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

Chiung-Chun Huang, Shiow-Win Lo and Kuei-Sen Hsu

1. The striatum is a crucial site of action for the motor effects of cannabinoids (CBs). However, the electrophysiological consequences of activation of CB receptors on the striatal neurons have not been established. Here we report for the first time that the cannabimimetic aminoalkylindole WIN 55,212-2 and the endogenous cannabinoid anandamide substantially depress corticostriatal glutamatergic synaptic transmission onto striatal neurons in the brain slice preparation. The selective CB₁ receptor antagonist SR 141716 effectively reversed this inhibition.
2. WIN 55,212-2 significantly increased the paired-pulse facilitation of synaptically evoked EPSCs, while having no effect on the sensitivity of postsynaptic neurons to -amino-3-hydroxy-5-methylisoxazole-4-propionic acid. 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 accompanied by a decrease in input resistance. Both effects were blocked by intracellular caesium. In contrast, intracellular caesium failed to affect WIN 55,212-2-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 antagonist bicuculline or GABA_B receptor antagonist SCH 50911.
5. Pretreatment with the N-type Ca²⁺ channel antagonist -conotoxin GVIA selectively abolished the WIN-55,212-2-mediated synaptic inhibition.
6. These results suggest that cannabinoids depress the corticostriatal glutamatergic synaptic transmission through the activation of presynaptic CB₁ receptors to inhibit N-type Ca²⁺ channel activity, which in turn reduces glutamate release. The presynaptic action of cannabinoids is mediated by a PTX-sensitive G_i/o protein-coupled signalling pathway.

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