ACTIVATION OF GLYCOGEN-PHOSPHORYLASE BY SEROTONIN AND 3,4-METHYLENEDIOXYMETHAMPHETAMINE IN ASTROGLIAL-RICH PRIMARY CULTURES - INVOLVEMENT OF THE 5-HT2A RECEPTOR

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.