UPDATED: 04 May 2024
Added information on some recent data on "Ca+ ion channel" research at the end of Gabapentinoids.
**GABA or Gamma-AminoButyric Acid** is a protein-creating amino acid and is the most abundant neurotransmitter distributed throughout most areas of CNS, which includes the brain. However, **most of the brain’s neurons are excitatory**.
It is the **main inhibitory neurotransmitter** which slows down your brain by blocking specific signals, and by reducing nerve cell (neuronal) excitability, and produces a calming or sedating effect. It's thought to play a major role in **controlling anxiety, stress and fear**.
As opposed to **Glutamate**, which **is the** most abundant and **main excitatory neurotransmitter** of the glutamatergic system, that activates other neurons and propagate electrical signals.
A glutamatergic agent (or drug) is a chemical that directly modulates the excitatory amino acid (glutamate/aspartate) system in the body or brain, and are found in the same areas as GABA.
**GABA agents** that include **GABAergics, CCBs and Gabapentinoids**, include many recreational, therapeutic and essential drugs but **can rapidly cause dependence and/or a dangerous addiction** due to complex (cross-)tolerance evolution, and have a **ceiling effect dose** (or receptor saturation), and are often misunderstood by many users including myself.
There are a lot of **complex interactions with other neurotransmitters** such as Serotonin (a modulator of GABA) and Dopamine (modulated by GABA) which is associated with movement disorders triggered by antipsychotics, for example. GABA also modulates Norepinephrine and works with Epinephrine.
The GABA binding site is directly responsible for opening the **Cl− (chloride ion) channel**.
High levels of GABA can cause paradoxical side effects such as anxiety, irritability, overstimulation and suicidal thoughts.
* **Gabapentinoids**
Gabapentinoids **are intracellular neuronal Voltage-Gated** (or Voltage-Dependent) **Calcium Channel** (VGCC or VDCC) **current blockers** that calms neurons in the nervous system (can reduce pain) and the brain so it is effective for anxiety and sleep too.
They are **not metabolised**, at least not Lyrica (PGB or Pregabalin) and Neurontin (GBP or Gabapentin), because they are **not protein bound**.
In this case, tolerance development has been purported to be influenced by the rate of absorption into the bloodstream by means of the various ROAs or Routes Of Administration, and alternating them can slow it down.
They are also called **α2δ ligands** (substances that bind to receptors) that **depress neuronal excitability** or slow down nerve transmission so they **inhibit calcium-mediated neurotransmitter release through effects on α2δ, α2δ-1 subunits**.
There are 3 types of calcium channels but only two of these are affected in this case, with L-type being the most significant -- **L-type channels are “long-lasting”** and require a strong depolarization for their activation, whereas T-type channels are "transient" or not long lasting, and are fast in their deactivation.
Gabapentinoids are **structurally similar to GABA** yet its mode of action remains uncertain. It is water-soluble and GI tract **absorption occurs via the L-amino acid transport system** in the proximal small bowel.
Gabapentinoids differ from GABAergics as they operate on **different ion channels** and by means of an increased intracellular Ca2+ concentration, **they cause a transient augmentation of the GABA current**.
Calcium Ca2+ ions are bioelectrically positively charged molecules, that by entering through L-type VGCCs, activate **different signaling pathways that lead to alterations in GABA-A receptors**.
The **actions** of gabapentinoids are mainly at an **intracellular site and require active uptake**. They undergo facilitated transport across cell membranes through system L-amino acid transporters (LAT) as both drugs are structurally similar to the amino acid leucine.
Since VGCCs **control the opening and closing** of the neuron's **small sacs**, which are called vesicles, holding the neurotransmitters ready to be released, this is how they're able to slow the amount released, consequently slowing down the rate of transmission.
