Endocannabinoid System

The endocannabinoid system is an endogenous signaling system composed of endocannabinoids, their receptors, and the proteins involved in their synthesis and degradation (Pazos et al. 2005). Anandamide and 2-arachidonoylglycerol, the two principal endocannabinoids in the brain, bind to and activate the G protein-coupled cannabinoid receptors, CB1 and CB2. The CB1 receptor, the predominant endocannabinoid receptor in the brain, mediates most of the behavioral effects of endogenous and exogenous cannabinoids (Zimmer et al. 1999). The CB2 receptor is principally expressed in non-neural tissues, such as immune system organs (e.g., spleen). CB1 receptors are located primarily on presynaptic axon terminals and mediate the retrograde signaling of endocannabinoids in synaptic plasticity processes, such as depolarization-induced suppression of inhibition (Alger 2002).

Distribution of the CB1 receptor is widespread, with many areas of the brain expressing high levels (Figure 4-7). Specifically, the neocortex, hippocampus, amygdala, globus pallidus, and cerebellum all exhibit high densities of the CB1 receptor (Biegon and Kerman 2001; Eggan and Lewis 2007; Herkenham et al. 1991). Within the primate cerebral cortex, association regions, such as the prefrontal cortex, contain the highest levels of CBi-immunoreactive axons, whereas primary sensory regions, particularly primary visual cortex, have the lowest densities (Eggan and Lewis 2007). Within the prefrontal cortex, dorsolateral area 46 contains the highest densities of CBi-immunoreactive axons. The density of CBi-labeled axons in the hippocampus is similar to that in the prefrontal cortex. Interestingly, within the amygdala, the cortical-like basolateral complex has a higher density of CB1 axons than does the striatal-like central and medial nuclei (Figure 4-7). Of the basal ganglia nuclei, the globus pallidus has the highest and the striatum the lowest levels of CB1 immunoreactivity. As is evident in Figure 4-7, the thalamus is completely devoid of CB1 axons.

FIGURE 4-7. Brightfield photomicrograph of a coronal section through macaque monkey brain illustrating the distribution of cannabinoid CB1 receptor-immunoreactive axons.

FIGURE 4-7. Brightfield photomicrograph of a coronal section through macaque monkey brain illustrating the distribution of cannabinoid CB1 receptor-immunoreactive axons.

Copyright © American Psychiatric Publishing, Inc., or American Psychiatric Association, unless otherwise indicated in figure legend. All rights reserved.

Association areas such as the cingulate cortex (area 32), insula (Ig, Idg), auditory association cortex (RP), and entorhinal cortex (Ei) have an overall higher density of CBi-immunoreactive axons than do primary somatosensory areas (areas 3, 1, 2) and primary motor cortex (area 4). Note the distinct differences in laminar distribution of labeled processes at the boundaries of some cytoarchitectonic regions (arrows). In subcortical structures, the intensity of CB1 immunoreactivity is high in the claustrum (Cl), the basal and lateral nuclei of the amygdala, and both segments of the globus pallidus (GP); intermediate to low in the caudate (Cd) and putamen (Pu) and the central and medial nuclei of the amygdala; and not detectable in the thalamus (Th). Scale bar = 2 mm. ABmc = accessory basal nucleus, magnocellular division; ABpc = accessory basal nucleus, parvicellular division; Bi = basal nucleus, intermediate division; Bmc = basal nucleus, magnocellular division; Bpc = basal nucleus, parvicellular division; CC = corpus callosum; Cd = caudate; Ce = central amygdaloid nucleus; Cgs = cingulate sulcus; Cl = claustrum; COp = posterior cortical nucleus; cs = central sulcus; Ei = entorhinal cortex, intermediate field; GPe = globus pallidus, external; GPi = globus pallidus, internal; Idg = insula, dysgranular; Ig = insula, granular; ips = intraparietal sulcus; Ldi = lateral nucleus, dorsal intermediate division; lf = lateral fissure; Lv = lateral nucleus, ventral division; Lvi = lateral nucleus, ventral intermediate division; Me = medial amygdaloid nucleus; PN = paralaminar nucleus; Pu = putamen; R = rostral auditory area (core primary auditory); rf = rhinal fissure; RM = rostromedial auditory belt; RP = rostral auditory parabelt; SII = second somatosensory cortex; sts = superior temporal sulcus; TE = inferotemporal cortex; Th = thalamus; TPO = temporal parieto-occipital associated area in sts.

Source. Reprinted from Eggan SM, Lewis DA: "Immunocytochemical Distribution of the Cannabinoid CB1 Receptor in the Primate Neocortex: A Regional and Laminar Analysis." Cerebral Cortex 17:175-191, 2007. Copyright 2007, Oxford. Used with permission.

In the neocortex, the CB1 receptor is highly expressed in the subpopulation of GABA-containing inhibitory interneurons (Marsicano and Lutz 1999) that also synthesize the neuropeptide cholecystokinin (Bodor et al. 2005). In addition, in rodent hippocampus (Katona et al. 1999) and monkey prefrontal cortex (Melchitzky et al. 2007), CB1-immunoreactive axons have been shown to be collocated with cholecystokinin. This association of CB1 with GABA neurons in the prefrontal cortex suggests that the endocannabinoid system may be involved in cognitive processing as well as in disorders characterized by impaired cognition, such as schizophrenia. Indeed, cannabis use impairs cognitive processes such as working memory (D'Souza et al. 2004) and has been associated with an increased risk for schizophrenia (Smit et al. 2004). In addition, a reduction in CB1 mRNA levels in the prefrontal cortex of subjects with schizophrenia (Eggan et al. 2008) provides further evidence for a role of the endocannabinoid system in the pathophysiology of schizophrenia.

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