Presynaptic adenosine A2A receptors dampen cannabinoid CB1 receptor‐mediated inhibition of corticostriatal glutamatergic transmission

• Published in: British journal of pharmacology Vol. 172; no. 4; pp. 1074 - 1086
• Main Authors: Ferreira, S G, Gonçalves, F Q, Marques, J M, Tomé, Â R, Rodrigues, R J, Nunes‐Correia, I, Ledent, C, Harkany, T, Venance, L, Cunha, R A, Köfalvi, A
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.02.2015; Wiley; BlackWell Publishing Ltd
• Subjects: Adenosine; Adenosine Triphosphate - metabolism; Animals; Brain - metabolism; Brain - physiology; Glutamic Acid - metabolism; Life Sciences; Male; Medicin och hälsovetenskap; Mice, Knockout; Rats, Wistar; Receptor, Adenosine A2A - metabolism; Receptor, Cannabinoid, CB1 - metabolism; Receptors, Presynaptic - metabolism; Research Papers; Synapses - metabolism; Synaptic Transmission; Adenosine Triphosphate, Animals, Brain, Glutamic Acid, Male, Mice, Knockout, Rats, Wistar, Receptor, Adenosine A2A, Receptor, Cannabinoid, CB1, Receptors, Presynaptic, Synapses, Synaptic Transmission
• ISSN: 0007-1188; 1476-5381; 1476-5381
• DOI: 10.1111/bph.12970

Background and Purpose Both cannabinoid CB1 and adenosine A2A receptors (CB1 receptors and A2A receptors) control synaptic transmission at corticostriatal synapses, with great therapeutic importance for neurological and psychiatric disorders. A postsynaptic CB1−A2A receptor interaction has already been elucidated, but the presynaptic A2A receptor‐mediated control of presynaptic neuromodulation by CB1 receptors remains to be defined. Because the corticostriatal terminals provide the major input to the basal ganglia, understanding the interactive nature of converging neuromodulation on them will provide us with novel powerful tools to understand the physiology of corticostriatal synaptic transmission and interpret changes associated with pathological conditions. Experimental Approach Pharmacological manipulation of CB1 and A2A receptors was carried out in brain nerve terminals isolated from rats and mice, using flow synaptometry, immunoprecipitation, radioligand binding, ATP and glutamate release measurement. Whole‐cell patch‐clamp recordings were made in horizontal corticostriatal slices. Key Results Flow synaptometry showed that A2A receptors were extensively co‐localized with CB1 receptor‐immunopositive corticostriatal terminals and A2A receptors co‐immunoprecipitated CB1 receptors in these purified terminals. A2A receptor activation decreased CB1 receptor radioligand binding and decreased the CB1 receptor‐mediated inhibition of high‐K+‐evoked glutamate release in corticostriatal terminals. Accordingly, A2A receptor activation prevented CB1 receptor‐mediated paired‐pulse facilitation and attenuated the CB1 receptor‐mediated inhibition of synaptic transmission in glutamatergic synapses of corticostriatal slices. Conclusions and Implications Activation of presynaptic A2A receptors dampened CB1 receptor‐mediated inhibition of corticostriatal terminals. This constitutes a thus far unrecognized mechanism to modulate the potent CB1 receptor‐mediated presynaptic inhibition, allowing frequency‐dependent enhancement of synaptic efficacy at corticostriatal synapses.