Firstly, any chemical that binds to a larger chemical complex is called a ligand. That is a way in which almost all neurotransmitters are alike, they bind to a receptor. These receptors being proteins.

Antagonists fit into receptors, but they do not create an impulse. They block part(s) of a receptor from being activated. Caffeine is an antagonist at adenosine receptors. Note that antagonists aren’t necessarily inhibitory chemicals. Caffeine antagonizes receptors that when agonized, make us sleepy. So it indirectly increases excitatory neurotransmitters.

Full agonists, such as the endogenous (created by the body) chemical glutamate, activate neurons. Just the same as an antagonist isn’t necessarily inhibitory, an activated neuron doesn’t automatically mean we become excited. For example, ethanol (drinking alcohol) makes GABA neurons work more, but when that happens, it makes neurons that excite us work less. Similarly, Evzio (naloxone) stops opiate receptors from working as much, but that creates less excitement.

Image result for agonist antagonist

Inverse agonists produce the opposite effects of agonists. Unlike antagonists, which simply occupy a receptor, inverse agonists make the receptor act inverse to how an agonist works. Benadryl (diphenhydramine) is an inverse agonist.

Partial agonists keep activity within a range. If neural activity is too low, the function as agonists. If it is too high, they play the role of the antagonist. THC, the well-known recreational drug in marijuana, is a partial agonist at the CB1 (psychoactive) receptor subtype. A full agonist of the same site is the synthetic cannbinoid JWH-018. The synthetic cannabinoids, most of which are full agonists, create side effects, addiction, and withdrawal of a much higher magnitude than marijuana. Such is the differing effects of partial agonists from full agonists.

Abilify (aripiprazole) is also an example of a partial agonist, this time at the D2 and D3 dopamine receptor subtypes.

Partial agonists have varying efficacy: the degree to which a response is created as a result of a ligand interacting with a receptor. A drug such as Abilify has low efficacy, it much more readily decreases neuronal activiy, than increases it. Thus, given this information, and that it is a ligand for the receptor subtype that is well-known in contributig to psychosis, D2, Abilify is an antipsychotic.

Affinity refers to the binding force, the degree of attraction, between the ligand and the receptor. High affinity means that the chemical is interacting with its receptor for a longer period of time, as the attraction is stronger. This in turn means that a lower amount of the ligand is needed to fully exploit the activation potential of the recpetor. A chemical’s potency is sometimes used synonymously with affinity. It’s the bare amount needed to produce a desired response.

Let’s move on to other ways in which neurochemicals affect neurotransmission.

Reuptake inhibitors block neurotransmitters from being pumped back into the presynaptic neuron by what’s called the reuptake pump, or, transmembrane transporter. This effectively increases concentrations of the neurotransmitter in the synapse, leading to more postsynaptic binding. An example is methylphenidate (Ritalin), which inhibits the reuptake of the catecholamine neurotransmitters (dopamine, norepinephrine, and epinephrine). Another, are the SSRI antidepressants, shown below, which selectively inhibit the reuptake of serotonin.

Attached to the mitochondria (energy producing organelle) of the presynptic neuron, are monoamine oxidase chemicals. They catch a portion of neurotransmitters that have been transported back into the presynaptic neuron, and aid in their controlled destruction and recycling. As such, monoamine oxidase inhibitors lead to a higher concentration of these neurotransmitters.

  • Monoamine oxidase A breaks down epinephrine, serotonin, and dopamine
  • Monoamine oxidase B metabolizes norepinephrine, dopamine, and trace amines (such as phenylethylamine and tryptamine)
  • Catechol-O-Methyltransferase (COMT) metabolizes the catecholamines (dopamine, norepinephrine, epinephrine)

Some chemicals are more selective for either enzyme. For instance, selegiline (Deprenyl/Emsam) works solely on MAOI-B until a certain dose is surpassed. Tranylcypromine (Parnate) and phenelzine (Nardil) work on both forms.

MAOI drugs can also be reversible, or irreversible. The former means that they will break down more readily if doing is stopped. Irreversible MAOIs create a state such that the enzyme they bind to will not resume its activity until two weeks after use has ended.

Similarly, some psychoactive chemicals stop enzymes that work on neurochemicals when they are attached to a receptor site.This occurs in ionotrophic neurons (whereas in metabotorpic receptors, the enzymes are located within neurons). Below is the normal functioning of acetylcholinesterase, an enzyme that deactivates acetylcholline.

Seen below is another depiction of acetylcholline without an intervention. Lower down illustrates the action of acetylcholinesterase inhibitors. Aricept (Donepezil) is an acetylcholinesterase inhibitor.

Acetylcholinesterase inhibitors (donepezil, edrophonium) dopamine agonists (levodopa, pramipexole), MAO-B inhibitors (selegiline, rasagiline), memantine (NMDA antagonist),  and other drugs that promote cognition, are used in such neurodegenerative diseases such as parkinson’s, demantia, and alzheimer’s.

Allosteric modulators change the conformation of receptors to either increase or decrease the probability of a neurotransmitter binding to them. They bind to the allosteric site of a receptor.

Here we have a picture of the GABA channel protein (ligand-gated ion channel). We see that there are different regions (subtypes) that are associated with certain chemicals.

  • Benzodiazepines are anti-anxiety agents, such as Xanax and Valium, that are given a spot.
  • Barbiturates, also anti-anxiety agents (rarely prescribed these days)
  • We also see a region linked to a toxin
  • And a steroid binding site

All of the named chemicals bind to the GABA receptor. The area at which they bind, though, corresponds to their differing effects, however slight.

Even benzodiazepines differ in the subunits they affect. For instance, Xanax binds super strongly to the α2 subunit, and a bit less so to the α3 subunit of the benzdiazepine region, whereas Valium binds more evenly across the α1, α2, α3, and α5 subunits.

There are drugs that increase the synthesis of neurotransmitters or their precursor chemical(s). One such drug is Lithobid (lithium), which increases production of tryptophan, the precursor to the important mood chemical, serotonin. How it does so, isn’t very clear. Lithium is theorized to have many, many mechanisms.

Reverse transport, or, facilitated exchange diffusion, is another way by which some drugs work. It sounds complicated, but in simple terms means that the drug attaches to the reuptake pump and makes its way into the vesicles of the presynpatic neuron, effectively pushing out neurotransmitters into the synapse. The best example of this is Adderall/Dexedrine (amphetamine).

Just as lithium, amphetamine has several mechanisms of action. Please see pages four to seven of my essay on the mechanism of dextroamphetamine.

Here’s a summary of the many ways by which psychoactive chemicals change brain activity:

Agonist-Antagonist-Mechanism-Chart

Many drugs work through a variety of complicated mechanisms. For instance, please see pages four to seven of my essay on the mechanism of dextroamphetamine.

Sources: Uppers, Downers, All Arounders: Physical and Mental Effects of Psychoactive Drugs, Stahl’s Essential Psychopharmacology, https://www.thinglink.com/scene/512620683662983169