Presynaptic mechanisms underlying cannabinoid inhibition of excitatory synaptic transmission in rat striatal neurons

1. The striatum is a crucial site of action for the motor effects of cannab inoids (CBs). However, the electrophysiological consequences of activation of CB receptors on the striatal neurons have not been established. Here we report fur the first time that the cannabimimetic aminoalkylindole WIN 55,2 12-2 and the endogenous cannabinoid anandamide substantially depress cortic ostriatal glutamatergic synaptic transmission onto striatal neurons in the brain slice preparation. The selective CB1 receptor antagonist SR 141716 ef fectively reversed this inhibition. 2. WIN 55,212-2 significantly increased the paired-pulse facilitation of sy naptically evoked EPSCs, while having no effect on the sensitivity of posts ynaptic neurons to alpha -amino-3-hydroxy-5-methylisoxazole-4-propionic aci d. WIN 55,212-2 also reduced the frequency of spontaneous, action potential -dependent EPSCs (sEPSCs) without altering their amplitude distribution. 3. Superfusion of WIN 55,212-2 elicited a membrane hyperpolarization accomp anied by a decrease in input resistance. Both effects were blocked by intra cellular caesium. In contrast, intracellular caesium failed to affect WIN 5 5,212-2-mediated synaptic inhibition. 4. The WIN 55,212-2-mediated synaptic inhibition was blocked by the G(i/o) protein inhibitor pertussis toxin (PTX), but not by the GABA(A) receptor an tagonist bicuculline or GABA(B) receptor antagonist SCH 50911. 5. Pretreatment with the N-type Ca2+ channel antagonist omega -conotoxin GV IA selectively abolished the WIN-55,212-2-mediated synaptic inhibition. 6. These results suggest that; cannabinoids depress the corticostriatal glu tamatergic synaptic transmission through the activation of presynaptic CB1 receptors to inhibit N-type Ca2+ channel activity, which in turn reduces gl utamate release. The presynaptic action of cannabinoids is mediated by a PT X-sensitive G(i/o) protein-coupled signalling pathway.