AG to be a full agonist, while anandamide has a lower intrinsic efficacy. Thus, at synapses with relatively low CB1 receptor densities, 2-AG will act as a full agonist while anandamide might only be a partial agonist. Finally, the catabolic pathways for these two endocannabinoids are distinct. Anandamide and related fatty acid amides are primarily degraded by fatty acid amino hydrolase (FAAH), while 2-AG appears to be primarily degraded by a monoacyl glycerol lipase (MAGL). Fatty acid amino hydrolase tends to be post-synaptically localized while MAGL is mostly found presynaptically,14 implying distinct sites of degradation for these different families of endocannabinoids.
Interaction of endogenous and exogenous cannabinoids
The presence of a cannabinoid receptor that binds Δ9THC suggests that cannabis might produce its psychoactive effects in the same way that opium extracts do. Namely, that by binding to and activating the CB1 receptor, Δ9THC mimics the actions of endogenous cannabinoids. While this idea is attractive, it appears to be too simplistic. While under most conditions, release of endogenous opioids is low – this does not seem to be the case for endocannabinoids.15, 16 Thus, in ‘normal’ CNS tissue, opioids receptors are relatively unoccupied and exogenously administered opiates can bind to and activate them. In contrast, the continuous production of endocannabinoids results in CB1 receptors having a greater level of occupancy and activation compared to opioids receptors. Therefore, the effects of exogenous cannabinoids, such as Δ9THC, will depend on the level of CB1 occupancy, as well the nature of endocannabinoid binding to the receptor.
Most studies have found that Δ9THC and anandamide are partial agonists with similar efficacy, while 2-AG has a substantially greater efficacy.17 Thus, in one way, Δ9THC and anandamide can be thought of being roughly equivalent – activating CB1 receptors to a similar extent. In this way, Δ9THC will be mimicking the effects of anandamide where this endocannabinoid predominates. In contrast, at synapses where 2-AG is the major endocannabinoid, the partial agonism of Δ9THC could antagonize 2-AG's action, causing a decrease in CB1-mediated effects. This scheme predicts that the psychoactive effects of Δ9THC would not necessarily be fully antagonized by a CB1 receptor antagonist. Indeed, this appears to be the case. In a study investigating the ability of the CB1 receptor antagonist, rimonabant, to reverse the effects of Δ9THC, Marilyn Heustis and her colleagues found that even very high doses of rimonabant (90 mg) were only modestly effective in reducing most of the subjective components of the ‘high’ elicited by smoking of a cannabis cigarette.18 Interestingly, the autonomic effect (tachycardia) elicited by cannabis was more effectively antagonized by rimonabant than the subjective effects,18 suggesting that the former might be mediated by fatty acid amides and the latter mediated by 2-AG.
Endocannabinoid release mediates short-term plasticity at specific synapses
The observation that endocannabinoids are produced following increases in intracellular calcium or increases in cAMP suggested that they might be produced during periods of intense CNS activity. This appears to be the case. Endocannabinoids mediate a process called DSI (i.e. depolarization-induced suppression of inhibition). Depolarization-induced suppression of inhibition occurs after a neuron, for example a hippocampal pyramidal cell or cerebellar Purkinje neuron, is strongly depolarized. The depolarization robustly attenuates the inhibitory input onto that neuron. A similar phenomenon occurs with some excitatory inputs; the process here is referred to as DSE (depolarization-induced suppression of excitation). Both DSI and DSE were thought to involve a retrograde messenger as depolarization of the post-synaptic cell was required, but the phenomenon was manifested by a decrease in neurotransmitter release from the presynaptic terminal – thus a signal passed from the post-synaptic to the presynaptic cell. In a pair of studies published in 2001, Rachel Wilson and Roger Nicoll elegantly demonstrated that endocannabinoids are involved in hippocampal DSI.19, 20 Endocannabinoids were soon implicated in hippocampal DSE and cerebellar DSE. These initial studies were followed by numerous other studies, all with the general conclusion that if CB1 receptors are expressed presynaptically to a neuron, then DSI or DSE could usually be evoked at that synapse.12, 21 Of particular relevance to consumptive behavior is that leptin inhibits DSI in lateral hypothalamic slices; furthermore, DSI was prolonged in leptin-deficient, ob/ob mice.22
Endocannabinoid involvement in DSI and DSE has gained widespread acceptance. However, there are several features of the process and experimental details that need to be considered. The first is that endocannabinoids are widely believed to be the retrograde messenger involved in DSI and DSE. Yet, as of now, there is no direct demonstration that endocannabinoids made post-synaptically diffuse presynaptically to cause DSI or DSE. It is conceivable that the post-synaptic cell makes an, as yet unknown, retrograde messenger that diffuses presynaptically eliciting endocannabinoid production. The second is that glial cells, particularly astrocytes and microglial cells, but likely oliogodendrocytes as well, are prolific producers of endocannabinoids.23 Thus, the involvement of glia in these schemes needs to be considered. The third is that CB1 activation not only inhibits GABA and glutamate release but also inhibits release of neuropeptides from CB1 receptor-containing nerve terminals. In the case of forebrain CB1 receptors, this would often mean the inhibition of CCK release.11 Since CCK is generally excitatory in nature, decreasing its release will complicate the perhaps overly simplistic interpretation that activation of CB1 receptors in DSI solely decreases inhibition. Rather the net effect will be a balance of the decreased inhibition because of less activation of GABA A receptors (GABA B receptors do not seem to be involved, at least in hippocampal DSI) and decreased excitation because of less activation of CCK receptors. A fourth consideration is the spatial influence of DSI and DSE. As described above, DSI and DSE will diminish release only from nerve terminals adjacent to the depolarized neuron. This is because a number of experiments have shown that the retrograde transmitter released following depolarization acts only over a distance of 10 μm, or so. However, if the soma of a neuron adjacent to the depolarized neuron expresses CB1 receptors, activation of these receptors by endocannabinoids can open inwardly rectifying potassium channels, decreasing the spontaneous firing of the adjacent neuron. This will potentially decrease neurotransmitter release over a wide area, limited only by the extent of the adjacent neuron's axonal network. This sort of widespread influence of local endocannabinoid release has been found in both cerebellum and cortex.24, 25 A final consideration is that stimuli other than step depolarizations can produce DSI and DSE. For example, near physiological firing patterns in cerebellum cause DSE and muscarinic and metabotropic glutamate receptor activation can cause DSI in the hippocampus. Taking these considerations into account, it is clear that DSI and DSE are mechanisms that allow a quite flexible degree of control of short-term, but not necessarily local, neuronal plasticity.
