Do stimulants (amphetamines, cocaine) cause downregulation of glutamate signalling (in addi… by Connie b. Dellobuono
Answer by Connie b. Dellobuono:
Glutamate (Glutamic acid) is the most prominent neurotransmitter in the body, and it is the main excitatory neurotransmitter,[1] being present in over 50% of nervous tissue.[2] Glutamate was initially discovered to be a neurotransmitter in insect studies in the early 1960s.
Glutamate is also used by the brain to synthesize GABA (γ-Aminobutyric acid), the main inhibitory neurotransmitter of the mammalian central nervous system, which plays a role in regulating neuronal excitability throughout the nervous system and is also directly responsible for the regulation of muscle tone in humans. Glutamate receptors are also expressed in pancreatic islet cells. Small unmyelinated sensory nerve terminals in the skin also express NMDA and non-NMDA (glutamate) receptors.
Source: Wiki
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Glutamate down-regulation can be lead to Alzheimer's disease (a type 3 diabetes).
Alcohol and narcotics () shrink the brain. Poor nutrition, drugs/narcotics, alcohol, advancing age, infection and other neurotoxins downregulate glutamate receptors.
Glutamate receptors are thought to be responsible for the reception and transduction of umami taste stimuli. As we age, we have decreasing number of taste buds, decreasing muscle tones, skin tissues are more sensitive to pain and decreasing number of glutamate receptors.
Connie's comments
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From wiki:
Autoimmunity and antibody interactions with glutamate receptors and their subunit genes.
Various neurological disorders are accompanied by antibody or autoantigen activity associated with glutamate receptors or their subunit genes (e.g. GluR3 in Rasmussen's encephalitis,[31] and GluR2 in nonfamilial olivopontocerebellar degeneration.[In 1994 GluR3 was shown to act as an autoantigen in Rasmussen's encephalitis, leading to speculation that autoimmune activity might underlie the condition.[33] Such findings "suggest" links between glutamate receptors and autoimmune interactions are possible and may be significant in some degenerative diseases,[32] however the exact role of such antibodies in disease manifestation is still not entirely known.[
Excitotoxicity
Overstimulation of glutamate receptors causes neurodegeneration and neuronal damage through a process called excitotoxicity. Excessive glutamate, or excitotoxins acting on the same glutamate receptors, overactivate glutamate receptors (specifically NMDARs), causing high levels of calcium ions (Ca2+) to influx into the postsynaptic cell.[35]
High Ca2+ concentrations activate a cascade of cell degradation processes involving proteases, lipases, nitric oxide synthase, and a number of enzymes that damage cell structures often to the point of cell death.[36] Ingestion of or exposure to excitotoxins that act on glutamate receptors can induce excitotoxicity and cause toxic effects on the central nervous system.[37] This becomes a problem for cells, as it feeds into a cycle of positive feedback cell death.
Glutamate excitotoxicity triggered by overstimulation of glutamate receptors also contributes to intracellular oxidative stress. Proximal glial cells use a cystine/glutamate antiporter (xCT) to transport cystine into the cell and glutamate out. Excessive extracellular glutamate concentrations reverse xCT, so glial cells no longer have enough cystine to synthesize glutathione (GSH), an antioxidant.[38] Lack of GSH leads to more reactive oxygen species (ROSs) that damage and kill the glial cell, which then cannot reuptake and process extracellular glutamate.[39] This is another positive feedback in glutamate excitotoxicity. In addition, increased Ca2+ concentrations activate nitric oxide synthase (NOS) and the over-synthesis of nitric oxide (NO). High NO concentration damages mitochondria, leading to more energy depletion, and adds oxidative stress to the neuron as NO is a ROS.[40]
Neurodegeneration
In the case of traumatic brain injury or cerebral ischemia (e.g., cerebral infarction or hemorrhage), acute neurodegeneration caused by excitotoxicity may spread to proximal neurons through two processes. Hypoxia and hypoglycemia trigger bioenergetic failure; mitochondria stop producing ATP energy. Na+/K+-ATPase can no longer maintain sodium/potassium ion concentration gradients across the plasma membrane. Glutamate transporters (EAATs), which use the Na+/K+ gradient, reverse glutamate transport (efflux) in affected neurons and astrocytes, and depolarization increases downstream synaptic release of glutamate.[41] In addition, cell death via lysis or apoptosis releases cytoplasmic glutamate outside of the ruptured cell.[42] These two forms of glutamate release cause a continual domino effect of excitotoxic cell death and further increased extracellular glutamate concentrations.
Glutamate receptors' significance in excitotoxicity also links it to many neurogenerative diseases. Conditions such as exposure to excitotoxins, old age, congenital predisposition, and brain trauma can trigger glutamate receptor activation and ensuing excitotoxic neurodegeneration. This damage to the central nervous system propagates symptoms associated with a number of diseases.