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Vol. 54, Issue 5, 834-843, November 1998
9-Tetrahydrocannabinol-Induced Stimulation of
Glucose Metabolism in Primary Astrocytes
Department of Biochemistry and Molecular Biology I, School of
Biology, Complutense University, 28040-Madrid, Spain
The effects of cannabinoids on metabolic pathways and signal
transduction systems were studied in primary cultures of rat astrocytes. 
9-Tetrahydrocannabinol (THC), the major
active component of marijuana, increased the rate of glucose oxidation
to CO2 as well as the rate of glucose incorporation into
phospholipids and glycogen. These effects of THC were mimicked by the
synthetic cannabinoid HU-210, and prevented by forskolin, pertussis
toxin, and the CB1 receptor antagonist SR 141716. THC did not affect
basal cAMP levels but partially antagonized the forskolin-induced
elevation of intracellular cAMP concentration. THC stimulated p42/p44
mitogen-activated protein kinase (MAPK) activity, Raf-1
phosphorylation, and Raf-1 translocation to the particulate cell
fraction. In addition, the MAPK inhibitor PD 098095 and the
phosphoinositide 3-kinase inhibitors wortmannin and LY 294002 were able
to antagonize the THC-induced stimulation of glucose oxidation to
CO2, phospholipid synthesis and glycogen synthesis. The
possible involvement of sphingomyelin breakdown in the metabolic
effects of THC was studied subsequently. THC produced a rapid
stimulation of sphingomyelin hydrolysis that was concomitant to an
elevation of intracellular ceramide levels. This effect was prevented
by SR 141716. Moreover, the cell-permeable ceramide analog
D-erythro-N-octanoylsphingosine,
as well as exogenous sphingomyelinase, were able in turn to stimulate
MAPK activity, to increase the amount of Raf-1 bound to the particulate
cell fraction, and to stimulate glucose metabolism. The latter effect was prevented by PD 098059 and was not additive to that exerted by THC.
Results thus indicate that THC produces a cannabinoid receptor-mediated
stimulation of astrocyte metabolism that seems to rely on sphingomyelin
hydrolysis and MAPK stimulation.
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