rational exploration of the underground

Nerve cells are designed to fire repetitively, and are subject to a barrage of stimuli. The brain prevents itself from spiraling out of control into hyperexcitable states by inhibition, a way of “turning down the volume” in the brain. The major workhorse for this is gamma animobutyric acid, or GABA. In a strange parallel, the brain synthesizes GABA in one step from glutamate, the brain’s major excitatory neurotransmitter. Excitation can therefore be efficiently followed by the capacity for inhibition, two naturally opposing processes depending on, and counterbalancing, the other. GABA and glutamate are the yin and yang of our nervous system.

There is hardly a single behavior that does not involve GABA. It is estimated to be involved in one third of all transmissions at synapses, and GABA nerve cells alone make up 40 percent of the total population of nerve cells, with glutamate cells adding perhaps another 30 percent. Broadly, the brain applies its fast acting GABA circuits at all levels to hold in check the local excitatory processes. Some GABA cells inhibit pivotal nerve cells that directly command other essential nerve cell populations. GABA mechanisms hold aggressive behavior in check in many animal species. If rats are made hyperactive by injection of dopamine into the nucleus accumbens, they will quickly quiet down after GABA is injected into the same nucleus.

GABA agonists include alcohol and benzodiazepines such as Xanax. Widely used for their tranquilizing, anti-anxiety, or sleep producing properties, they can create an incredibly risky state of addiction if used too frequently. Unlike other drugs that when withdrawn simply cause the perception of extreme suffering, cold turkey withdrawal causes GABA action to drop precipitously, inducing states of extreme agitation or convulsions, possibly causing death. A slow tapering of the drug, allowing natural GABA to rebound slowly, is the typically recommended course of action.

The inhibitory effects of GABA can be related to the “tunnel vision” experienced during states of drunkenness, where the visual field is reduced and attention is paid only to the objects directly in front of the subject. In contrast, bicluculline is a drug that stops the inhibitory role of GABA. When applied to the visual cortex, it expands the apparent visual fields by three to five times.

A traveller taking a benzodiazepine for a long haul flight and a frat boy on his 21st birthday both may experience periods of retrograde amnesia. This emphasizes the fact that when GABA systems become overactive, they can block the way a person accesses recently produced memories.

The anti-anxiety properties of GABA agonism are not limited to the “higher” civilized frustrations of the overworked executive as well. They can also relieve the deep primal anxiety of a baby monkey separated from his mother. Diazepam, a benzodiazepine, quickly stops their agitated behavior and cries of distress. High brain levels of dopamine are reduced, as well as high blood levels of ACh and cortisol which are correlated with stressful experiences.

We know that receptors in a synapse bind to neurotransmitters, and this binding can change the likelyhood of a nerve cell to fire. But do these receptors only bind to one specific neurotransmitter, or is there more to it? We can think of a receptor as a lock that only a specific key can open, a particular geometric and chemical structure that only certain molecules can interact with.

Agonists, Partial Agonists, and Antagonists

This is the nicotinic acetylcholine receptor, one of two acetylcholine receptors. It is a complex tangle of amino acids, where only molecules of a specific geometry can fit inside.

Obviously acetylcholine fits, as this is an acetylcholine receptor. This means acetylcholine is called a agonist at this receptor. Nicotine is also a agonist at the nicotinic acetylcholine receptor.

Since the structure of the receptor is so complex, other molecules can “kind of” fit, but activate the receptor only partially. Varenicline is one of these compounds, and is called a partial agonist. It simulates the pleasurable effects of nicotine, although not nearly as well, and prevents nicotine from binding to the receptors it is already attached to - which is why it is sold as an aid to quit smoking.

Other compounds can fit in the receptor, but do not activate it at all. Bupropion is one of these, and is called an antagonist. It is sold as an antidepressant and smoking cessation aid, as it binds to nicotinic acetylcholine receptors but does not activate them.

Selective Agonists

But there are two acetylcholine receptors, nicotinic and muscarinic. Acetylcholine is an agonist at both, while each compound is selective for its particular receptor.

Compound	Nicotinic Acetylcholine Agonist?	Muscarinic Acetylcholine Agonist?
Acetylcholine
Nicotine
Muscarine

We then call nicotine and muscarine selective agonists at the acetylcholine receptor. This concept is important in modern medicine, as a certain drug may want to target only a specific subreceptor to create a certain effect, as a full agonist may activate far too many other receptors and overwhelm the intent of the drug.

The people trying to make drugs that mimic the cancer inhibiting effects of cannabis without the pleasurable high? Yep, they’re searching for selective cannabinoid agonists, although they may be missing the point.