BACKGROUND AND PURPOSE:

Both CB1 cannabinoid and A2A adenosine receptors (CB1 Rs and A2A Rs) control synaptic transmission at corticostriatal synapses, with great therapeutic importance for neurological and psychiatric disorders. A post-synaptic CB1 R-A2A R interaction has already been unraveled, but the presynaptic A2A R-mediated control of presynaptic neuromodulation by CB1 Rs remains to be defined. Since the corticostriatal terminals provide the major input of 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:

Here we employ selective presynaptic tools to study the putative presynaptic interaction between the two neuromodulator systems. Pharmacological manipulation of CB1 R and A2A R was carried out in isolated nerve terminals used for flow synaptometry, immunoprecipitation, radioligand binding, ATP and glutamate release measurement, as well as in whole-cell patch-clamp recordings in horizontal corticostriatal slices.

RESULTS:

Flow synaptometry showed that A2A R are extensively co-localized with CB1 R-immunopositive corticostriatal terminals, and A2AR co-immunoprecipitated CB1 R in these purified terminals. A2A R activation decreased CB1 R radioligand binding and decreased the CB1R-mediated inhibition of high-K+ -evoked glutamate release in corticostriatal terminals. Accordingly, A2A R activation prevented CB1 R-mediated paired-pulse facilitation and attenuated the CB1 R-mediated inhibition of synaptic transmission in glutamatergic synapses of corticostriatal slices.

CONCLUSIONS AND IMPLICATIONS:

These results show that presynaptic A2A R dampens CB1 R-mediated inhibition of corticostriatal terminals. This constitutes a thus far unrecognized mechanism to shut-down the potent CB1 R-mediated presynaptic inhibition, enabling a frequency-dependent enhancement of synaptic efficacy at corticostriatal synapses.
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