Gun Lover's Psychedelic Jargon Thread

[Rizzo in a box]

This was originally by my niggah Gun Lover

Hai BLTC

It has come to my attention that many who frequent BLTC are often overwhelmed by some of the higher-level pharmacological discussion that takes place here sometimes. I'm going to attempt to explain what some of this jargon means, and hope it helps some of you. If it still seems daunting, just remember, the hardest part of getting into pharmacology is the excessive jargon.

Jargon Reference Guide:

Ligand - loosely defined as a signal triggering molecule, binding to a site on a target protein such as a receptor. All neurotransmitters are ligands for one or more receptors.

Ions - charged particles (Na⁺, K⁺, Mg²⁺, Ca²⁺, etc). What people mean when they say the brain is a biochemical electric machine, well this is the "electric" part.

Ionotropic Receptor – also known as a Ligand-gated ion channel, these are a sequence of proteins that open a tiny pore through which ions can travel into the neuron once a ligand binds to it. This picture helps explain
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As you can see, when a ligand binds to the active site on the receptor, its shape changes and ions are allowed to flow.

Neuron - A special type of cell that is an integral part of the nervous system. They allow signaling from cell to cell.
 
Synaptic Cleft - The area in between two neurons that contains the actual drugs and neurotransmitters.


BTW -- vesicles are just little balls that carry around stuff (like neurotransmitters) inside your cells.

Neurotransmitters (NTs) - relatively small, simple molecules whose function is to facilitate electrical signaling between neurons in the synaptic cleft through physical and chemical means.

Dopamine (DA) - Among its other functions, dopamine is the most important molecule in the brain's reward system. Feelings of confidence, satisfaction, motivation, accomplishment, and attention are all largely controlled by DA. Drugs like cocaine and amphetamine cause there to be an abnormal excess of DA in the synaptic cleft, thus eliciting a recreational effect due to stimulation of the reward system.

Serotonin (5-HT) - 5-HT is the shorthand way of writing the chemical name of serotonin, 5-hydroxytryptamine. Serotonin plays a gigantic role in life: everything from heart development, controlling appetite & temperature, bone growth, and behavior is largely mediated by 5-HT. All psychedelics have efficacy at the serotonin type 2A receptor (5-HT_2A) to help elicit their effects. Depression is thought to be caused by low levels of 5-HT, thus doctors often prescribe SSRIs (selective serotonin reuptake inhibitors) to increase the amount of 5-HT neurotransmission.

Norepinephrine (NE) - Also known as noradrenaline, this neurotransmitter contributes to a change in heart rate, breathing patterns, and arousal. Along with DA, it is the basis of the reward system. This is the major neurotransmitter that is most responsible for the fight-or-flight mechanism.

Histamine - The primary NT in controlling the immune response, this NT is has a variety of functions including sleep regulation, alertness, gastric acid secretion, and inhibition of NT release. There are four different receptors for histamine, H₁-H₄, and each does a different function. By blocking the H₁ receptor with an antihistamine like benadryl, histamine can no longer bind to H₁, decreasing wakefulness. This is why H₁ antagonists are commonly used as sleep aids (diphenhydramine, doxylamine). More interestingly, the H₃ receptor which is the mostly expressed HR in the brain, modulates the release of many neurotransmitters in the brain. H₃ antagonists actually elicit stimulant and nootropic effects, likely due to the disinhibition of histamine-controlled NT release.

Catecholamines - a name referring to any of the three endogenous NTs that contain catechol: Dopamine, Epinephrine, and Norepinephrine. Here's a picture I made that explains it:


Endorphin - a portmanteau of "endogenous" and "morphine." This class of molecules are one of our bodies' natural opioid receptor ligands. Endorphins make you feel good because they bind to the MOR.

Endomorphin - more recently discovered than endorphins, these two endogenous opioids (endomorphin-1 & endomorphin-2) actually have the highest known affinity for the Mu-Opioid receptor than any other endogenous opioid.

Dynorphin - This is the second class endogenous opioids and has affinity for the kappa-opioid receptor. It plays a role in stress, analgesia, pain, and appetite.

Enkephalin - The third class of endogenous opioids. There are two different endogenous enkephalins, [Met]-enkephalin and [Leu]-enkephalin. The only structural difference between the two are the different amino acids at the end Methionine and Leucine. They both act similarly and are strong agonists of the Delta-Opioid receptor and weak agonists at the Mu-Opioid receptor.

Opiate - a naturally derived opioid receptor ligand originating from papaver somniferum, the opium poppy. Examples are morphine, codeine, and thebaine.

Opioid - any substance that acts upon any of the four major opioid receptors (Sigma, Kappa, Mu, Nociceptin). All opiates are opioids, but not all opioids are opiates.

Mu-Opioid Receptor (MOR) - this is the receptor responsible for blocking pain signals and what allows opioids to make us feel so fucking good. Specifically, the MOR type 2 receptor is responsible for that amazing euphoria. When an agonist binds to the MOR, the GABA molecules that regulate the release of dopamine in surrounding neurons are "hyperpolarized." Essentially, MOR agonists stop GABA from preventing dopamine neurotransmission, causing dopamine to start firing insanely fast, providing the high.

Kappa-Opioid Receptor (KOR) - activation of this receptor generally causes dysphoria, but partial agonists such as the primary active compound in Salvia, Salvinoran A, prove that activation of this receptor can also cause delirium, dissociation, and hallucinations.

