Adenosine A2A receptor antagonists are psychomotor stimulants that also hold therapeutic promise for movement disorders. However, the molecular mechanisms underlying their stimulant properties are not well understood. Here, we show that the robust increase in locomotor activity induced by an A2A antagonist in vivo is greatly attenuated by antagonizing cannabinoid CB1 receptor signaling or by administration to CB 1-/- mice. To determine the locus of increased endocannabinoid signaling, we measured the amount of anandamide [AEA (N-arachidonoylethanolamine)] and 2-arachidonoylglycerol (2-AG) in brain tissue from striatum and cortex.Wefind that 2-AG is selectively increased in striatum after acute blockade ofA2A receptors, which are highly expressed by striatal indirect-pathway medium spiny neurons (MSNs). Using targeted whole-cell recordings from direct- and indirect-pathway MSNs, we demonstrate that A 2A receptor antagonists potentiate 2-AG release and induction of long-term depression at indirect-pathway MSNs, but not direct-pathway MSNs. Together, these data outline a molecular mechanism by which A2A antagonists reduce excitatory synaptic drive on the indirect pathway through CB1 receptor signaling, thus leading to increased psychomotor activation.
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