Abstract
The Gamma-aminobutyric acid (GABA) system is the main inhibitory neurotransmitter system in the central nervous system (CNS) of vertebrates and is involved in critical cellular communication and brain function. The endocannabioid system (ECS) was only recenty discovered and quickly recognized to be abundantly expressed in GABA-rich areas of the brain. The strong relationship between the GABA system and ECS is supported both by studies of the neuraoanatomy of mammalian nervous systems and the chemical messaging between neurons. The ECS is currently known to consist of two endocannabinoids, Anandamide (AEA) and 2-Arachidonyl Glycerol (2-AG), that function as chemical messengers between neurons, at least two cannabinoid receptors (CB1 and CB2), and complex synthetic and degradative metabolic systems. The ECS differs from the GABA system and other neurotransmitter systems in multiple ways including retrograde communication from the activated post-synaptic neuron to the presynaptic cell. Together, this molecular conversation between the ECS and GABA systems regulate the homeostasis and the chemical messaging essential for higher cortical functions such as learning and memory and may play a role in several human pathologies. Phytocannabinoids are synthesized in the plant Cannabis sativa (C. sativa). Within the family of phytocannabinoids at least 100 different cannabinoid molecules or derivatives have been identified and share the properties of binding to the endogenous cannabinoid receptors CB1 and CB2. The well-known psychoactive phytocannabinoid Δ9-tetrahydrocannabinol (THC) and the non-psychoactive cannabidiol (CBD) are just two of the many substances synthesized within C. sativa that act on the body. Although the phytocannabinoids THC and CBD bind to these endogenous receptors in the mammalian CNS, these plant derived molecules have little in common with the endocannabinoids in structure, distribution and metabolism. This overlap in receptor binding is likely coincidental since phytocannabinoids evolved within the plant kingdom and the ECS including the endocannabinoids developed within animals. The GABA and ECS networks communicate through carefully orchestrated activities at localized synaptic level. When phytocannabinoids become available, the receptor affinities for CB1 and CB2 may compete with the naturally occurring endocannabinoid ligands and influence the GABA-ECS communication. In some instances this addition of phytocannabinoids may provide some therapeutic benefit while in other circumstances the presence of these plant derived ligands for the CB1 and CB2 receptors binding site may lead to disruption of important functions within the CNS. The regulatory approval of several THC products for nausea and vomiting and anorexia and CBD for rare pediatric seizure disorders are examples of some of the benefits of phytocannabinoids. Concerns regarding cannabis exposure in utero and in the child and adolescence are shrill warnings of the hazards associated with disrupting the normal maturation of the developing CNS.
Highlights
Introduction to the GABA systemGamma-aminobutyric acid (GABA), an amino acid, is the primary inhibitory neurotransmitter in the vertebrate central nervous system (CNS)
Reduced anterior cingulate cortex (ACC) glutamate levels in adolescents that habitually used cannabis had been reported in an earlier study [54] with MRS imaging and in this follow-up report these findings paralleled the reduction in glutamate with a similar reduction of GABA
In one randomized clinical trial (RCT) fifty patients with cannabis dependency were treated with Gabapentin 1200 mg/day or placebo for twelve weeks
Summary
Gamma-aminobutyric acid (GABA), an amino acid, is the primary inhibitory neurotransmitter in the vertebrate central nervous system (CNS). Activation of the CB1 receptor (the most abundant GPCR in the CNS) interacts with adjacent neurons including GABA and regulates neurotransmitter function to express their central effects. The endocannabinoids are synthesized in the post-synaptic membrane only after the cell is activated and rapidly degraded after binding to the presynaptic cannabinoid receptor, the effect of stimulation is localized and limited in duration similar to GABA and other neurotransmitters. These actions occur binding of AEA and 2-AG primarily to the CB1 receptor in the brain, other non-cannabinoid receptors have been identified that directly bind and are activated by endocannabinoids [28]. They are known to be involved in the metabolism of the eicosanoids including the prostaglandins [37]
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