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The effects of the cannabinoid receptor agonist WIN 55,212-2 on endogenous extracellular glutamate levels in the prefrontal cortex of the awake rat and in primary cultures of rat cerebral cortex neurons were investigated. In the prefrontal cortex WIN 55,212-2 (0.1 and 1 mg/kg i.p.) increased dialysate glutamate levels from of the awake rat, while the lower (0.01 mg/kg) and the higher (2 mg/kg) doses were ineffective. Furthermore, the WIN 55,212-2 (0.1 mg/kg)- induced increase of dialysate glutamate levels was counteracted by pretreatment with the selective CB 1  receptor antagonist SR141716A (0.1 mg/kg i.p.) and by the local perfusion with a low-calcium Ringer solution (Ca 2+  0.2 mM). In primary cultures of rat cerebral cortex neurons, WIN 55,212-2 (0.01–100 nM) increased extracellular glutamate levels, displaying a bell-shaped concentration–response curve. The facilitatory effect of WIN 55,212-2 (1 nM) was fully counteracted by SR141716A (10 nM), by the replacement of the normal Krebs Ringer-bicarbonate buffer with a low Ca 2+  medium (0.2 mM) and by the IP 3  receptor antagonist xestospongin C (1 μM). These  in vivo  and  in vitro  findings suggest an increase in cortical glutamatergic transmission by CB 1  receptors, an effect that may underlie some of the psychoactive and behavioural actions of acute exposure to marijuana.

The Cannabinoid Receptor Agonist WIN 55,212-2 Regulates Glutamate Transmission in Rat Cerebral Cortex: an In Vivo and In Vitro Study