TY - JOUR
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.
N1 - Funding Information:
The authors would like to acknowledge the help of Dr. Monroe Yoder, H. Kenneth Kramer, Efthimia Kokotos Leonardi, Nancy Kheck, Pamela Hou and Christine M. Poblete in the preparation of this work. Help in establishing astroglial cultures was provided by Dr. Patricia Whitaker-Azmitia. This work was supported by the National Institute on Drug Abuse (NIDA; Contract No. 271-90-7403 to Efrain C. Azmitia, Ph.D.)
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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UR - http://www.scopus.com/inward/citedby.url?scp=0029059315&partnerID=8YFLogxK
U2 - 10.1016/0006-8993(95)00201-Z
DO - 10.1016/0006-8993(95)00201-Z
M3 - Article
C2 - 7663989
AN - SCOPUS:0029059315
SN - 0006-8993
VL - 680
SP - 9
EP - 15
JO - Brain Research
JF - Brain Research
IS - 1-2
ER -