Co-application of the GABAB receptor agonist, baclofen, and of the mGlu receptor agonist, L-CCG-I, facilitate [3H]GABA release from rat cortical nerve endings.

Interaction between different transmitter receptor\r\nsystems is an emerging feature of neurotransmission at\r\ncentral synapses. G protein-coupled receptors’ ability to\r\nform dimers or larger hetero-oligomers probably serves to\r\nfacilitate the integration of diverse signals within the cell.\r\nWe found that, in nerve terminals isolated from the cerebral\r\ncortices of rats, co-application of the GABAB agonist,\r\nbaclofen, and of the non-selective mGlu agonist, L-CCG-I,\r\npotentiates the basal and depolarization-evoked release of\r\n[3H]GABA via a mechanism that involves mobilization of\r\nintracellular Ca2? ions. The effect of L-CCG-I ? baclofen\r\nwas abolished by the phospholipase C inhibitor U73122,\r\nreduced by Xestospongin C (an IP3 receptor blocker), and\r\nblocked by 2-APB, an IP3 receptor antagonist. Pretreatment\r\nof the synaptosomes with the lipid-soluble Ca2? chelator\r\nBAPTA-AM also inhibited the effects of L-CCGI\r\n? baclofen. Subtype-selective non-competitive group I\r\nmGlu receptor antagonists, MPEP and CPCCOEt, had no\r\neffect on the release enhancement produced by baclofen\r\n? L-CCG-I. The enhancement was reversed by the\r\nGABAB receptor antagonist, CGP54626, and by the group\r\nI/group II mGlu receptor antagonist (R,S)-MCPG. The\r\nGABA release-enhancing effects of L-CCG-I ? baclofen\r\nin our model might reflect the presence on cortical nerve\r\nendings of GABAB/group I mGlu receptor heteromers with\r\npharmacological properties distinct from those of the\r\ncomponent receptors. Activation of these heteromeric\r\nreceptors might modify the function of the GABAB\r\nreceptor in such a way that it facilitates GABAergic\r\ntransmission, an effect that might be useful under conditions\r\nof excessive glutamatergic activity.