Endocannabinoid involvement in long-term plasticity
The above discussion highlighted the involvement of endocannabinoids in a form of short-term neuronal plasticity. More recently, convincing evidence has emerged implicating endocannabinoids in a form of long-term plasticity, termed long-term depression, or LTD.26 Long-term depression typically results following sustained low-frequency stimulation of a neuronal pathway and can have many causes. Endocannabinoids have been found to be involved in LTD of two excitatory pathways, from cortex to the dorsal striatum and from prefrontal cortex to the nucleus accumbens and two inhibitory circuits, one in the hippocampus and the other in the amygdala.26 Given the role of some of these pathways (e.g., nucleus accumbens and amygdala) in reward and hedonistic behaviors, it is not surprising that a growing literature supports the notion that endocannabinoids are intimately involved in these behaviors.27
The hallmark of LTD is that the strength of neurotransmission decreases following a particular pattern of synaptic activity, typically prolonged low-frequency stimulation. That is, the quantity of neurotransmitter released is attenuated following the LTD stimulus. This phenomenon has been best studied in the nucleus accumbens and hippocampus and a fairly complete description of the mechanism is possible. Prolonged low-frequency stimulation of excitatory inputs leads to a substantial release of glutamate. These act at post-synaptic group I metabotropic glutamate receptors causing the synthesis of endocannabinoids. The endocannabinoids (likely 2-AG) then diffuse retrogradely, activating presynaptic CB1 receptors. Through a mechanism that is not well understood, sustained activation of these presynaptic CB1 receptors triggers a change in the terminal that leads to a long-term inhibition of neurotransmitter release. Activation of cannabinoid receptors is only needed for the initiation of LTD. Once established, CB1 receptor antagonists do not block LTD. Note that although prolonged low-frequency stimulation of excitatory neurons is needed for LTD to occur, the synapses undergoing LTD are those that have CB1 receptors. These may or may not be glutamatergic. For example, in nucleus accumbens, it is the persistently firing glutamate terminals from prefrontal cortex that undergo LTD, while in hippocampus the glutamate input is provided by the Schaffer collaterals, but it is the terminals of the CCK-positive GABAergic basket cells that undergo LTD. Another form of LTD sometimes involving endocannabinoids is a specific form of (spike) timing-dependent LTD.28 This type of LTD occurs if a postsynaptic cell depolarizes (at times a sub-threshold depolarization is sufficient) just prior to a synaptic terminal release of glutamate release in a repetitive fashion. This form of LTD involves endocannabinoids, and is distinct from the previously discussed form of LTD in that presynaptic NMDA glutamate receptors are required.
Ample evidence has accumulated over the past decade that endocannabinoids serve as mediators of short- and long-term neuronal plasticity. Thus, in addition to being the target for Δ9THC, the principal psychoactive component of cannabis, CB1 cannabinoid receptors are also central to important normal behavioral pathways. The behaviors involved are diverse and include: movement, sensory learning, analgesia, anxiety, and appetitive behaviors, to name a few. At the current time, the most relevant of these for therapeutic manipulation are obesity (with involvement of both central and peripheral mechanisms – alternatively homeostatic and hedonic mechanisms) and craving-based disorders, such as alcohol and tobacco dependency. As our understanding of the basic biology of the endocannabinoid system develops, it is likely that additional therapeutically beneficial manipulations of this system will be developed, as we have seen with the CB1 receptor antagonist, rimonabant.
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Cite this article
Mackie, K. Mechanisms of CB1 receptor signaling: endocannabinoid modulation of synaptic strength. Int J Obes 30, S19–S23 (2006). https://doi.org/10.1038/sj.ijo.0803273
- neuronal plasticity
- retrograde signalling
- unsaturated fatty acid
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