> **pre-synaptic send from the axon**
Gabapentin molecules bind to the **Gabapentin receptor** or **α2δ-1** (alpha2-delta-1) **subunit** (1 of 5) which **regulates the current density and activation/inactivation kinetics** of VGCCs in the CNS' billions of neurons which **transmit the signal away, out of the **axon** (the end of the nerve cell) towards** (i.e., pre-synaptic) **the space or junction between the neurons** (the synapse) thereby **modulating the release of several excitatory neurotransmitters** including **glutamate**, **substance-P** (our behavioural response to stress and pain perception or nociception), **serotonin, dopamine, norepinephrine and GGRP** (Calcitonin Gene Related Peptide) -- which is a potent vasodilator involved with the cardiovascular system, wound healing and is implicated in pain pathways.
> **triggering acetylcholine release**
The **release of acetylcholine** occurs when an action potential is relayed and **reaches the axon terminus** in which depolarization (exert a particular effect on the post-synaptic neuron) causes **voltage-gated calcium channels to open and conduct an influx of calcium, which will allow the axon buttons of the vesicles containing acetylcholine for release** into the synaptic cleft.
> **transmit**
Inter-cellular impulses **diffuse over the synaptic cleft** (the signal/impulse transmission mechanism) is sent from the axon of each neuron **by a neurotransmitter** via multiple branches, across 100 trillion+ synapses, to the dendrites in many neighbouring neurons.
> **post-synaptic receive by dendrite**
The **pre-synaptic nerve cell sends the signal/impulse by releasing an endogenous chemical called a neurotransmitter which travels/diffuses through the synaptic cleft space and may branch out and communicate with several other post-synaptic neurons that **receive the signal/impulse** by being **transduced into electrical and biochemical changes** which activate or **bind to the Gabapentin receptor** which consist of special protein molecules that are contained within the **dendritic spine** -- which are projections from the main body of the **post-synaptic nerve cell**.
> **recycle/reuptake**
**After a neurotransmitter has performed it's function** of transmitting a neural impulse, **it is reabsorbed back into the cell** that previously released it (**called** the **REUPTAKE** mechanism) **by a** neurotransmitter **TRANSPORTER** that is located along the plasma membrane of an **axon terminal** (i.e., the pre-synaptic neuron at a synapse) **or glial cell** (cells which provide physical and chemical support to neurons and maintain their environment).
* **What is the latest information on the way neurons work ?**
Every neuron can handle multiple neurotransmitters and bidirectional traffic and, as I assumed, calcium infux is also involved in receiving signals (from the neurotransmitters), and **not** just sending) also, Ca+ ions are held in various logical compartments within the dendritic spines, mediated by NMDAr and AMPr, with the excitatory neurotransmitter, Glutamate.
GlucR is involved with, amongst other things, Insulin levels and GABA synthesis, and all which are associated with **memory formation, plasticity**, cognition, and mood regulation.
* **The bad: ⚠️ -- Warning**
> The study shows that they block the formation of new brain synapses1, drastically reducing the potential for rejuvenating brain plasticity – meaning that these drugs will cause brain decline faster than any substance known to mankind.
* Neurontin and Lyrica are a Death Sentence for New Brain Synapses : Shocking Study
Read more at:
https://forum.facmedicine.com/threads/neurontin-and-lyrica-are-a-death-sentence-for-new-brain-synapses-shocking-study.36840/Chronic use of Gabapentin **may cause an increase in neurodegenerative changes** in the adult brain, **cause cognitive impairment, may inhibit synaptogenesis** of excitatory neurons and prevent synaptogenesis between sensory and spinal cord neurons.
**Chronic Pregabalin (PGB) dependence induces neurotoxic effects** mainly in the form of neuronal apoptosis, gliosis, and oxidative stress injury of the frontal cortex. The PGB-induced neurotoxic effects persisted after withdrawal.
PGB (Lyrica) and GBP (Neurontin) and are both systemic CNS **synaptogenesis** (neuroplasticity) **inhibitors** so pregnant women and the elderly are at risk of developing potentially adverse neurological outcomes concerning the fetus and the aged mind, respectively.
