Presynaptic glutamate receptors facilitate release of norepinephrine and 5-hydroxytryptamine as well as dopamine in the normal and ischemic striatum

We investigated the effects of selective glutamate (Glu) agonists on the release of monoamine neurotransmitters and their implication in the enhanced monoamine release in cerebral ischemia. In the striatum of anesthetized Sprague-Dawley rats, in vivo microdialysis was performed and the release of excitatory amino acids (Glu and aspartate (Asp)) and monoamines (dopamine (DA), norepinephrine (NE) and 5-hydroxytryptamine (5-HT)) was measured by high-performance liquid chromatography with an electrochemical detector. (1) Forebrain ischemia by 4-vessel occlusion generated significant correlations between the Glu and Asp levels and the DA, NE and 5-HT levels (r = 0.922 ∼ 0.967, P < 0.01, n = 6). (2) l-Glu and its selective agonists (N-methyl-d-aspartate) (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and kainate (KA) evoked a simultaneous release of striatal DA, NE and 5-HT in a dose-dependent manner (P ' < 0.01, ANOVA, n - 8). The maximal monoamine release evoked by the Glu agonists showed different magnitudes in the order of DA >> NE > 5-HT (118-, 16- and 9-fold from the baseline levels by 62.5 mM l-Glu, respectively). Each Glu agonist exerted a different magnitude of transmitter release and the order of agonist efficacy was different among NE, 5-HT and DA release: AMPA = KA > l-Glu = NMDA for DA release, AMPA > l-Glu = NMDA = KA for NE release, and l-Glu = NMDA = KA = AMPA for 5-HT release. In conclusion, both presynaptic NMDA and AMPA/KA receptors regulating the transmitter release exist widely on the monoaminergic (DA, NE and 5-HT) nerve terminals in the rat striatum, with a variety of receptor subtypes and variation in the agonist efficacy. Their implication in the augmentation of monoamine release in cerebral ischemia was suggested.