How Cannabis Receptors Work in Your Brain
By Kenneth Anderson, MA
The reason that humans can get high from cannabis is that there are receptors in the brain that the chemical components of cannabis, such as THC, can bind to. Why does the brain have such receptors? Because the brain naturally produces neurotransmitters which are similar to THC. These naturally occurring neurotransmitters are called endocannabinoids. This word is easier to remember if we break out down into its component parts: “endo-” is a prefix meaning “inside,” “cannabis” is of course “cannabis,” and “-oid” is a suffix meaning “similar to.” So, endocannabinoids are molecules which are similar to cannabis but found inside the human body.
There are two types of cannabinoid receptors: CB1 receptors, which are found primarily in the brain, and CB2 receptors, which are found primarily outside the brain in the immune system, peripheral nervous system, the stomach and intestine, and elsewhere. Before we proceed to discuss how the cannabinoid receptor works, let’s review how standard neurotransmission works.
Normally, when a neuron fires, an electrical signal known as an action potential travels down the axon until it reaches the axon (presynaptic) terminal, where it causes little sacks known as vesicles to burst open. These vesicles are filled with chemicals known as neurotransmitters, and when they burst open, they release these neurotransmitters, which travel across the synaptic gap, and bind to receptors located dendrite (postsynaptic) terminal. When the neurotransmitter binds to a receptor, the receptor responds either electrically or chemically, depending on what type of receptor it is. All this is illustrated in Figure 1.
Now let’s look at endocannabinoid neurotransmission. Endocannabinoid neurotransmission is weird in every way. Instead of traveling from the axon (presynaptic) terminal to the dendrite (postsynaptic) terminal like normal neurotransmitters do, endocannabinoids travel backwards, going from the dendrite (postsynaptic) terminal to the axon (presynaptic) terminal. This is known as retrograde neurotransmission and is represented by the red block arrow in Figure 1. Moreover, instead of being manufactured ahead of time and stored in a vesicle like most other neurotransmitters, endocannabinoids are manufactured on demand when something triggers their need. But before we further describe the functions of endocannabinoids, let’s review the types of receptors.
The receptors in the brain which are involved in neurotransmission can be divided into two broad categories. One type of receptor changes the voltage of the neuron by letting in either positive or negative ions. This type of receptor is called “ionotropic.” The word “ionotropic” comes from the words “ion,” an electrically charged atom, and “tropism,” to turn or to move.” So, an ionotropic receptor is literally a receptor that moves ions in or out of the neuron. An example of an ionotropic receptor is the GABA-A receptor. When the neurotransmitter GABA binds to the GABA-A receptor, the receptor lets in negative ions which decrease the odds of the neuron firing. This is why the neurons that release GABA are called inhibitory.
The other type of receptor affects chemical reactions which take place in the neuron by sending out a chemical message. This type of receptor is called “metabotropic.” The word “metabolism” literally means “the sum of the chemical changes within the body.” So, metabotropic receptors are literally receptors which involve the movement of chemicals in the neuron, or more succinctly put, receptors which send chemical messages. The GABA-B receptor is an example of a metabotropic receptor; when it is activated by GABA, the GABA-B receptor releases a chemical message which inhibits the neuron from firing.
Glutamate receptors are the primary excitatory receptors in the brain. Some glutamate receptors are ionotropic receptors and increase the odds of a neuron firing by letting in positive ions when glutamate binds to them. Other glutamate receptors are metabotropic receptors and increase the odds of the neuron firing by sending out chemical messages when glutamate binds to them. Endocannabinoids are also metabotropic receptors which have their effect by sending chemical messages.
Endocannabinoids kick in when the axon (presynaptic) terminal is releasing too much neurotransmitter. Endocannabinoids act like a brake, telling the axon (presynaptic) terminal to slow down its release of neurotransmitters. How does this work? Let’s first look at an example with glutamate receptors.
