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Copyrighted Papers => My Collaborative Ideas Using Native and Browser-embedded MS Copilot & OpenAI's ChatGPT => Topic started by: Chip on December 14, 2024, 10:55:38 PM
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UPDATED: 14 Nov 2024
Actually, **the reptilian brain is the oldest part of the human brain** as it developed about 400 million years ago whereas the **limbic brain system anatomically surrounds the reptilian brain** and serves to **regulate somatosensory experience, emotion, memory, some social behavior, and learning**.
Our **Histaminergic system** is actually our ancient "big daddy" neurotransmission system and it **modulates all other neurotransmitters** but will not be discussed here today but be aware that **H3R Antagonists** have the potential to exert the **most psychoactive influence** overall.
But I am personally more interested in this TAA **neuromodulatory system** because, and this just my own hypothesis, that it may support the function of our original, **less evolved, pleasure circuitry**, when we were primarily motivated by the simple fundamental need of **food**, a high degree of **reactivity**, and **sex**/reproduction, merely to prevent extinction and in a more hostile environment, by virtue of it's anatomical location.
On this topic, **our original ancient reward/pleasure source** originated from fermented fruit: a drug we all recognise as **alcohol** but is too boring to discuss or research further but it is an Ethane derivative as is Phenethylamine, which also known as 1-amino-2-phenyl**ethane**.
TAAR1 is **associated** with the **"God gene"** but please see https://www.reddit.com/r/Drugs/s/jySKHF8453 first.
* **What is the God gene theory ?**
Wiki says that the God gene hypothesis proposes that human spirituality is influenced by heredity and that a specific gene, called **VMAT2** or Vesicular MonoAmine Transporter 2, predisposes humans towards **spiritual or mystic experiences**.
> "These findings provide the **first evidence of a TAAR1-VMAT2 interaction**, as activation of TAAR1 mitigated MA-induced impairment of VMAT2 function, independently of change in VMAT2 expression."
* **What are the potential benefits of TAAR1 research ?**
• a valuable tool to **treat drug abuse and addiction**.
• an **effective treatment for schizophrenia** and related disorders.
• an exploitable **modulator of the CNS**.
• a **sleep disorder** therapy.
• a **multi-druggable target** 👈 (like some of us,❤️ that term) 😋 for the future antidepressant, antipsychotic, and **anti-addiction** drugs.
• a treatment for **immunomodulatory disorders**.
* **What are TAAR or trace amine associated receptors and what do they do ?**
They are **associated with the limbic brain system**, which is also known the **"smell brain"** which handles the processing of **behaviour, motivation, emotions, long term memories, arousal, and learning**.
They are evolutionarily **distant relatives of intracellular** G protein-coupled biogenic **aminergic** (dopamine, norepinephrine or serotonin) **receptors**, and are **found in the brain as well as in the olfactory epithelium** or "one cell layer thin", and were discovered in 2001.
**Trace amines are our natural or endogenous compounds** that act as agonists to the TAARs and are classically regarded as comprising β-phenylethyalmine, p-tyramine, tryptamine, p-octopamine, and some of their metabolites.
They are also **abundant in common foodstuffs** and can be produced and degraded by the constitutive microbiota.
The term **"trace amine"** was coined to reflect the **low tissue levels in mammals**, however, invertebrates have relatively high levels where they function like mammalian adrenergic systems, involved in "fight-or-flight" responses.
We humans have **six functional mRNA molecules** or isoforms (hTAAR1, hTAAR2, hTAAR5, hTAAR6, hTAAR8, and hTAAR9), and **three pseudogenes** or DNA that's **mutated into an inactive form** over the course of evolution (TAAR3, TAAR4P, and TAAR7P).
With the exception of TAAR1, **TAARs** are expressed in olfactory epithelium neurons, where they **detect** diverse ethological signals including **predators, spoiled food, migratory cues, and 👉 pheromones**.
TAARn, Species, Ligand, Source Behaviour:
TAAR3 m,h Isopentylamine, ,aversion (m)
TAAR4 m,h 👉 **2-phenethylamine**, ,carnivore urine, aversion (m,r)
TAAR5 m,h,r Trimethylamine, male mouse urine
aversion (r, h), attraction (m)
TAAR13 z Cadaverine, ,aversion (z,m)
Our olfactory system is essential to our existence as our **sense of smell provides a vital survival function** and **bypasses our "thinking" brain** because if we smell something which is putrid or rotting, we have an automatic physical reaction – we are repelled by it to **avoid a dangerous or unhealthy situation**.
The sense of smell is also able to affect us in other ways at a sub-conscious level, can **influence our choice of sexual partner**, **bonding between mother and child**, elicit **immediate** remembering and **uncovering forgotten memories** and the promotion of **relaxed states of mind**.
TAAR serves as a direct intracellular target for amphetamines in DA neurons.
