Activation of glycogen phosphorylase by serotonin and 3,4-methylenedioxymethamphetamine in astroglial-rich primary cultures: involvement of the 5-HT2A receptor

Jose Conrado Poblete, Efrain C. Azmitia

Research output: Contribution to journalArticle

Abstract

Neurotransmitters, neuropeptides, and ions regulate glycogen levels in the brain by modulating the activity of glycogen synthase (GSase) and glycogen phosphorylase (GPase). GPase is co-localized with glial fibrillary acidic protein (GFAP), an astroglia-specific marker, suggesting that glycogen is localized in astroglial cells. Additionally, functional serotonin (5-HT) receptors are found in both neurons and glia, and 5-HT is known to stimulate glycogenolysis. It is reported that 3,4-methylenedioxymethamphetamine (MDMA), a drug of abuse, stimulates the release and inhibits the reuptake of 5-HT, and selectively inhibits the activity of MAO-A. These biochemical consequences of MDMA lead to increased extra-cellular 5-HT levels. This study investigates the effects of MDMA(+) and serotonin (5-HT) on glycogen metabolism in the rat brain. A histochemical method was designed to visualize active glycogen phosphorylase (GPase) in an astroglial-rich primary culture. Serotonin activated GPase in a concentration-dependent manner (100 nM-100 μM). Maximal activation by 5-HT was achieved by 50 μM and resulted in a 167% increase in the number of reactive sites (P < 0.001). MDMA(+) (500 nM-50 μM) directly stimulated GPase activity with maximal activation induced by 5 μM, which caused a 70% increase in the number of reactive sites (P < 0.001). The 5-HT2 receptor agonist, 1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB), also displayed a concentration-dependent increase in the number of GPase reactive sites. Maximal stimulation by DOB occurred at 100 nM which increased the number of reactive sites by 166% (P < 0.001). These effects of 5-HT and MDMA(+) were significantly attenuated by mianserin (200 nM), a 5-HT2 receptor antagonist. An astrocyte-neuron metabolic link may be vital for synaptic homeostasis. By increasing 5-HT levels in the synapse, MDMA(+) may increase GPase activity and promote glycogenolysis via activation of the 5-HT2 receptor. Prolonged GPase activity may lead to depletion of synaptic energy stores, thereby compromising the energy state of the synapse. The resulting deficiency in synaptic energy may contribute to terminal degeneration induced by substituted amphetamines.

Original languageEnglish (US)
Pages (from-to)9-15
Number of pages7
JournalBrain Research
Volume680
Issue number1-2
DOIs
StatePublished - May 22 1995

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Glycogen Phosphorylase
N-Methyl-3,4-methylenedioxyamphetamine
Receptor, Serotonin, 5-HT2A
Serotonin
Catalytic Domain
Glycogen
Glycogenolysis
Astrocytes
Synapses
Serotonin 5-HT2 Receptor Agonists
Mianserin
Serotonin 5-HT2 Receptor Antagonists
Neurons
Amphetamines
Glycogen Synthase
Serotonin Receptors
Glial Fibrillary Acidic Protein
Monoamine Oxidase
Brain
Street Drugs

Keywords

  • 3,4-Methylenedioxymethamphetamine
  • Astrocyte
  • Glycogen
  • Glycogen phosphorylase
  • Metabolism
  • Serotonin

ASJC Scopus subject areas

  • Developmental Biology
  • Molecular Biology
  • Clinical Neurology
  • Neuroscience(all)

Cite this

@article{549a815789634f78a6ac4ec2caacc89b,
title = "Activation of glycogen phosphorylase by serotonin and 3,4-methylenedioxymethamphetamine in astroglial-rich primary cultures: involvement of the 5-HT2A receptor",
abstract = "Neurotransmitters, neuropeptides, and ions regulate glycogen levels in the brain by modulating the activity of glycogen synthase (GSase) and glycogen phosphorylase (GPase). GPase is co-localized with glial fibrillary acidic protein (GFAP), an astroglia-specific marker, suggesting that glycogen is localized in astroglial cells. Additionally, functional serotonin (5-HT) receptors are found in both neurons and glia, and 5-HT is known to stimulate glycogenolysis. It is reported that 3,4-methylenedioxymethamphetamine (MDMA), a drug of abuse, stimulates the release and inhibits the reuptake of 5-HT, and selectively inhibits the activity of MAO-A. These biochemical consequences of MDMA lead to increased extra-cellular 5-HT levels. This study investigates the effects of MDMA(+) and serotonin (5-HT) on glycogen metabolism in the rat brain. A histochemical method was designed to visualize active glycogen phosphorylase (GPase) in an astroglial-rich primary culture. Serotonin activated GPase in a concentration-dependent manner (100 nM-100 μM). Maximal activation by 5-HT was achieved by 50 μM and resulted in a 167{\%} increase in the number of reactive sites (P < 0.001). MDMA(+) (500 nM-50 μM) directly stimulated GPase activity with maximal activation induced by 5 μM, which caused a 70{\%} increase in the number of reactive sites (P < 0.001). The 5-HT2 receptor agonist, 1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB), also displayed a concentration-dependent increase in the number of GPase reactive sites. Maximal stimulation by DOB occurred at 100 nM which increased the number of reactive sites by 166{\%} (P < 0.001). These effects of 5-HT and MDMA(+) were significantly attenuated by mianserin (200 nM), a 5-HT2 receptor antagonist. An astrocyte-neuron metabolic link may be vital for synaptic homeostasis. By increasing 5-HT levels in the synapse, MDMA(+) may increase GPase activity and promote glycogenolysis via activation of the 5-HT2 receptor. Prolonged GPase activity may lead to depletion of synaptic energy stores, thereby compromising the energy state of the synapse. The resulting deficiency in synaptic energy may contribute to terminal degeneration induced by substituted amphetamines.",
keywords = "3,4-Methylenedioxymethamphetamine, Astrocyte, Glycogen, Glycogen phosphorylase, Metabolism, Serotonin",
author = "Poblete, {Jose Conrado} and Azmitia, {Efrain C.}",
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T1 - Activation of glycogen phosphorylase by serotonin and 3,4-methylenedioxymethamphetamine in astroglial-rich primary cultures