When too much neurotransmitter is stimulating the metabotropic glutamate receptors on the dendrite (postsynaptic) terminal, the glutamate receptor sends out a chemical message which tells certain enzymes in the neuron to start producing endocannabinoids. The endocannabinoids leave the dendrite (postsynaptic) terminal and travel backwards across the synaptic gap to bind to the cannabinoid (CB) receptors on the axon (presynaptic) terminal. Once they bind, the CB receptor sends a chemical message to the calcium channels in the membrane of the axon terminal which tells the calcium channels to let fewer positively charged calcium ions into the cell. Because calcium ions are required in order for the neurotransmitter sacks to fuse with the cell membrane, burst, and release their neurotransmitters, the ultimate result of fewer calcium ions is to lower the odds of neurotransmitters being released.
Now let’s take a closer look at how metabotropic receptors send chemical signals. Figures 2, 3, and 4 show how metabotropic receptors send chemical signals, Near the bottom of each metabotropic receptor is a protein named a G protein. It is named a G protein because it can bind to GDP (guanosine diphosphate) or GTP (guanosine triphosphate). The G protein consists of two subunits: an alpha subunit and a beta/gamma subunit. Although beta and gamma are each subunits themselves, since they always stick together, we can treat them as a single subunit. When GDP is bound to the alpha subunit of the G protein, the G protein is inactive; it just sits there and does nothing. However, when a neurotransmitter binds to the metabotropic receptor, GDP is replaced by GTP, and the G protein is activated. When the G protein is activated, it splits into two parts: the alpha subunit which remains bound to the GTP, and the beta/gamma subunit. The alpha subunit/GTP complex can move away from the receptor and carry a message to another part of the neuron. The beta/gamma subunit can also move away and carry a message elsewhere.
In the case of the cannabinoid receptor, the beta/gamma subunit goes to the calcium channel and tells the calcium channel to let less calcium into the neuron; this reduces the odds that neurotransmitters will be released. In the case of a metabotropic glutamate receptor, the alpha subunit/GTP complex carries a message to certain enzymes telling them to produce endocannabinoids. After the messages are delivered, the subunits can return to their original configuration (Figure 2) and wait until they are called to carry another message.
So, what happens with GABA-A receptors, which are inotropic instead of metabotropic? When a neurotransmitter binds to a GABA-A receptor, a pore opens in the receptor which lets negatively charged chloride ions in. This increases the negative charge of the neuron and makes it less likely to fire. But this can also lead to an influx of positively charged calcium ions. If there is an influx of positively charged calcium ions, certain enzymes sense this and begin to synthesize endocannabinoids. These endocannabinoids then cross the synaptic gap, backwards as always, and bind to the cannabinoid receptors on the axon (presynaptic) terminal. The cannabinoid receptors then inhibit the release of neurotransmitter by stopping the vesicles from bursting, as described above.
What we have with the endocannabinoid system is a simple feedback mechanism like a thermostat. When the house gets sufficiently warm, the thermostat turns off the heat until the house cools back down again, when the thermostat turns the heat back on. The endocannabinoids released by neurons in the brain have no subjective effects; they simply serve to keep the system in a state of homeostasis: i.e., a state of balance. However, cannabinoids introduced from the outside (exogenous cannabinoids), such as THC, can have large subjective effects by upsetting this homeostasis.
Cannabinoid receptors are most prevalent on axon terminals which release GABA and on axon terminals which release glutamate. Since GABA is the primary inhibitory neurotransmitter, and glutamate is the primary excitatory neurotransmitter, this means that ingesting cannabis has the paradoxical effect of both increasing excitement in the brain by inhibiting GABA and decreasing excitement by inhibiting glutamate. Because cannabis inhibits GABA, one should never try to treat acute alcohol withdrawal by smoking or otherwise ingesting cannabis. Acute alcohol withdrawal can only be treated by increasing GABA activity by taking a benzodiazepine or similar medication. By inhibiting GABA, cannabis can make acute alcohol withdrawal much worse. In a future blog post, I will discuss the effects exogenous cannabinoids such as THC in detail.
