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Drugs Affecting Neurotransmitter Synthesis01:29

Drugs Affecting Neurotransmitter Synthesis

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Drugs affecting neurotransmitter synthesis can impact the adrenergic neuron and the synthesis of neurotransmitters. For example, α-methyltyrosine and carbidopa target specific enzymes involved in catecholamine synthesis. α-methyltyrosine inhibits the enzyme tyrosine hydroxylase, which converts tyrosine into dopamine. By blocking this enzyme, α-methyltyrosine reduces dopamine production and other catecholamines. Carbidopa, on the other hand, inhibits the enzyme dopa decarboxylase,...
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Phase II Reactions: Methylation Reactions01:17

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Methylation is a phase II biotransformation process involving the attachment of a methyl group to a substrate. Enzymes known as methyltransferases orchestrate this reaction.
The mechanism of methylation unfolds in two stages. The first stage sees a methyltransferase enzyme facilitating the transfer of a methyl group from S-adenosylmethionine (SAM) to the substrate, forming S-adenosylhomocysteine (SAH). The second stage involves further metabolism of SAH into homocysteine, which can be recycled...
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Drug Toxicity: Dose-Dependent Reactions01:24

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Drug toxicities can be stratified into pharmacological, pathological, or genotoxic based on their mechanisms. The incidence and severity of these toxicities generally increase with the drug's concentration in the body and exposure time.Pharmacological toxicity is evident when the therapeutic effects of drugs overshoot into adverse reactions in a predictable, dose-dependent manner. Central nervous system (CNS) depression from barbiturates is a classic example, with effects escalating from...
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Adrenergic Neurons: Neurotransmission01:27

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Postganglionic sympathetic fibers (except those supplying the sweat glands) releasing noradrenaline or norepinephrine are called noradrenergic or adrenergic neurons. Noradrenaline, dopamine, adrenaline, or epinephrine are collectively called "catecholamines" as they contain a catechol moiety and an amine side chain. The five stages of neurotransmitter release involve their synthesis, storage, release, reuptake and metabolism.
Synthesis: Catecholamine synthesis requires tyrosine, which...
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Adrenergic Agonists: Indirect-Acting Agents01:25

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Indirect-acting adrenergic agonists potentiate the effects of endogenous catecholamines through different mechanisms without directly binding to adrenoceptors.
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Drugs Affecting Neurotransmitter Release or Uptake01:21

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Certain drugs can affect how neurotransmitters called catecholamines, are released or taken back up in the adrenergic neuron. They can have different effects on the body's sympathetic transmission. Reserpine, a natural compound found in the Rauwolfia shrub, blocks a transporter called vesicular monoamine transporter (VMAT), which leads to a buildup of catecholamines in the cell and reduces sympathetic transmission. Another drug called guanethidine works in multiple ways, including blocking...
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Catechol-o-methyltransferase and 3,4-({+/-})-methylenedioxymethamphetamine toxicity.

Joseph M Herndon1, Aram B Cholanians, Lucina E Lizarraga

  • 1Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85721.

Toxicological Sciences : an Official Journal of the Society of Toxicology
|March 5, 2014
PubMed
Summary

Catechol-O-methyltransferase (COMT) enzyme activity is crucial for limiting 3,4-(±)-methylenedioxymethamphetamine (MDMA) neurotoxicity. Inhibiting or lacking COMT potentiates MDMA

Keywords:
3,4-(±)-methylenedioxymethamphetaminecatechol-O-methyltransferasehyperthermia

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Biochemistry

Background:

  • 3,4-(±)-methylenedioxymethamphetamine (MDMA) metabolism is essential for its neurotoxic effects.
  • Hepatic enzyme activity, particularly catechol-O-methyltransferase (COMT), influences MDMA's neurotoxic profile.
  • COMT regulates the conversion of MDMA metabolites into potentially toxic compounds.

Purpose of the Study:

  • To investigate the role of COMT in modulating MDMA-induced toxicity.
  • To determine how altering COMT activity affects MDMA's impact on neurotransmitter levels and body temperature.

Main Methods:

  • Pharmacological inhibition of COMT in rats.
  • Utilizing a genetic mouse model deficient in functional COMT.
  • Assessing MDMA-induced changes in serotonin and dopamine concentrations.
  • Monitoring acute hyperthermic responses to MDMA.

Main Results:

  • COMT inhibition in rats potentiated MDMA-induced serotonin deficits and hyperthermia.
  • COMT-deficient mice showed greater dopamine depletion compared to wild-type mice.
  • COMT-deficient mice exhibited increased susceptibility to MDMA-induced hyperthermia, leading to mortality.
  • Neither WT nor COMT-deficient mice showed MDMA-induced serotonin depletion.

Conclusions:

  • COMT plays a pivotal role in determining the neurotoxic response to MDMA.
  • Modulating COMT activity significantly impacts MDMA's effects on neurotransmitter systems and thermoregulation.
  • COMT's function is critical in mitigating the acute and potentially fatal toxicity of MDMA.