* **What is TAAR1, why is it interesting and what does it do ?**
**TAAR1 is a** TAAR or trace amine-associated **receptor protein** that in humans is encoded by the TAAR1 gene.
**TAAR1 is an intracellular amine-activated** Gs-coupled and Gq-coupled **G protein-coupled receptor** (GPCR) that is primarily expressed **in several peripheral organs and cells** (e.g., the stomach, small intestine, duodenum, and white blood cells), **astrocytes** and in the **intracellular** milieu within the **pre-synaptic** plasma membrane (i.e., **axon terminal**) of monoamine **neurons in the CNS**.
It **prevents hyperactivity of the dopaminergic system**.
It **lies outside the olfactory system** and is the most thoroughly studied and has both central and peripheral roles. It has gained considerable interest in academic and proprietary pharmaceutical research.
It's **widely expressed throughout the brain** and has been found in areas that are **associated with** the emergence of **schizophrenia** symptoms, including the frontal cortex as well as the ventral tegmental area and dorsal raphe nucleus.
In the **brain it acts as a neuromodulator of dopaminergic, glutamatergic, and serotonergic neurotransmission** and has been identified as a novel **therapeutic target for schizophrenia, depression, and addiction**, therefore it plays an essential role in the **regulation of pleasure and reward circuits, cognitive processes, and mood states**, probably to reinforce the importance of, and to keep on seeking out, food and water and reproduction or sex.
In the **periphery it regulates** nutrient-induced **hormone secretion** and it may also regulate **immune responses** by regulating leukocyte differentiation and activation.
It is a high-affinity endogenous **receptor for** the trace amines **phenethylamine, tyramine, and tryptamine** – metabolic **derivatives of the amino acids phenylalanine, tyrosine and tryptophan**, respectively, which are the **building blockd for dopamine, norepinephrine and serotonin**.
TAAR1 **agonists** such as ephedrine, amphetamine, methamphetamine, MDMA, and v3-iodothyronamine have been shown to **stimulate metabolism, physiology, and behavior**.
* **How can it help all those poor drug addicts ?**
It is hypothesized that TAAR1 interaction with DA transporter (DAT) and dopamine D2 receptor (D2) and the subsequent modulation of cellular cascades may contribute to the effects of TAAR1 in **regulating drug abuse-related behaviour by inhibiting drug-induced DA or dopamine transmission** therefore being a promising therapeutic target for treating drug addiction.
It has been *hypothesised* that **stimulants that do not interact with TAAR1**, like many of the moreish, often compulsively redosed, 👉 **cathinones**, may have an increased risk of dependence **in contrast to** drugs like MDMA that **enhance monoamine neurotransmission** but also **stimulate TAAR1**.
The brain mRNA coding for TAAR1 is localised in the limbic system and the regions associated with catecholamines. As a result, TAAR1 is a **highly influential neuromodulator** for emotional and motivated **behaviors associated** with psychotropic **drug abuse** usually associated with monoaminergics.
**Antagonists of TAAR1 modulate the locomotor activation** produced by the **methamphetamine, cocaine** and other psychostimulants. The **addictive properties of methamphetamine and cocaine** also appear to be **regulated** by the receptor.
* **Why is the amino acid phenethylamine, the fundamental structure that so many fun and useful drugs are derived from, so interesting ?**
**Phenylalanine** is metabolised into both **Phenethylamine, the body's "natural amphetamine" and Tyrosine** which then metabolise into our catecholamines.
Phenethylamine has been shown to bind to human trace amine-associated receptor 1 (hTAAR1) as an agonist. **β-Phenethylamine** is also an odorant binding TAAR4 in mice and **thought to mediate predator avoidance**.
**Phenethylamine is an endogenous amphetamine** and present in only **small amounts** in the brain compared to classic neurotransmitter amines such as norepinephrine, dopamine, and serotonin.
Phenethylamine is a functional **neurotransmitter and neuromodulator, influencing the effects of central monoamine neurotransmitters** (catecholamines and serotonin) and is **synthesised in monoaminergic nerve terminals** and have their own set of TAARs.
These receptors are widely expressed in the brain and are involved in:
•Attention
•Cravings
•Focus
•Mental health
•Lood
•Nerve health
* **How does it exert its effects or what is it's mechanism of action ?**
At the site of the action that **agonists** operate within the synaptic cleft, present inside the neurons, **increase the concentration of the associated monoamines** in the synaptic cleft, causing the **increased post-synaptic receptor binding**.
TAAR1 induces the activation of G protein-coupled inwardly rectifying potassium channels (GIRKs) which **attenuates the firing frequency of DA neurons**, thus, mitigating the establishment of the hyperdopaminergic state.
The dopamine transporter (DAT) uptake triggers the competitive inhibition between the TAs and amphetamine for their reuptake to the transporter.