* **The interesting and even possibly amazing**
Here, **systemic** influence on fetal development is suggested as PGB is seen to interfere with the nuerogenesis and morphogenesis of **v**entral **m**idbrain* **dopamine** nerve cells:
> " data suggested that pregabalin abuse in pregnant women, or even at therapeutic doses, may impair fetal development. We used primary mouse embryonic VM neurons to investigate whether prenatal exposure to pregabalin can impair fetal brain development. This study focused on vmDA neurons, which are responsible for cognition, movement, and behavior. The current study demonstrated that exposure to pregabalin during early brain development could interfere with the neurogenesis and morphogenesis of vmDA neurons. Additionally, several genes were identified that allowed pregabalin have an impact on vmDA. These findings are crucial for the clinical use of pregabalin during pregnancy ..."
* The Effects of Prenatal Exposure to Pregabalin on the Development of Ventral Midbrain Dopaminergic Neurons
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8909856/ > "Emerging perspectives on calcium channels in **DNA damage response: potential implications**. Calcium channels, which allow the selective passage of calcium ions across the cell membrane, play a fundamental role in a multitude of cellular processes"
* Novel insights into the role of ion channels in cellular DNA damage response
https://www.sciencedirect.com/science/article/pii/S1383574224000012#:~:text=Emerging%20perspectives%20on%20calcium%20channels,a%20multitude%20of%20cellular%20processes.
* **GABAergics**
The opening of a **chloride channel** by GABA weakly depolarizes the nerve terminal membrane and **blocks action potentials** (which are a rapid sequence of changes in the voltage across a membrane and are the basic "all-or-nothing" events the nerve cells use to transmit information from one place to another. It either fires off in its entirety or does not fire off at all).
In this way, GABA limits **secretion** (which is the synthesis of a neurotransmitter that lives as long as it not subjected to it's ultimate demise by (auto-)oxidisation or catabolisation) depends on the **exocytosis** of neurotransmitter-containing **synaptic vesicles**) **by retarding the spread of excitation** into the terminal arborisation (which is a complex branching pattern found at axonal terminals that innervates the target tissue).
**Exocytosis** is the fusion of secretory vesicles with the plasma membrane and results in the discharge of vesicle content into the extracellular space and the incorporation of new proteins and lipids into the plasma membrane.
Synaptic vesicles are small, electron-lucent vesicles that are clustered at presynaptic terminals. They store neurotransmitters and release them by calcium-triggered exocytosis, and are made locally at the terminals and are regenerated after exocytosis. In respect to their pivotal functions in neurotransmitter release, they should be equipped with two sets of functional components, proteins for nuerotransmitter uptake and for membrane trafficking.
The **GABA reuptake inhibitor** (GRI) is a type of drug which acts as a reuptake inhibitor for the neurotransmitter gamma-Aminobutyric acid (GABA) by blocking the action of the gamma-Aminobutyric acid transporters (GATs).
**Receptors, their subtypes and binding sites**
The **GABA-A receptors mediate fast** inhibitory signals (some agonists are **muscle relaxants**) and are coupled to the BzD (Benzodiazepine) (there are others like the non-BzD for Barbiturates) receptor binding site.
**PAMs** (Positive Allosteric Modulators) **are not the same as agonists** and are also known as GABAkines or **GABA-A receptor potentiators**, which are molecules that increase the activity of the GABA-A receptor protein in the vertebrate central nervous system.
Benzodiazepines and Z-drugs act on γ-aminobutyric acid (GABA-A) receptor binding sites that potentiates GABA's inhibitory effect.
It is thought that modulation of GABA-A receptor activity by the primary excitatory neurotransmitter *glutamate* (via NMDA receptors) that may be brought about via **changes in intracellular Calcium (Ca2+)**.
The GABA-A receptor is a **pentameric protein complex**, whose subunits **((α1)2(β2)2(γ2))** are drawn from the following different isoforms: α(1–6), β(1–4), γ(1–3), δ, ε, θ, π and ρ(1–3), that consists of five combined subunits that form the **protein, the chloride (Cl-) ion channel pore, the two GABA active binding sites at the α1 and β2 interfaces, and the benzodiazepine (BZD) allosteric binding site at the α1 and γ2 interface**.
Neurosteroids and some general anesthetics like propofol and high doses of **barbiturates** that are found within the TMD (transmembrane domain) of α and β subunits, may not only be positive allosteric modulators of GABA-A receptors but **also direct agonists of these receptors**.
