Glutamate Metabolism and Receptors
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Questions and Answers

What is one of the therapeutic effects of CNS drugs on neurotransmission?

  • They enhance the degradation of neurotransmitters.
  • They affect gene expression in the nucleus.
  • They modify specific steps in neurotransmission. (correct)
  • They inhibit protein synthesis.

    • Which of the following is not a step in the process modified by CNS drugs?

  • Influence organelles' function. (correct)
  • Affect receptor interactions.
  • Affect release of neurotransmitters.
  • Inhibit metabolism of neurotransmitters.

    • Glutamate and GABA play critical roles in which aspect of the CNS?

  • Mediating neurotransmission effects. (correct)
  • Facilitating immune responses.
  • Regulating muscle contractions.
  • Controlling visual processing.

    • Which class of drugs is indicated as acting on glutamate neurotransmission?

    <p>Anti-ND drugs.</p> Signup and view all the answers

    The term 'retrograde signaling' in CNS pharmacology primarily refers to?

    <p>Communication from postsynaptic to presynaptic neurons.</p> Signup and view all the answers

    What is a primary target for presynaptic drugs acting on GABAergic transmission?

    <p>Enhancing GABA synthesis, degradation, or reuptake</p> Signup and view all the answers

    Which GABA receptor type is currently targeted by the fewest therapeutic agents?

    <p>GABAC receptors</p> Signup and view all the answers

    Which subunit modification of the GABAA receptor is associated with anxiolysis?

    <p>α2 or α3 subunits</p> Signup and view all the answers

    What is one of the goals in the development of new anxiolytics and sedatives?

    <p>To reduce adverse effects such as ataxia and tolerance</p> Signup and view all the answers

    What pharmacologic characteristic is unique to GABAA receptors containing different β subunits?

    <p>They possess distinct pharmacology and physiology</p> Signup and view all the answers

    What condition is directly associated with excitotoxicity resulting from excessive glutamate?

    <p>Hyperanalgesia</p> Signup and view all the answers

    Which drug is an NMDA receptor antagonist used in the treatment of Alzheimer's disease?

    <p>Memantine</p> Signup and view all the answers

    What primary mechanism does Riluzole utilize to decrease glutamate release?

    <p>Blocking voltage-gated Na+ channels</p> Signup and view all the answers

    What common side effect is associated with the use of anti-amyloid monoclonal antibodies in Alzheimer’s treatment?

    <p>Amyloid-related imaging abnormalities</p> Signup and view all the answers

    Which of the following diseases is NOT linked to the pathophysiology of glutamatergic neurotransmission?

    <p>Autoimmune diseases</p> Signup and view all the answers

    What is the primary function of Amantadine in Parkinson's disease management?

    <p>Block NMDA receptors</p> Signup and view all the answers

    Which treatment option is specific for ALS among the drugs mentioned?

    <p>Riluzole</p> Signup and view all the answers

    What is the frequency of administration for Donanemab in patients with mild cognitive impairment?

    <p>Every four weeks</p> Signup and view all the answers

    What is the primary action of AMPA receptors in glutamatergic neurotransmission?

    <p>Increase Na+ influx</p> Signup and view all the answers

    Which glutamatergic receptor subtype is primarily responsible for the influx of Ca2+?

    <p>NMDA-R</p> Signup and view all the answers

    How do Group II metabotropic glutamate receptors affect neuronal activity?

    <p>Decrease cAMP and neuronal activity</p> Signup and view all the answers

    What is the role of glutamine synthetase in glial cells?

    <p>Convert glutamate to glutamine</p> Signup and view all the answers

    What is the mechanism of action for mGluR1 and mGluR5 receptors?

    <p>Activate phospholipase C</p> Signup and view all the answers

    Which subtype of ionotropic receptor is primarily distributed throughout the hippocampus?

    <p>AMPA receptors</p> Signup and view all the answers

    What effect do Group I metabotropic receptors have on calcium concentration?

    <p>They promote calcium influx through phospholipase C activation</p> Signup and view all the answers

    What is the primary transporter responsible for the uptake of glutamate into presynaptic terminals?

    <p>Gt(n)</p> Signup and view all the answers

    Which of the following actions is NOT associated with the NMDA receptor?

