Endocannabinoid signaling mediates psychomotor activation by adenosine A_2A antagonists

Adenosine A_2A 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 A_2A 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 ofA_2A 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 A_2A antagonists reduce excitatory synaptic drive on the indirect pathway through CB₁ receptor signaling, thus leading to increased psychomotor activation.