The **GABA-B receptors mediate slow and prolonged** inhibitory signals (some agonists are **hypnotics**) through activating inwardly rectifying **K+ ion channels**, **inactivating 😲 VGCCs** !
GABA-B Receptors are similar in structure to and in the same receptor family with **metabotropic** glutamate receptors (G-protein-couple receptors driven metabolic steps indirectly linked to ion channels).
There are two subunits of the receptor, GABA-B1 and GABA-B2, and these appear to assemble as obligate heterodimers (2 different peptide chains) in neuronal membranes by linking up by their intracellular C termini.
In the mammalian brain, two predominant, differentially genetically expressed **mRNA** molecules or isoforms of the GABA-B1 are transcribed from the Gabbr1 gene, GABA-B(1a) and GABA-B(1b), which are conserved in different species including humans.
* **References**
https://www.nature.com/articles/s41380-021 ok-01386-6
https://en.m.wikipedia.org/wiki/%CE%93-Aminobutyric_acid https://pubmed.ncbi.nlm.nih.gov/12495646/#:~:text=Gabapentins%20(GBP)%20is%20structurally%20similar,in%20the%20proximal%20small%20bowel.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265598/#:~:text=The%20actions%20of%20gabapentinoids%20are,to%20the%20amino%20acid%20leucine.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374141/#:~:text=GABA%20type%20A%20(GABAA,G%20proteins%20and%20second%20messengers.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374141/#:~:text=GABAB%20receptors%20are%20G,channels%2C%20and%20inhibiting%20adenylate%20cyclase.
https://www.sciencedirect.com/topics/neuroscience/voltage-gated-calcium-channel#:~:text=VGCC%20represent%20a%20group%20of,and%20Di%20Biase%2C%202022).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304739/#:~:text=Calcium%20influx%20through%20voltage%2Dgated,alterations%20in%20GABAA%20receptors.
https://www.ncbi.nlm.nih.gov/books/NBK557825/#:~:text=The%20release%20of%20acetylcholine%20occurs,release%20into%20the%20synaptic%20cleft.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826832/#:~:text=Whe n%20GABA%20molecules%20or%20GABA,flow%20decreases%20the%20cell's%20excitability.
https://pubmed.ncbi.nlm.nih.gov/9426294/#:~:text=An%20increased%20intracellular%20Ca2%2B%20concentration,10%20nM%20to%2034%20muM).
https://en.m.wikipedia.org/wiki/GABA_receptor_agonist https://en.m.wikipedia.org/wiki/GABAA_receptor_positive_allosteric_modulator#:~:text=In%20psychopharmacology%2C%20GABAA%20receptor,Ambien)%20and%20the%20barbiturate%20drugs.
https://pubmed.ncbi.nlm.nih.gov/8380942/#:~:text=The%20opening%20of%20a%20chloride,excitation%20into%20the%20terminal%20arborization.
https://www.sciencedirect.com/topics/medicine-and-dentistry/synaptic-vesicle https://pubmed.ncbi.nlm.nih.gov/8822150/#:~:text=Exocytosis%20is%20the%20fusion%20of,lipids%20into%20the%20plasma%20membrane.
* **Potentiation & Metabolism: What Happens When You Eat Grapefruit With Xanax ?**
Like most medications, Xanax can interact with other drugs, and its beneficial properties and side effects can be altered by agents that either accelerate or delay its metabolism. Grapefruit affects the metabolism of many drugs, including Xanax. It blocks CYP3A4, thereby allowing higher amounts of many drugs to enter your bloodstream.
https://www.livestrong.com/article/443427-what-happens-when-you-eat-grapefruit-with-xanax/ * **Cross-tolerance is complex**
Pregabalin (a VGCC blocker), when used as adjunctive therapy in benzodiazepine discontinuation, **does not exhibit cross tolerance with benzodiazepines**.
However, the development of tolerance and **cross tolerance can occur during chronic treatment with positive modulators acting at different sites on GABA-A receptors**, such as neuroactive steroids like pregnanolone.
