Endocannabinoid signaling mediates psychomotor activation by adenosine A2A 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 CB(1) 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. We find that 2-AG is selectively increased in striatum after acute blockade of A(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 CB(1) receptor signaling, thus leading to increased psychomotor activation.
Gladstone Institute of Neurological Disease, University of California, San Francisco, San Francisco, California 94158, USA.
Talia N
TN
Lerner
Eric A
EA
Horne
Nephi
N
Stella
Anatol C
AC
Kreitzer
D058917:Adenosine A2 Receptor Antagonists; D000344:Afferent Pathways / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D063388:Endocannabinoids; D018698:Glutamic Acid / Q000378:metabolism; D005989:Glycerides / Q000378:metabolism; D036881:Long-Term Synaptic Depression; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects*; D009474:Neurons / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction
D058917:Adenosine A2 Receptor Antagonists; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D000697:Central Nervous System Stimulants; D063388:Endocannabinoids; D005989:Glycerides; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D011743:Pyrimidines; D043884:Receptor, Cannabinoid, CB1; C103505:AM 251; D018698:Glutamic Acid; C094503:glyceryl 2-arachidonate; C078814:anandamide; C416650:SCH 442416