T2 - involvement of the 5-HT2A receptor

AU - Poblete, Jose Conrado

AU - Azmitia, Efrain C.

PY - 1995/5/22

Y1 - 1995/5/22

N2 - Neurotransmitters, neuropeptides, and ions regulate glycogen levels in the brain by modulating the activity of glycogen synthase (GSase) and glycogen phosphorylase (GPase). GPase is co-localized with glial fibrillary acidic protein (GFAP), an astroglia-specific marker, suggesting that glycogen is localized in astroglial cells. Additionally, functional serotonin (5-HT) receptors are found in both neurons and glia, and 5-HT is known to stimulate glycogenolysis. It is reported that 3,4-methylenedioxymethamphetamine (MDMA), a drug of abuse, stimulates the release and inhibits the reuptake of 5-HT, and selectively inhibits the activity of MAO-A. These biochemical consequences of MDMA lead to increased extra-cellular 5-HT levels. This study investigates the effects of MDMA(+) and serotonin (5-HT) on glycogen metabolism in the rat brain. A histochemical method was designed to visualize active glycogen phosphorylase (GPase) in an astroglial-rich primary culture. Serotonin activated GPase in a concentration-dependent manner (100 nM-100 μM). Maximal activation by 5-HT was achieved by 50 μM and resulted in a 167% increase in the number of reactive sites (P < 0.001). MDMA(+) (500 nM-50 μM) directly stimulated GPase activity with maximal activation induced by 5 μM, which caused a 70% increase in the number of reactive sites (P < 0.001). The 5-HT2 receptor agonist, 1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB), also displayed a concentration-dependent increase in the number of GPase reactive sites. Maximal stimulation by DOB occurred at 100 nM which increased the number of reactive sites by 166% (P < 0.001). These effects of 5-HT and MDMA(+) were significantly attenuated by mianserin (200 nM), a 5-HT2 receptor antagonist. An astrocyte-neuron metabolic link may be vital for synaptic homeostasis. By increasing 5-HT levels in the synapse, MDMA(+) may increase GPase activity and promote glycogenolysis via activation of the 5-HT2 receptor. Prolonged GPase activity may lead to depletion of synaptic energy stores, thereby compromising the energy state of the synapse. The resulting deficiency in synaptic energy may contribute to terminal degeneration induced by substituted amphetamines.

AB - Neurotransmitters, neuropeptides, and ions regulate glycogen levels in the brain by modulating the activity of glycogen synthase (GSase) and glycogen phosphorylase (GPase). GPase is co-localized with glial fibrillary acidic protein (GFAP), an astroglia-specific marker, suggesting that glycogen is localized in astroglial cells. Additionally, functional serotonin (5-HT) receptors are found in both neurons and glia, and 5-HT is known to stimulate glycogenolysis. It is reported that 3,4-methylenedioxymethamphetamine (MDMA), a drug of abuse, stimulates the release and inhibits the reuptake of 5-HT, and selectively inhibits the activity of MAO-A. These biochemical consequences of MDMA lead to increased extra-cellular 5-HT levels. This study investigates the effects of MDMA(+) and serotonin (5-HT) on glycogen metabolism in the rat brain. A histochemical method was designed to visualize active glycogen phosphorylase (GPase) in an astroglial-rich primary culture. Serotonin activated GPase in a concentration-dependent manner (100 nM-100 μM). Maximal activation by 5-HT was achieved by 50 μM and resulted in a 167% increase in the number of reactive sites (P < 0.001). MDMA(+) (500 nM-50 μM) directly stimulated GPase activity with maximal activation induced by 5 μM, which caused a 70% increase in the number of reactive sites (P < 0.001). The 5-HT2 receptor agonist, 1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB), also displayed a concentration-dependent increase in the number of GPase reactive sites. Maximal stimulation by DOB occurred at 100 nM which increased the number of reactive sites by 166% (P < 0.001). These effects of 5-HT and MDMA(+) were significantly attenuated by mianserin (200 nM), a 5-HT2 receptor antagonist. An astrocyte-neuron metabolic link may be vital for synaptic homeostasis. By increasing 5-HT levels in the synapse, MDMA(+) may increase GPase activity and promote glycogenolysis via activation of the 5-HT2 receptor. Prolonged GPase activity may lead to depletion of synaptic energy stores, thereby compromising the energy state of the synapse. The resulting deficiency in synaptic energy may contribute to terminal degeneration induced by substituted amphetamines.

KW - 3,4-Methylenedioxymethamphetamine

KW - Astrocyte

KW - Glycogen

KW - Glycogen phosphorylase

KW - Metabolism

KW - Serotonin

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