Endocannabinoid system

The endocannabinoid system (ECS) tightly regulates the probability of neurotransmitter release in a host of neuronal tissues like the hippocampus, amygdala, basal ganglia, and cerebellum [1] [2] [3] Data from immunologists, developmental biologists, and embryologists show that the ECS is also intimately involved in crosstalk between lymphocytes and synchronizing the timing between uterine receptivity and embryo implantation (Paria et al., 2001; Paria et al., 2002; Bai et al., 2005). In the central nervous system, however, the ECS is involved in a specific type of retrograde signaling in which endogenous cannabinoids (endocannabinoids) are released from the post-synaptic neuron and bind to nearby cannabinoid receptor 1 (CB1) -expressing presynapses; this binding elicits a sharp, but temporary, suppression of presynaptic neurotransmitter release (Gebremedhin et al., 1999). In this way, the post-synaptic neuron can regulate its own excitability by adjusting synaptic inputs via endocannabinoids that act as retrograde messengers. The endocannabinoid system is thought important in long-term potentiation and memory[4] [5], motor learning [6], and synaptic plasticity [7].

Introduction

Endocannabinoid Synthesis & Release

In standard neurotransmission, the pre-synaptic neuron releases neurotransmitter into the synaptic cleft which binds to cognate receptors expressed on the post-synaptic neuron. Upon binding, the neuron depolarizes. This depolarization facilitates in the influx of calcium into the neuron; this increase in calcium activates an enzyme called [[transacylase] which catalyzes the first step of endocannabinoid biosynthesis by converting phosphatidylethanolamine, a membrane-resident phospholipid into N-acyl-phosphatidylethanolamine (NAPE). Experiments have shown that both phospholipase C and phospholipase D cleave NAPE to yield anandamide and 2-AG, respectively (Okamoto et al., 2004; Liu et al, 2006). In phospholipase D (PLD) knockouts, the PLD-mediated cleavage of NAPE is reduced, not abolished, in low calcium concentrations, suggesting multiple, distinct pathways are involved in 2-AG biosynthesis (Leung et al., 2006). Once released into the extracellular space by a putative endocannabinoid transporter, messengers are vulnerable to glial inactivation. Endocannabinoids are uptaken via a putative transporter and degraded by fatty acid amide hydrolase (FAAH) which cleaves anandamide and 2-AG to arachidonic acid & ethaloamine and arachidonic acid & glycerol, respectively (reviewed in Pazos et al., 2005). While arachidonic acid is a substrate for leukotriene and prostaglandin synthesis, it is unclear whether this degradative byproduct has novel functions in the CNS (Yamaguchi et al., 2001; Brock, T., 2005). Emerging data in the field also points to FAAH being expressed in the postsynaptic neuron, suggesting it also contributes to the clearance and inactivation of anandamide and 2-AG by endocannabinoid reuptake.

ECS changes induced by Cannabis Consumption

Appetite

Those who use cannabis are familiar with its appetite-enhancing effects. Emerging data suggests that THC act via CB1 receptors on hypothalamic nuclei, thus directly increasing appetite[8][9]. It is thought that hypothalamic neurons tonically produce endocannabinoids that work to tightly regulate hunger. Interestingly, the amount of endocannabinoids produced is inversely correlated with the amount of leptin in the blood[10]. For example, mice without leptin not only become massively obese but have higher-than-normal levels of hypothalamic endocannabinoids [11]. Similarly, when these mice were treated with an endocannabinoid antagonist, such as Rimonabant, food intake was reduced[12]. While there is need for more research, these results (and others) suggest that exogenous cannabinoids (as from smoking marijuana) in the hypothalamus activates a pathway responsible for food-seeking behavior [13].

ECS and female reproduction

The developing embryo expresses cannabinoid receptors early in development that are responsive to anandamide which is secreted in the uterus. This signaling is important in regulating the timing of embryonic implantation and uterine receptivity. In mice, it has been shown that anandamide modulates the probability of implantation to the uterine wall . For example, in humans, the likelihood of miscarriage increases if uterine anandamide levels are too high or low [14]. These results suggest that proper intake of exogenous cannabinoids (e.g. marijuana) can decrease the likelihood for pregnancy[15][16].

ECS and Multiple Sclerosis

Historical records from ancient China and Greece suggest that preparations of Cannabis Sativa were commonly prescribed to ameloriate multiple sclerosis-like symptoms such as tremors and muscle pain; unfortunately, however, treatment of marinol hasn’t shown the same efficacy as inhaled Cannabis (reviewed in Pertwee, 2001). Due to the illegality of Cannabis and rising incidence of multiple sclerosis patients who self-medicate with the drug, there has been much interest in exploiting the cerebellar endocannabinoid system to provide a legal and effective relief (reviewed in Pertwee, 2001). In mouse models of multiple sclerosis, there is a profound reduction and reorganization of CB1 receptors in the cerebellum (Cabranes et al., 2006). Serial sections of cerebellar tissue subjected to immunohistochemistry revealed that this aberrant expression occurred during the relapse phase but returned to normal during the remitting phase of the disease (Cabranes et al., 2006). There is recent data indicating that CB1 agonists promote the in vitro survival of oligodendrocytes, specialized support glia that are involved in axonal myelination, in the absence of growth and trophic factors; in addition, these agonist have been shown to promote mRNA expression of myelin lipid protein. (Kittler et al., 2000; Mollna-Holgado et al., 2002). Taken together, these studies point to the exciting possibility that cannabinoid treatment may not only be able to attenuate the symptoms of multiple sclerosis but also improve oligodendrocyte function (reviewed in Pertwee, 2001; Mollna-Holgado et al., 2002).