Pre-synaptic adenosine A2A receptors control cannabinoid CB1 receptor-mediated inhibition of striatal glutamatergic neurotransmission

P>An interaction between adenosine A(2A) receptors (A(2A)Rs) and cannabinoid CB1 receptors (CB(1)Rs) has been consistently reported to occur in the striatum, although the precise mechanisms are not completely understood. As both receptors control striatal glutamatergic transmission, we now probed the putative interaction between pre-synaptic CB1R and A(2A)R in the striatum. In extracellular field potentials recordings in corticostriatal slices from Wistar rats, A(2A)R activation by CGS21680 inhibited CB1R-mediated effects (depression of synaptic response and increase in paired-pulse facilitation). Moreover, in superfused rat striatal nerve terminals, A(2A)R activation prevented, while A(2A)R inhibition facilitated, the CB1R-mediated inhibition of 4-aminopyridine-evoked glutamate release. In summary, the present study provides converging neurochemical and electrophysiological support for the occurrence of a tight control of CB1R function by A(2A)Rs in glutamatergic terminals of the striatum. In view of the key role of glutamate to trigger the recruitment of striatal circuits, this pre-synaptic interaction between CB1R and A(2A)R may be of relevance for the pathogenesis and the treatment of neuropsychiatric disorders affecting the basal ganglia.