Neuroscience Vol. 47, No. 2, pp. 333-339,1992 Printed in Great Britain 0306-4522/92 $5.00 + 0.00 Pergamon Press plc 0 1992 IBRO L-GLUTAMATE-EVOKED RELEASE OF DOPAMINE FROM SYNAPTOSOMES OF THE RAT STRIATUM: INVOLVEMENT OF AMPA AND N-METHYL-D-ASPARTATE RECEPTORS J. M. DESCE, G. GODF,HBU, T. GALLI, F. ARTAUD, A. CH~RAMY and J. GLOVVINSKI College de France--INSERM U 114, 11 place Mar&in Eerthelot, 75231 Paris Cedex 05, France A&r&-Previously, using purified synaptosomes from the rat striatum, we have shown that agonists of D,L-a-amino-3-hydroxy-5-methyl-4-isoxa~ole propionate (AMPA) receptors stimulate the release of (3H]dopamine continuously synthesized from [‘Hltyrosine. Similar results were obtained with N-methyl-n- aspartate in the absence of magnesium. In the present study, using the same approach, attempts were made to determine whether in the presence of magnesium, the combined stimulation of AMPA receptors allows us to demonstrate the presynaptic facilitation of [‘Hldopamine release through N-methyl-D-aspartate receptors. L-Glutamate (IO-’ M) markedly stimulated the release of [3H]dopamine from synaptosomes, this effect being about twice that found with AMPA (IO-’ M) while N-methyl-D-aspartate (lo-’ M) even in the presence of glycine (10e6 M) was ineffective. In agreement with previous results, a stimulatory effect of N-methyl-D-aspartate and glycine was only observed in the absence of magnesium. This response was blocked by 6,7_dinitro-quinoxaline-2,3-dione (3 x 10e5 M), confirming that this compound, generally used as an AMPA antagonist, also blocks N-methyl-o-aspartate receptors. The AMPA (lo-‘M)-evoked release of [3H]dopamine was markedly potentiated by the combined application of N-methyl-o-aspartate (lo-’ M) and glycine (low6 M) in the presence of strychnine, indicating that the concomitant activation of AMPA receptors removes the voltage-dependent magnesium block of N-methyl-D-aspartate receptors. The L-glutamate (lo-‘M)-evoked release of [‘Hldopamine was potentiated by glycine (10W6M), only partially reduced by ( + )-5-methyl-l0,ll-dihydro-5H-dibenzo(n,d)cyclohepten-5,10-imine maleate (MK801) (lo-’ M) and almost completely abolished by 6,7-dinitro-quinoxaline-2,3-dione (3 x 10e5 M). In addition, the L-glutamate (lo-) M)-evoked release of [‘Hldopamine was of similar amplitude in either the presence or absence of magnesium. Altogether, these results demonstrate that L-glutamate, in high concentration, facilitates the release of [‘Hldopamine from rat striatal synaptosomes by acting both on AMPA and N-methyl-n-aspartate receptors, even in the presence of magnesium. The first demonstration of a stimulatory effect of L-glutamate on the release of dopamine (DA) was made on rat striatal slices by Giorguieff et ~1.‘~and Roberts and Sharif.33 These authors also indicated that the glutamate-evoked release of DA still occurs in the presence of tetrodotoxin (TTX), a neurotoxin which prevents most if not all indirect effects. A TI’X-resistant stimulation of DA release by gluta- mate has also been described in viva in the caudate nucleus of halothane-anesthetized cats implanted with push-pull cannulae. ‘g6Together, these results suggest that glutamate presynaptically regulates the release of DA by acting on receptors located on nerve terminals of the nigrostriatal dopaminergic neurons. Then, experiments carried out either on rat striatal slices*~‘g~23~30~37 or in the striatum of halothane- anesthetized cats*.” or rats’ implanted with either Abbreviations: AMPA, &L-a-amino-3-hydroxy-5-methyl4 isoxazole propionate; CSF, cerebrospinal fluid; DA, dopamine; DNQX, 6,7dinitro-quinoxaline-2,3-dione; MKSOI, ( + )-5-methyl-lo,1 l-dihydro-5Hdibenzo(a,d)- cyclohepten-5,10-imine maleate; NMDA, N-methyl-n- aspartate; ‘ITX, tetrodotoxin. push-pull cannulae or microdialysis tubes have shown that agonists of D,L-CL -amino-3-hydroxy-5- methyl4isoxazole propionate (AMPA) and N- methyl-D-aspartate (NMDA) receptors also stimulate the release of DA through the TTX-resistant process. This is in favor of the presence of both AMPA and NMDA receptors on dopaminergic nerve terminals. More direct pharmacological evidence for the occur- rence of both types of glutamate receptor on dopa- minergic neurons has been provided by release studies made on primary cultures of mesencephalic cells from the rat embryo. 26,27 However, these elegant investi- gations on cultured cells did not allow the precise localization of glutamate receptors on either den- drites, soma and/or nerve terminals of the dopa- minergic neurons. More recently, using purified synaptosomes from the rat striatum, we demon- strated that dopaminergic nerve terminals indeed possess AMPA and NMDA receptors which are involved in the presynaptic facilitator-y control of DA release. By acting on the same receptors, kainate, quisqualate and AMPA stimulated the release of newly synthesized [HIDA and the AMPA-evoked response was found to be antagonized by known 333