> The pre-synaptic neuronal cleft harbours the TAs and amphetamine, which cause the activation of TAAR1 via the PKA and PKC signaling pathway leading to DAT phosphorylation.
The **TA signaling pathway is one of the most recent pathways** which have not yet been elucidated comprehensively. It presents **an excellent model system to understand the crosstalk** between various cell receptors, transporters, channels, neuronal receptors, metabolic or signaling enzymes (PKA and PKC), secreted factors, DAT phosphorylation, signal transduction proteins, and transcription factors.
**Crosstalk**
Regulation of other neurotransmitter systems by TAAR1 has also been reported, in particular TAAR1-mediated **regulation of pre-synaptic , 5HT1A receptors**.
A TAAR1-mediated **regulation of NMDA receptor** sub-units has also been reported.
* **What has amphetamine got to do with it ?**
Amphetamine regulates the trafficking of both dopamine and glutamate transporters in dopamine neurons by directly activating TAAR1 and then signaling.
**TAAR1 can be activated by amphetamines, trace amines, and biogenic amine metabolites** and mediates the effects of amphetamine signaling.
These observations define **TAAR1** as an obligate **target for amphetamines in dopamine neurons** and support a model in which distinct pools of TAAR1 mediate the activation of signaling pathways in different compartments to **regulate excitatory and dopaminergic neurotransmission**.
* **What do we already know about how the different mechanisms involved in how amphetamine and cocaine work ?**
Amphetamine and a variety of analogues have well established actions as substrates and competitive inhibitors of the dopamine, norepinephrine, and/or serotonin transporters (DAT, NET, and/or SERT).
These compounds gain entry into neurons through DAT, NET, and/or SERT, displace neurotransmitters from vesicular stores and facilitate efflux through the plasma membrane carriers.
Amphetamine **indirectly releases** the monoamines as it activates signal transduction pathways that lead to the internalisation of the DAT and of the neuronal glutamate **transporter** through a series of intracellular events that appear to be distinct from the established actions of competitive inhibitors of monoamine transport, described below"
Cocaine and other drugs that **inhibit the transport** of amphetamine readily block the effects of amphetamine on transporter trafficking, consistent with the idea that amphetamine triggers these events within the cell. This builds up, **increasing** the amount of intrasynaptic **concentrations** of the 4 main monoamines.
* **In addition**
> The activation of signaling pathways occurs in cells that lack the capacity for DA synthesis and vesicular packaging, which suggests that the effects of amphetamine are not mediated by DA.
> These apparent direct effects of amphetamine signaling suggests the existence of a novel intracellular target for the drug and led us to examine potential intracellular targets for amphetamine and other related compounds.
**References**
* The Case for TAAR1 as a Modulator of Central Nervous System Function
https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2017.00987/full
* Neurotransmitters
https://my.clevelandclinic.org/health/articles/22513-neurotransmitters
* Trace Amines and Their Receptors
https://pubmed.ncbi.nlm.nih.gov/29941461/#:~:text=Trace%20amines%20are%20endogenous%20compounds,degraded%20by%20the%20constitutive%20microbiota.
https://en.m.wikipedia.org/wiki/Trace_amine-associated_receptor#cite_note-TAAR_2015_review_-_olfactory_TAARs-9
* The oldest part of the brain
https://menteath.com/blogs/grow-gather-give/the-oldest-part-of-the-brain
* Chapter Eleven - Trace amine-associated receptor 1 and drug abuse
https://www.sciencedirect.com/science/article/abs/pii/S1054358921000600
* Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges
> Functional activity (EC50) and binding potency (Ki) of endogenous, selected psychoactive, non-selective and selective TAAR1 agonists in rat, mouse and human.
https://www.sciencedirect.com/science/article/pii/S0163725817301626
* Trace Amine-Associated Receptor
https://www.sciencedirect.com/topics/neuroscience/trace-amine-associated-receptor#:~:text=Trace%20amine%2Dassociated%20receptor%201%20(TAAR1)&text=It%20has%20been%20hypothesized%20that,stimulate%20TAAR1%5B12%5D.
* A collection of books
https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/taar1#:~:text=The%20brain%20mRNA%20coding%20for,the%20regions%20associated%20with%20catecholamines.&text=As%20a%20result%2C%20TAAR1%20is,abuse%20usually%20associated%20with%20monoaminergics.
* Amphetamines signal through intracellular TAAR1 receptors coupled to Gα13 and GαS in discrete subcellular domains
https://www.nature.com/articles/s41380-019-0469-2
* What Is Phenylethylamine and How Does It Improve Mood and Focus?
https://sanescohealth.com/blog/what_is_phenylethylamine/
* The Role of Biogenic Amine Transporters in Trace Amine–Associated Receptor 1 Regulation of Methamphetamine-Induced Neurotoxicity
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750185/
This concludes **The oldest part of our brain and the TAAR1: The trace amine associated receptor 1**