The cannabinoid receptor agonist WIN 55,212-2 regulates glutamate transmission in rat cerebral cortex: an in vivo and in vitro study

The effects of the cannahinoid receptor agonist WIN 55,212-2 on endogenous extracellular glutamate levels in the prefrontal cortex of the awake rat an d 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 dialysa te 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 CB1 receptor antagonist SR141716A (0.1 mg/kg i.p.) and by the local perfusion with a low-calcium Ringer solution ( Ca2+ 0.2 mM), In primary cultures of rat cerebral cortex neurons, WIN 55,21 2-2 (0.01-100 nM) increased extracellular glutamate levels, displaying a be ll-shaped concentration-response curve. The facilitatory effect of WIN 55,2 12-2 (1 nM) was fully counteracted by SR141716A (10 nM), by the replacement of the normal Krebs Ringer-bicarbonate buffer with a low Ca2+ medium (0.2 mM) and by the IP3 receptor antagonist xestospongin C (1 muM). These in viv o and in vitro findings suggest an increase in cortical glutamatergic trans mission by CB1 receptors, an effect that may underlie some of the psychoact ive and behavioural actions of acute exposure to marijuana.