The effects of the principal psychoactive component of marijuana, Delta(9)-tetrahydrocannabinol (2-THC), on endogenous extracellular glutamate levels in primary cultures of rat cerebral cortex neurons were investigated. Locally applied Delta(9)-THC (0.03, 3, 300, and 1,000 nM) concentration-dependently increased basal extracellular glutamate levels (+18% +/- 11%, +54% +/- 10%, +90% +/- 14%, +149% +/- 33% vs. basal). The facilitatory effects of Delta(9)-THC (3 and 300 nM) on cortical glutamate were fully counteracted in the presence of the selective CB, receptor antagonist SR141716A (10 nM) and by replacement of the normal Krebs-Ringer bicarbonate buffer with a low-Ca2+ (0.2 mM) medium. Delta(9)-THC application also induced an enhancement in K+-evoked glutamate levels. These findings suggest that an increase in cortical glutamatergic transmission mediated by local CB, receptor activation may underlie some of the psychoactive and behavioral effects of acute marijuana consumption. (C) 2002 Wiley-Liss, Inc.