> Cross-tolerance bidirectional weighting
Studies have shown that benzodiazepine treatment does **not result in rapid cross tolerance** to barbiturates, but barbiturate treatment can confer **rapid cross tolerance to benzodiazepines**.
https://typeset.io/questions/does-pregabalin-have-a-cross-tolerance-with-benzodiazepines-571qlnks4o > **Who is likely to develop cross-tolerance ?**
For those on benzodiazepines, you’re most likely to develop cross-tolerance if:
* you’ve been prescribed drugs from the **same or similar classes**, such as two different types of benzo.
* you are taking medications with **similar effects**, like an anti-anxiety drug and a sedative/hypnotic.
* you drink alcohol while taking any of the **drugs that affect your GABA-A receptors**.
* you take any other medications that **hit the same (GABA-A) receptors** in your brain including steroids, barbiturates, Z drugs and other sedatives.
> **The dangers of cross-tolerance**
**Cross-tolerance** means that if you become dependent on one drug in the class, you’re more likely to develop dependence on the others.
Someone who suffers from **alcohol dependence/addiction is more likely to develop a dependence issue with benzos as well**.
If you are taking benzos please do the research on all new medications to **check if they affect the GABA-A receptor** so you don’t end up taking something that makes you tolerant to your benzos, giving you more symptoms to manage.
Interestingly, **Alcohol is also cross-tolerant with caffeine and nicotine**.
Cross-tolerance can be used as a medical tool. For example, **benzodiazepines are sometimes utilized when detoxing from alcohol abuse to ease withdrawal symptoms** - something I know only too well 😋.
https://www.benzowarrior.com/cross-tolerance * **More confusion (introducing Baclofen)**
**Baclofen which is identical to Phenibut but with a Chlorine molecule hanging off it** yet it's classed as a GABAergic and **not a GABApentinoid**:
Baclofen is a γ-aminobutyric acid (GABA) analogue that acts as an **agonist at central GABAB receptors** in much the same way as the inhibitory neurotransmitter, GABA.
Similarly to phenibut (β-phenyl-GABA), as well as pregabalin (β-isobutyl-GABA), which are close analogues of baclofen, baclofen (β-(4-chlorophenyl)-GABA) **blocks α2δ subunit-containing voltage-gated calcium channels (VGCCs)**.
Which is textbook one of the
https://en.m.wikipedia.org/wiki/Gabapentinoid family yet it isn't.
> Other differences between Phenibut and Baclofen
Phenibut has a much greater affinity to the GHB receptor but I'm not sure what that means because it never gave me that empathogenic feeling that GHB did. It is said to be more euphoric and therefore more addictive.
The biggest difference is that 1 gram of Phenibut is equal to only 10 mg of Chloro-Phenibut (Baclofen).
* **Seizures, TBI and Epilepsy**
Interestingly, severe TBI (traumatic brain injury) can cause GABA disturbances that can lead to epilepsy. GABA counterbalances neuronal excitation but all it takes is a **deep disturbance** in levels (too much or too little) to trigger a seizure -- beyond the usual trigger of just a sudden **sizable drop** in levels such as seen in withdrawal.
One case, 150 mg for the day was all it needed for one epileptic lady to experience a sudden worsening of seizures, bear in mind that Pregabalin is also used as an anticonvulsant.
> Isodicentric 15 syndrome (IDIC-15) is due to (**partial duplications of chromosome 15q** which plays an important role in **human neurobehavioral development**.
> ... *may* be related to **abnormal** GABA **receptor** function and morphology ...
* Paradoxical worsening of seizure activity with pregabalin in an adult with isodicentric 15 (IDIC-15) syndrome involving duplications of the GABrB3, GABrA5 and GABrG3 genes.
Which are the **genes that express** or encode those GABA **receptor** (**r**) subunits.
https://bmcneurol.biomedcentral.com/articles/10.1186/1471-2377-13-43This concludes **GABA (γ-Aminobutyric acid) - GABAergics, GABApentinoids and (cross-) tolerance explored**
November 30, 2019, 06:00:55 AM
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