    <p>Sodium efflux</p> Signup and view all the answers

    What is the role of calcium in the exocytosis of glutamate?

    <p>It promotes vesicle fusion</p> Signup and view all the answers

    What is the primary clinical application for Vigabatrin?

    <p>Epilepsy treatment</p> Signup and view all the answers

    Which of the following drugs is a competitive antagonist at GABAA receptor binding sites?

    <p>Bicuculline</p> Signup and view all the answers

    What effect do benzodiazepines primarily have on the GABAA receptor?

    <p>Enhance GABA receptor Cl- channel gating</p> Signup and view all the answers

    Which of these classifications of GABAergic drugs is known for inducing sedation and sleep?

    <p>GABAA receptor agonists</p> Signup and view all the answers

    What is a notable side effect of zolpidem as highlighted in the content?

    <p>Impaired driving skills</p> Signup and view all the answers

    How do benzodiazepines affect the treatment of alcohol withdrawal symptoms?

    <p>They act as anxiolytics.</p> Signup and view all the answers

    Which drug is used to treat benzodiazepine overdose?

    <p>Flumazenil</p> Signup and view all the answers

    What type of drugs potentiates the effects of GABA?

    <p>GABAA receptor modulators</p> Signup and view all the answers

    Which of the following describes the action of Tiagabine?

    <p>Inhibits GABA transporter, GAT-1</p> Signup and view all the answers

    What major pharmacologic effect do benzodiazepines share?

    <p>Potentiating GABA's inhibitory effects</p> Signup and view all the answers

    Which statement regarding the metabolism of benzodiazepines is true?

    <p>They are metabolized by hepatic P450 enzymes, especially CYP3A4.</p> Signup and view all the answers

    What clinical application is NOT commonly associated with benzodiazepines?

    <p>Antidepressant therapy</p> Signup and view all the answers

    Which long-acting benzodiazepine is mentioned as a treatment for anxiety and alcohol withdrawal syndrome?

    <p>Chlordiazepoxide</p> Signup and view all the answers

    What is a key characteristic of Z-drugs compared to traditional benzodiazepines?

    <p>Structural differences yet bind to GABAA receptors</p> Signup and view all the answers

    Study Notes

    Glutamate Metabolism

    • Glutamate is synthesized from alpha-ketoglutarate in glutamatergic nerve terminals by GABA transaminase (GABA-T).
    • Glutamate is stored in synaptic vesicles by H+-ATPase/vesicular glutamate transporter (VGLUT).
    • Glutamate is released in response to an action potential, which causes an increase in intracellular calcium ([Ca2+]i) and triggers exocytosis.

    Glutamate Deactivation

    • Glutamate is taken up by presynaptic nerve terminals via neuronal Gt(n) transporters.
    • Glutamate is taken up by glial cells via glial Gt(g) transporters.
    • In glial cells, glutamate is converted to glutamine (Gln) by glutamine synthetase.
    • Glutamine is transferred to presynaptic nerve terminals via Gln transporters.
    • Glutamine is converted to glutamate by mitochondria-associated glutaminase.

    Glutamate Receptors

    • Ionotropic glutamate receptors are divided into three subtypes: AMPA, kainate, and NMDA.
    • Ionotropic receptors are glutamate-gated Na+, K+, and Ca2+ channels, which cause fast, excitatory responses.
    • Metabotropic glutamate receptors (mGluRs) have eight subtypes, grouped into three categories: Group I (mGluR1 & mGluR5), Group II (mGluR2 & mGluR3), and Group III (mGluR4, mGluR6, mGluR7, & mGluR8).
    • Metabotropic glutamate receptors affect ion channels through second messengers and cause slow responses. The final effects depend on the type of ion channels.

    Ionotropic Glutamate Receptor Subtypes

    • AMPA receptors (AMPA-R) are found throughout the CNS, particularly in the hippocampus and cerebral cortex.
    • Kainate receptors (Kainate-R) are also found throughout the CNS, particularly in the hippocampus and cerebellum.
    • NMDA receptors (NMDA-R) are primarily found in the hippocampus, cerebral cortex, and spinal cord.

