Common Drug Mechanisms
Going Through Common Mechanisms of Action
What is a drug? A drug is any substance that elicits a physiological effect when put into the body. Yes, caffeine is a drug, but so are many supplements. Drugs that have psychological or behavioral effects usually do so by acting on one or more neurotransmitter systems in the brain. Mechanisms vary though, and they can affect any step in the cycle of neurotransmitter synthesis, release, clearance from the synapse, or receptor binding. Let's discuss some of the most popular drug mechanisms, with some examples of course.
First, two important definitions before we go on:
Agonist: binds to a receptor and elicits or enhances the response of the endogenous neurotransmitter
Antagonist: blocks a receptor or does not allow it to function
Drugs may have an agonistic or antagonistic effect on the neurotransmitter system they affect. Meaning they may not bind directly to the receptor, but can increase or decrease the effect of a neurotransmitter by affecting its production or release. This will make more sense in a bit.
Receptor Agonists
Receptor agonists bind to the receptor and act in one of two ways. They can act as a replacement for the endogenous neurotransmitter, or bind to a distinct site on the receptor and cause a conformational change in shape to the receptor. This change in shape may facilitate neurotransmitter binding or keep ion channels open longer, enhancing the effect of the neurotransmitter. Both work to achieve the same thing, activate the receptor they bind to directly or indirectly.
Examples:
-Various opioids (i.e morphine, heroin, opium) directly activate opioid receptors, which causes their euphoric and pain killing effects.
-Some psychedelics (i.e. LSD, DMT, psilocybin) directly activate serotonin receptors, which increases glutamate activity in the cortex leading to an altered sensory state.
-Nicotine directly activates nicotinic acetylcholine receptors, giving nicotine cognitive enhancing properties .
-Benzodiazepines (i.e. Xanax, Valium) and alcohol facilitate increased GABA binding, explaining their depressant effects.
-Barbiturates (i.e. pentobarbital) bind to GABA receptors and keep associated ion channels open longer enhancing GABA’s effects. They can act in absence of GABA as well, giving them a large overdose risk.
Receptor Antagonists
Receptor antagonists are essentially the exact opposite of their agonist counterparts. They work to block the effects of a neurotransmitter, and do so by occupying the receptors binding location, blocking the associated ion channel, or binding at a distinct site to cause a conformational change that decreases neurotransmitter binding.
Examples:
-Caffeine is an adenosine receptor antagonist. It blocks the activity of adenosine, a molecule that slows neural activity, resulting in its stimulative effects.
-PCP is an NMDA glutamate receptor antagonist. Its effects on glutamate have downstream effects on other neurotransmitter systems as well, contributing to the dissociative state it produces.
-Alcohol also acts as an NMDA receptor antagonist, decreasing excitatory transmission.
Breakdown Inhibition
Enzymatic breakdown is one of the ways neurotransmitters are cleared from the synapse after release. These enzymes can be inhibited, leaving more neurotransmitters in the synapse for longer. The result here is more neurotransmitter signaling.
Examples:
-Monoamine Oxidase Inhibitors (MAOI’s, i.e. selegiline) decrease activity of the enzyme responsible for the breakdown of serotonin, dopamine and norepinephrine and epinephrine, which is why it is used as an antidepressant.
-Huperzine A inhibits acetylcholinesterase which breaks down acetylcholine, leading to cognitive enhancement due to more cholinergic activity.
Reuptake Inhibitors
Reuptake transporters are another way that neurotransmitters are removed from the synapse. They are located on the presynaptic cell and essentially suck up excess neurotransmitters, so their inhibition will also result in more activity from the targeted neurotransmitter.
Examples:
-Selective Serotonin Reuptake Inhibitors (SSRI’s, i.e. prozac, zoloft, lexapro) block reuptake of serotonin leaving more in the synapse for increased serotonergic signaling. Increased serotonin is thought to be a treatment for depression and anxiety disorders.
-Cocaine inhibits dopamine reuptake, causing its euphoric effects and making it highly addictive at the same time.
Neurotransmitter Release
There are three main ways that neurotransmitter release can be affected. We’ll go through them one at a time.
The first is through interactions with autoreceptors. These are receptors located on the presynaptic cell that are part of a negative feedback loop in neurotransmission. Excess neurotransmitters in the synapse will bind to these receptors and inhibit neurotransmitter release. This is typically done by decreasing calcium’s ability to enter the cell, since calcium is required for vesicular release. Inhibiting these autoreceptors will result in more neurotransmitter release, while activating them will decrease neurotransmitter release.
Example:
-Yohimbine is a supplement that blocks adrenergic autoreceptors, leading to an increased output of norepinephrine. This results in a state of autonomic arousal (increased blood pressure/heart rate, sweating).
The second is cannabinoid receptors, which work in a similar way. Their activation works to slow neurotransmitter release by decreasing calcium influx in the presynaptic terminal, but are activated by endogenous cannabinoids in response to an excess of neurotransmitter signaling.
Example:
-THC, the main psychoactive component in marijuana, is an agonist for these receptors in the brain. Its use resulting in decreased neurotransmitter release is responsible for the cognitive dampening effects of this drug (relaxation, tougher time forming memories, etc.)
Lastly in this category, we have drugs that directly cause an increase in neurotransmitter release by reversing reuptake transporters. These transporters normally act to remove neurotransmitters from the synapse, but drugs can cause a reversal resulting in more being released into the synapse.
Example:
-Methamphetamine reverses the action of DAT, the transporter responsible for dopamine reuptake. This results in a tremendous amount of dopamine release into the synapse which results in its euphoric effects and also makes it highly addictive.
Synthesis
Almost all neurotransmitters are synthesized in the presynaptic cell from precursors using a series of enzymes. For example the catecholamines dopamine, epinephrine and norepinephrine, are all synthesized from l-tyrosine in that order. What determines the neurotransmitter the neuron will produce is the enzymes present (dopamine can’t become norepinephrine if dopamine b-hydroxylase isn’t present to make it). A drug can introduce more of a precursor or inhibit a particular enzyme in order to increase or decrease neurotransmitter production.
Examples:
-AMPT inhibits the enzyme tyrosine hydroxylase, which converts l-tyrosine to l-dopa, the precursor to dopamine. Inhibiting this enzyme results in less dopamine synthesis and therefore less dopamine release.
-L-dopa, dopamine’s precursor, can be administered to directly provide more substrate for dopamine production. This can be used as a treatment for the motor symptoms in Parkinson's disease since dopamine plays a role in the initiation and cessation of movement.
-Citicoline is a source of choline, an acetylcholine precursor. Its use allows for more acetylcholine production, resulting in improvements in learning and memory.
Storage
After neurotransmitters are created they are stored in vesicles in the presynaptic terminal to await release. This process can be disrupted by a drug that inhibits the transporter responsible for moving neurotransmitters into the vesicle. Less neurotransmitters in vesicles, means less neurotransmitters available for release.
Example:
Reserpine inhibits VMAT, the transporter that moves dopamine, norepinephrine, and epinephrine into vesicles. If these molecules can’t be packaged for release, they can’t be released at all. It used to be a treatment for hypertension, but was phased out due to its negative side effects caused by significantly decreased signaling of the monoamines.
Conclusions
This article certainly does not describe all of the intricacies that come to play with different drugs and different receptor subtypes (that would require a whole book), but this should serve as an introduction to the world of drug mechanisms. Most people that consume some of these drugs don’t know how they work in the slightest, just that they were prescribed them or enjoy them recreationally, so just by reading this you’re ahead of most of the population.
Until next time, thank you for reading.