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Presynaptic adenosine A 2A receptors dampen cannabinoid CB 1 receptor‐mediated inhibition of corticostriatal glutamatergic transmission
Author(s) -
Ferreira S G,
Gonçalves F Q,
Marques J M,
Tomé Â R,
Rodrigues R J,
NunesCorreia I,
Ledent C,
Harkany T,
Venance L,
Cunha R A,
Köfalvi A
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12970
Subject(s) - glutamatergic , neuroscience , receptor , cannabinoid , neurotransmission , cannabinoid receptor , chemistry , adenosine , 2 arachidonoylglycerol , biology , microbiology and biotechnology , biochemistry , glutamate receptor , agonist
Background and Purpose Both cannabinoid CB 1 and adenosine A 2A receptors ( CB 1 receptors and A 2A receptors) control synaptic transmission at corticostriatal synapses, with great therapeutic importance for neurological and psychiatric disorders. A postsynaptic CB 1 − A 2A receptor interaction has already been elucidated, but the presynaptic A 2A receptor‐mediated control of presynaptic neuromodulation by CB 1 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 CB 1 and A 2A 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 A 2A receptors were extensively co‐localized with CB 1 receptor‐immunopositive corticostriatal terminals and A 2A receptors co‐immunoprecipitated CB 1 receptors in these purified terminals. A 2A receptor activation decreased CB 1 receptor radioligand binding and decreased the CB 1 receptor‐mediated inhibition of high‐ K + ‐evoked glutamate release in corticostriatal terminals. Accordingly, A 2A receptor activation prevented CB 1 receptor‐mediated paired‐pulse facilitation and attenuated the CB 1 receptor‐mediated inhibition of synaptic transmission in glutamatergic synapses of corticostriatal slices. Conclusions and Implications Activation of presynaptic A 2A receptors dampened CB 1 receptor‐mediated inhibition of corticostriatal terminals. This constitutes a thus far unrecognized mechanism to modulate the potent CB 1 receptor‐mediated presynaptic inhibition, allowing frequency‐dependent enhancement of synaptic efficacy at corticostriatal synapses.