Effects of exogenous and endogenous cannabinoids on GABAergic neurotransmission between the caudate-putamen and the globus pallidus in the mouse

Globus pallidus neurons receive GABAergic input from the caudate-putamen via the striatopallidal pathway. Anatomical studies indicate that many CB 1 cannabinoid receptors are localized on terminals of striatopallidal axons. Accordingly, the hypothesis of the present work was that activation of CB 1 receptors presynaptically inhibits neurotransmission between striatopallidal axons and globus pallidus neurons. In sagittal mouse brain slices, striatopallidal axons were electrically stimulated in the caudate-putamen, and the resulting GABAergic inhibitory postsynaptic currents (IPSCs) were recorded in globus pallidus neurons. The synthetic cannabinoid receptor agonists R(+)-[2,3-dihydro-5-methyl-3[(morpholinyl) methyl] pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanonemesylate (WIN55212-2) and (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol(CP55940) decreased the amplitude of IPSCs. The CB 1 receptor antagonist rimonabant prevented the inhibition by WIN55212-2, pointing to involvement of CB 1 receptors. Depolarization of globus pallidus neurons induced a weak and short-lasting suppression of IPSCs [i.e., depolarization-induced suppression of inhibition (DSI) occurred]. Prevention of DSI by rimonabant indicates that endocannabinoids released from the postsynaptic neurons acted on CB 1 receptors to suppress synaptic transmission. WIN55212-2 did not modify currents in globus pallidus neurons elicited by GABA released from its chemically bound ("caged") form by a flash pulse, suggesting that WIN55212-2 depressed neurotransmission presynaptically. For studying the mechanism of the inhibition of GABA release, terminals of striatopallidal axons were labeled with a calcium-sensitive fluorescent dye. WIN55212-2 depressed the action potential-evoked increase in axon terminal calcium concentration. The results show that activation of CB 1 receptors by exogenous and endogenous cannabinoids leads to presynaptic inhibition of neurotransmission between striatopallidal axons and globus pallidus neurons. Depression of the action potential-evoked calcium influx into axon terminals is the probable mechanism of this inhibition.