    Metabotropic Glutamate Receptor Subtypes

    • Group I mGluRs (mGluR1 & mGluR5) activate adenylyl cyclase (AC) and phospholipase C (PLC), causing increases in cAMP and IP3/DAG, ultimately increasing neuronal activity.
    • Group II mGluRs (mGluR2 & mGluR3) inhibit AC, causing a decrease in cAMP, and activate K+ channels, leading to decreased neuronal activity. Group II mGluRs also inhibit AC, Ca2+ channels, and glutamate release.
    • Group III mGluRs (mGluR4, mGluR6, mGluR7, & mGluR8) inhibit AC, and Ca2+ channels, leading to a decrease in glutamate release and neuronal activity.

    Glutamatergic Neurotransmission

    • Excitotoxicity describes neuronal death caused by an overstimulation of glutamate receptors.
    • Excessive glutamate release, decreased glutamate uptake, and increased intracellular calcium (Ca2+) concentration can all lead to excitotoxicity.
    • Excitotoxicity is associated with a number of neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), as well as stroke, trauma, hyperanalgesia, and epilepsy.

    Current Pharmacology of Glutamatergic Neurotransmission

    • Riluzole, an anti-ALS drug, blocks voltage-gated Na+ channels to reduce glutamate release.
    • Memantine, an anti-AD drug, acts as an NMDA receptor antagonist to reduce Ca2+ influx.
    • Amantadine, used in combination with levodopa to treat PD, acts as an NMDA receptor antagonist and reduces the severity of dyskinesia.
    • Lamotrigine, an anti-seizure drug, stabilizes the inactive state of voltage-gated Na+ channels to reduce glutamate release.
    • Felbamate, another anti-seizure drug, also acts an NMDA receptor antagonist.

    Recent Anti-AD Immunotherapies

    • Lecanemab (Eisai/Biogen) is a monoclonal antibody that targets amyloid. It is approved for patients with mild cognitive impairment or mild dementia stage of AD who have confirmed amyloid pathology. It is administered intravenously every two weeks and has a boxed warning for amyloid-related imaging abnormalities (ARIA).
    • Donanemab (Eli Lilly) is also a monoclonal antibody that targets amyloid. It is approved for patients with mild cognitive impairment or mild dementia stage of AD who have confirmed amyloid pathology. It is administered intravenously every four weeks and also carries a boxed warning for amyloid-related imaging abnormalities (ARIA).

    GABAergic Drugs

    • Inhibit GABA metabolism
    • Act as GABA receptor agonists or antagonists
    • Modulate GABAA receptors
    • Act as GABAB receptor agonists or antagonists
    • Some agents that affect GABA physiology are available over-the-counter.

    Clinical Applications of GABAergic Drugs

    • Sedation (anxiolysis)
    • Hypnosis (sleep induction, general anesthesia)
    • Control of seizures
    • Neuroprotection following stroke or head trauma
    • Muscle spasm
    • Treatment of alcohol withdrawal syndrome

    Inhibitors of GABA Metabolism

    • Tiagabine inhibits GABA transporter GAT-1, blocking reuptake and increasing GABAergic transmission.
    • Vigabatrin (gamma-vinyl GABA) inhibits GABA transaminase (GABA-T), blocking the conversion of GABA to succinate semialdehyde and increasing GABAergic transmission.

    GABAA Receptor Agonists and Antagonists

    • Muscimol is found in the hallucinogenic mushroom Amanita muscaria and is a full agonist at many GABAA receptor subtypes.
    • Bicuculline is a competitive antagonist at GABA binding sites.
    • Picrotoxin is a noncompetitive inhibitor that blocks the Cl- channel pore.
    • Bicuculline and Picrotoxin induce seizures and are only used for research.

    Benzodiazepines

    • Chlordiazepoxide was discovered in 1955 and marketed in 1960.
    • Diazepam was marketed in 1963.

