Getting high on the endocannabinoid system.

Cerebrum, November 2013 Getting High on the Endocannabinoid System By Bradley E. Alger, Ph.D. Editor’s Note: The endogenous cannabinoid system—named for the plant that led to its discovery—is one of the most important physiologic systems involved in establishing and maintaining human health. Endocannabinoids and their receptors are found throughout the body: in the brain, organs, connective tissues, glands, and immune cells. With its complex actions in our immune system, nervous system, and virtually all of the body’s organs, the endocannabinoids are literally a bridge between body and mind. By understanding this system, we begin to see a mechanism that could connect brain activity and states of physical health and disease. 1 Cerebrum, November 2013 Cannabis, derived from a plant and one of the oldest known drugs, has remained a source of controversy throughout its history. From debates on its medicinal value and legalization to concerns about dependency and schizophrenia, cannabis (marijuana, pot, hashish, bhang, etc.) is a hot button for politicians and pundits alike. Fundamental to understanding these discussions is how cannabis affects the mind and body, as well as the body’s cells and systems. How can something that stimulates appetite also be great for relieving pain, nausea, seizures, and anxiety? Whether its leaves and buds are smoked, baked into pastries, processed into pills, or steeped as tea and sipped, cannabis affects us in ways that are sometimes hard to define. Not only are its many facets an intrinsically fascinating topic, but because they touch on so many parts of the brain and the body, their medical, ethical, and legal ramifications are vast. The intercellular signaling molecules, their receptors, and synthetic and degradative enzymes from which cannabis gets its powers had been in place for millions of years by the time humans began burning the plants and inhaling the smoke. Despite records going back 4,700 years that document medicinal uses of cannabis, no one knew how it worked until 1964. That was when Yechiel Gaoni and Raphael Mechoulam1 reported that the main active component of cannabis is tetrahydrocannabinol (THC). THC, referred to as a “cannabinoid” (like the dozens of other unique constituents of cannabis), acts on the brain by muscling in on the intrinsic neuronal signaling system, mimicking a key natural player, and basically hijacking it for reasons best known to the plants. Since the time when exogenous cannabinoids revealed their existence, the entire natural complex came to be called the “endogenous cannabinoid system,” or “endocannabinoid system” (ECS). THC is a lipid, but in 1964, known or suspected neurotransmitters and neuromodulators were water-soluble molecules—peptides, amino acids, or amines—not lipids. Ordinary neuroactive agents interact with cells by binding to specific proteinaceous receptor molecules that are part of the cell surface. Each receptor has an intricate structural pocket into which a particular neurotransmitter fits. The interaction triggers the biochemical and biophysical reactions that affect the physiological properties of the cell. Lipids avoid water, and individual lipid molecules might simply drift freely around in a compatible lipophilic environment, such as the cell surface membrane, without having much to do with proteins. How could they influence neuronal behavior? 2 Cerebrum, November 2013 The best scientific guess at the time was that molecules such as THC would owe their psychotropic actions to “membrane fluidizing” properties, a vague notion that would not explain specificity of action, among other things. Nevertheless, strong evidence that THC and similar synthetic molecules could bind tightly to specific sites in the brain emerged,2 implying that THC does indeed work through true receptors. This hypothesis was confirmed in 1990 with the isolation and cloning of the first cannabinoid receptor, CB1,3 and later of CB2.4 In the central nervous system (CNS), CB1 is by far the predominant form, although it also exists outside the CNS; CB2 is primarily found outside the CNS, and is associated with the immune system. Both receptor subtypes are 7-transmembrane domain macromolecules of the “G-protein-coupled” class. Unexpectedly, CB1 turned out to be one of the most abundant G-protein-coupled receptors in the brain. It was immediately obvious that CB1 and CB2 must partner with an endogenous ligand, a natural agent for which they would normally act as the proper receptors. They did not evolve to react with rarely ingested, plant-derived chemicals. Indeed, Mechoulam’s group isolated an arachidonic acid derivative (N-arachidonoylethanolamide, “anandamide”) that activated CB1,5 and a second endogenous CB1 ligand two-arachidonolyl glycerol (2-AG) was later discovered.6,7 These endocannabinoids are the major physiological activators of CB1 and CB2, yet they are not standard neurotransmitters. For one thing, like THC, they are lipids, and brain cells, mainly neurons, are surrounded by an aqueous solution, an inhospitable environment for an intercellular lipid messenger. More surprisingly, endocannabinoids go against the flow of typical chemical synaptic signaling. A neuron that releases a chemical neurotransmitter (say, GABA or glutamate) is designated as “pre-synaptic”; the target neuron that expresses receptors for that neurotransmitter is “postsynaptic.” Endocannabinoids, however, are synthesized and released from postsynaptic cells, and travel backward (in the “retrograde” direction) across the synapse, where they encounter CB1s located on adjacent nerve terminals.8,9 Physiologically, CB1Rs act as communications traffic cops. Precisely positioned in synaptic regions,10 they inhibit the release of many excitatory and inhibitory neurotransmitters. Thus, by releasing endocannabinoids, postsynaptic target cells can influence their own incoming synaptic signals. CB1 is densely located in the neocortex, hippocampus, basal ganglia, amygdala, striatum, cerebellum, and hypothalamus. These major brain regions mediate a wide variety of high-order 3 Cerebrum, November 2013 behavioral functions, including learning and memory, executive function decision making, sensory and motor responsiveness, and emotional reactions, as well as feeding and other homeostatic processes. Within neuronal circuits, suppression of excitatory transmitter release tends to dampen excitation, while suppression of inhibitory transmitter release favors neuronal network excitation. Given the enormous complexity of the brain, the endocannabinoid system could affect behavior in an almost limitless number of ways: Simple generalizations of what will happen when CB1 receptors are globally turned on or off are not feasible. The challenge for developers of cannabinoid-based medicines is to find beneficial ways to exploit this powerful yet convoluted feedback system. From a therapeutic point of view, the near ubiquity of the endocannabinoi (...truncated)