Gamma-Aminobutyric Acid (GABA) and the Endocannabinoids: Understanding the Risks and Opportunities

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.

New Psychoactive Substances: A Potential Threat to Developing Countries

“… 36 Examples include altering the levels and activities of the monoamine neurotransmitters dopamine, adrenaline, and serotonin; functioning as an N-methyl-D-aspartate receptor antagonist; activating the cannabinoid receptor type 1 (CB1); acting on the GABAA receptor to generate sedative, hypnotic, and anxiolytic effects; and interacting with opioid receptors and inhibitory neurotransmitters. 37 , 38…”

“…36 Examples include altering the levels and activities of the monoamine neurotransmitters dopamine, adrenaline, and serotonin; functioning as an N-methyl-D-aspartate receptor antagonist; activating the cannabinoid receptor type 1 (CB1); acting on the GABAA receptor to generate sedative, hypnotic, and anxiolytic effects; and interacting with opioid receptors and inhibitory neurotransmitters. 37,38 Potential threats NPS are spreading at an incredible rate, endangering public health and complicating drug policy-making. 39 The negative health impacts and social harms of NPS are frequently poorly understood, which makes prevention and treatment extremely difficult.…”

Cannabis, Cannabinoids, and Stroke: Increased Risk or Potential for Protection—A Narrative Review

“…One of the possible mechanisms of the neuroprotective effects of CB1 receptor blockade is related to the receptor's role in the release of the neurotransmitter GABA. CB1 receptors have high expression on GABA neurons and these receptors' activity inhibits neurotransmitter release [71]. It has been found that upregulating GABA signaling aids in reducing injury in ischemic rat models; thus, blocking CB1 receptors should aid in producing this effect [72].…”