The effects of the cannabinoid receptor agonist WIN 55,212-2 (0.1–5 mg/kg i.p.) on endogenous extracellular γ-aminobutyric acid (GABA) levels in the cerebral cortex of the awake rat was investigated by using microdialysis. WIN 55,212-2 (1 and 5 mg/kg i.p.) was associated with a concentration-dependent decrease in dialysate GABA levels (–16% ± 4% and –26% ± 4% of basal values, respectively). The WIN 55,212-2 (5 mg/kg i.p.) induced-inhibition was counteracted by a dose (0.1 mg/kg i.p.) of the CB1 receptor antagonist SR141716A, which by itself was without effect on cortical GABA levels. These findings suggest that cannabinoids decrease cortical GABA levels in vivo, an action that might underlie some of the cognitive and behavioral effects of acute exposure to marijuana. J. Neurosci. Res. 66:298–302, 2001. © 2001 Wiley-Liss, Inc.