Delta-Opioid Receptor (DOR) - Though not extremely well-studied, along with the MOR this receptor is responsible for most all pain-killing actions within the body. Interestingly, while DOR activation is responsible for mild pain relief, co-administration with a MOR agonist prevents the potentially fatal respiratory depression that classical opioid ODs are known for. Theoretically, if you also took a DOR agonist, you could dose an amount of heroin that would normally kill you and still be fine.

GABA - stands for gamma-aminobutyric acid. This is the principal inhibitory NT. GABA is ubiquitous; it helps mediate almost all of our conscious and subconscious functions. Too much GABA transmission, and you become very inebriated. Too little and you start convulsing and seizing. Recreationally speaking, the GABA type A (GABA_A) receptor is the one responsible for the pleasant effects of alcohol and benzodiazepines.

Blood-Brain Barrier (BBB) - A highly lipophilic (fat-loving) membrane that prevents polar molecules/drugs from reaching the brain. This is why you can't just get high by injecting dopamine and serotonin themselves (they are too polar to cross the BBB and thus don't get you high).

Endogenous - originating from within the body. NTs are endogenous compounds.

Exogenous - originating outside the body. These are usually drugs, but exogenous NTs have applications in medicine as well (epinephrine, etc.)

Affinity - a measure of how strongly a drug binds to a receptor. The binding affinity of a drug is often given in the units K_i. Remember, the lower the K_i, the higher the affinity. Also keep in mind AFFINITY ≠ EFFICACY.

Efficacy - a measure of how well a drug activates the receptor.

Agonist - a drug that displays both affinity and efficacy at a given receptor site.

Partial Agonist - a drug that has less affinity than the receptor's endogenous NT and displays some efficacy. For instance, LSD binds with less affinity to certain serotonin receptors than serotonin itself.

Full Agonist - a drug that binds with equal or greater affinity to a given receptor than its main endogenous NT. For instance, 2,5-Dimethoxy-4-Bromo-Amphetamine a.k.a. DOB binds with greater affinity to the serotonin 2B receptor than serotonin.

Antagonist - a drug that displays affinity towards a receptor, but has no efficacy.

Inverse agonist – a drug that has affinity for a receptor, but has the opposite effect of an agonist.

Here is a nice picture to better help you understand agonism/antagonism:


GPCR - a.k.a. G-protein coupled receptor. These are the receptors that most interesting to psychopharmacologists because they are the most prevalent type of receptor that NTs activate. For a more in-depth mechanism of how they work, see this thread.

Metabotrobic Receptor - in this type of receptor, a ligand binds, changes the receptor's shape, and triggers a cascade of intracellular actions that eventually cause a change in the cell. They often work in concert with ionotropic receptors present inside the cell. All the GPCRs are metabotropic.

Median Lethal Dose (LD₅₀): Used to measure the acute toxicity of a given substance, this ratio conveys the dosage at which 50% of the subjects tested died. Usually given in mg/kg, for instance around 95mg of cocaine per kilogram is the dose at which 50% of a given test subject (mice, in this case) died.

Bioavailability (BA) - the extent to which, and sometimes rate at which, the active drug or metabolite enters the bloodstream thereby gaining access to the active receptor site. (Credit to Merck/Rizzo)

Sympathomimetic - any drug that mimics the action of a neurotransmitter. A good example is Salbutamol. This drug effectively mimics the NT epinephrine but has a much better bioavailability and activity as an exogenous ligand.

Metabolite - when a drug enters the body it is subjected to these specialized proteins called enzymes. In essence, these enzymes digest the chemical, altering its structure allowing it to be more easily excreted. The resultant molecule that has been attacked by one or more enzyme(s) is called a metabolite. Sometimes the metabolite is a more potent drug than the substance originally ingested, but often it is not. Regardless of its relative potency to the original drug ingested, if a metabolite is psychoactive, it is known as an active metabolite.

Prodrug - a substance that when metabolized, turns into the desired active drug. The classic example of this is GBL. GBL is attacked by the lactamase enzyme upon entering the body and then forms GHB, a sympathomimetic GABA analogue.

Allosteric Modulator - a drug that binds to a receptor but not on its active site. Instead of competing with the endogenous ligand for that receptor, it merely binds to a different place on the receptor, changing the conformation of the active site at which the endogenous NT binds. In the case of benzodiazepines, they attach to the GABA_A receptors and increase the efficacy of normal GABA. This results in the GABA_A receptor being activated for longer periods of time, inducing a greater inhibitory effect.

Vasoconstriction - constriction (narrowing) of the blood vessels. 5-HT plays a major role in this.

Vasodilation - dilation (widening) of the blood vessels. This is done mainly through the actions of another NT, histamine.

-Ergic - a suffix acknowledging the activation of whatever NT comes before it. For instance, a GABAergic drug is one that acts upon GABA -- a drug such as alcohol. A serotonergic is a drug such as LSD.

-RI - a suffix that stands for "reuptake inhibitor." Examples: DARI (dopamine reuptake inhibitor), SSRI (selective serotonin reuptake inhibitor), and SNRI (serotonin-norepinephrine reuptake inhibitor). Reuptake inhibition of any given NT means that they stay in the synaptic cleft longer, increasing signaling activity, instead of being quickly reabsorbed by a surrounding neuron where they will have no effect. Cocaine doesn't actually act like a neurotransmitter to induce its effect, it actually inhibits the reuptake of serotonin, norepinephrine, and dopamine, and thus is known as a SNDRI (a.k.a. triple reuptake inhibitor).

I know I've likely left some key terms out, so please ask me to clarify any others if necessary.