    Benzodiazepines Mechanism of Action

    • Benzodiazepines bind to the interface of alpha and gamma subunits on GABAA receptors containing alpha1, alpha2, alpha3, or alpha5 subunits (requiring a histidine residue)
    • They enhance GABAA receptor Cl- channel gating in response to GABA, increasing Cl- conductance and decreasing postsynaptic neuronal excitability.
    • Benzodiazepines potentiate GABA's inhibitory effects and enhance maximal activation by GABAA partial agonists.
    • Some benzodiazepines can directly activate certain mutant GABAA receptors, although they are weak agonists.

    Benzodiazepines Clinical Applications

    • Sleep enhancers
    • Anxiolytics
    • Sedatives
    • Muscle relaxants
    • Antiepileptics
    • Treatment of alcohol withdrawal symptoms.

    Benzodiazepine Duration of Action

    • Short-acting (3-8 hrs): clorazepate, midazolam
    • Intermediate-acting (11-20 hrs): alprazolam, lorazepam
    • Long-acting (1-3 days): chlordiazepoxide, clonazepam, diazepam, clobazam

    Specific Benzodiazepines and Clinical Uses

    • Clorazepate: anxiety, seizure disorders, alcohol withdrawal syndrome
    • Midazolam: anxiety, sedation, general anesthetic
    • Alprazolam (Xanax®): anxiety, panic disorder
    • Lorazepam (Ativan®): anxiety, insomnia, seizure disorders, premedication for anesthetic procedures
    • Chlordiazepoxide (Librium®): anxiety, alcohol withdrawal syndrome
    • Clonazepam (Klonopin®): panic disorder, seizure disorders
    • Diazepam (Valium®): anxiety, sedation, general anesthetic, seizure disorders, muscle spasm, alcohol withdrawal syndrome
    • Clobazam: anxiety, Lennox-Gastaut syndrome

    Other Benzodiazepines and Uses

    • Flurazepam: insomnia (long-acting)
    • Triazolam: insomnia (short-acting)
    • Quazepam: insomnia (long-acting)
    • Temazepam: insomnia (intermediate-acting)
    • Estazolam: insomnia (intermediate-acting)

    Flumazenil and Benzodiazepines

    • Flumazenil is a benzodiazepine antagonist that can reverse benzodiazepine overdose.
    • Flumazenil can induce a severe withdrawal syndrome in patients with benzodiazepine dependence.
    • Flumazenil does not block the effects of barbiturates or ethanol.

    Z-Drugs

    • Zolpidem (Ambien®), zaleplon, and eszopiclone are known as Z-drugs.
    • They are used to treat insomnia.
    • Z-drugs bind to the benzodiazepine binding site on GABAA receptors containing the alpha1 subunit.
    • Z-drugs can be reversed by flumazenil.
    • Z-drugs are structurally different from benzodiazepines, but their clinical applications are less diverse.
    • Z-drugs also have a risk of tolerance and amnesia.

    Conclusions and Future Directions

    • Each of the three main GABA receptor types has a distinct pharmacology.
    • GABAA receptors are targeted by the most drugs, including GABA binding site agonists, benzodiazepines, barbiturates, general anesthetics, and neuroactive steroids.
    • GABAB receptors are targeted by only a few therapeutic agents, which are used to treat spasticity.
    • GABAC receptors are not currently targeted by pharmacologic agents.

    Future Directions

    • To improve safety and reduce adverse effects (ataxia, tolerance, physical dependence), the development of new anxiolytics and sedatives focuses on low-efficacy compounds (e.g., benzodiazepines), and compounds with selective activity at specific GABAA receptor subtypes.
    • Animal models with selectively mutated GABAA receptor subunits suggest that sedation/hypnosis is produced by enhancing the activity of receptors containing the alpha1 subunit.
    • Anxiolysis is produced by modulation of alpha2 or alpha3 containing receptors, and amnesia is associated with alpha5 containing receptors.
    • New antagonists for glutamate receptor subtypes could potentially be used to protect the CNS in stroke, prevent tissue trauma and hyperalgesia, and treat epileptic seizures.

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    Glutamatergic & GABAergic Pharmacology 10-2024 PDF

    Description

    This quiz explores the synthesis, deactivation, and receptor types of glutamate, a key neurotransmitter in the brain. Learn about the intricate processes involved in glutamate metabolism and how it interacts with various receptors. Test your knowledge on glutamate's role in neurotransmission and its effects on synaptic function.

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