ACTIVATION OF GLYCOGEN-PHOSPHORYLASE BY SEROTONIN AND 3,4-METHYLENEDIOXYMETHAMPHETAMINE IN ASTROGLIAL-RICH PRIMARY CULTURES - INVOLVEMENT OF THE 5-HT2A RECEPTOR
Jc. Poblete et Ec. Azmitia, ACTIVATION OF GLYCOGEN-PHOSPHORYLASE BY SEROTONIN AND 3,4-METHYLENEDIOXYMETHAMPHETAMINE IN ASTROGLIAL-RICH PRIMARY CULTURES - INVOLVEMENT OF THE 5-HT2A RECEPTOR, Brain research, 680(1-2), 1995, pp. 9-15
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 fibr
illary acidic protein (GFAP), an astroglia-specific marker, suggesting
that glycogen is localized in astroglial cells. Additionally, functio
nal 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-me
thylene-dioxymethamphetamine (MDMA), a drug of abuse, stimulates the r
elease and inhibits the reuptake of 5-HT, and selectively inhibits the
activity of (MDMA. These biochemical consequences of MDMA lead to inc
reased extra-cellular 5-HT levels. This study investigates the effects
of MDMA(+) and serotonin (5-HT) on glycogen metabolism in the rat bra
in. A histochemical method was designed to visualize active glycogen p
hosphorylase (GPase) in an astroglial-rich primary culture. Serotonin
activated GPase in a concentration-dependent manner (100 nM-100 mu M).
Maximal activation by 5-HT was achieved by 50 mu M and resulted in a
167% increase in the number of reactive sites (P < 0.001). MDMA(+) (50
0 nM-50 mu M) directly stimulated GPase activity with maximal activati
on induced by 5 mu M, which caused a 70% increase in the number of rea
ctive sites (P < 0.001). The 5-HT2 receptor agonist, 1-(2,5-dimethoxy-
4-bromophenyl)-2-aminopropane (DOB), also displayed a concentration-de
pendent increase in the number of GPase reactive sites. Maximal stimul
ation by DOE occurred at 100 nM which increased the number of reactive
sites by 166% (P < 0.001). These effects of 5-HT and MDMA(+) were sig
nificantly attenuated by mianserin (200 nM), a 5-HT2 receptor antagoni
st. An astrocyte-neuron metabolic link may be vital for synaptic homeo
stasis. 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. T
he resulting deficiency in synaptic energy may contribute to terminal
degeneration induced by substituted amphetamines.