Regulation by glutamate- and adenosine-receptors of dopamine and acetylcholine release from rat striatal slices

Abstract: The striatum, which is cntically involved in sensonmotor integration, receivesan excitatory glutamat ergic input from the cerebral cortex and the thalamus. Theeffects of the glutamatergic stimulation are modulated by dopamine (DA) releasedfrom a prominent dopaminergic input, acetylcholine (ACh) released from cholinergicinterneurons and by the ubiquitous neuromodulator adenosine. The aim of present studywas to invesbgate the roles of glutamate- and adenosine-receptors in regulating releaseof DA and ACh in the striatum. Agonists at ionotropic glutamate receptors, of both NMDA and non-NMDA types, inducedDA and ACh release. The largest release was caused by NMDA receptors sensitive toMg2+ and MK-801. Of the non-NMDA receptors, kainate receptors may be moreimportant in causing release of ACh, and AMPA receptors in releasing DA. Three different NMDA receptor antagonists (kynureinate, AP-5 and MK-801) all caused,in the absence but not presence of Mg2+, a concentration-dependent decreasein electrically evoked release of DA and ACh. By contrast, CNQX (an antagonist atnon-NMDA receptors) significantly decreased the evoked release of these two transminersin the presence, but not in the absence of Mg2+. In addition, transmitterrelease evoked by the potassium channel blocker 4-AP is at least partly depen denton endogenous glutamate acting on both NMDA (for DA) and non-NMDA receptors (forDA and ACh). Thus, both NMDA and non-NMDA receptors regulating transmitter releaseare activated also by endogenous glutamate. Activation of adenosine Al receptors produced a concentration-dependent inhibitionof electrically evoked DA and ACh release. The adenosine A2A receptor-selectiveagonist CGS 21680 never caused any stimulation of DA and ACh release from the striatum.On the other hand, ACh release from the hippocampus was stimulated by agonists atadenosine A2A receptors and this was especially obvious after blockadeof adenosine Al receptors. These results show that only inhibitory Al are receptorspresent on dopaminergic terminals and cholinergic neurons m the striatum. WhereasCGS 21680 left the reduction of DA release by quinpirole unaffected, it did reducethe ability of this D2 receptor agonist to decrease ACh release. Since CGS 21680modulated ACh release both in the absence and in the presence of DPCPX, the receptorinvolved is probably an A2A receptor. This provides evidence that A2Aand D2 receptors interact at the level of neurotransmitter release. Mild hypoxia caused a significant increase of the evoked release of endogenousadenosine, hypo xanthine and inosine, and a significant decrease of the evoked releaseof DA and ACh. The addition of DPCPX antagonized the hypoxia-induced inhibition oftransmitter release. Thus, reduction of the oxygen supply to striatal slices resultsin an increased release of endogenous adenosine that, acting on adenosine A1receptors, decreases the evoked release of DA and ACh. Hypoglycemia, on the otherhand, increased the basal and evoked release of DA and ACh as well endogenous adenosine.This stimulation of transmitter release was slightly enhanced in the presence ofDPCPX and markedly inhibited in the presence of MK-801. The results suggest thatsubstrate lack induces release both of glutamate, which by actions on presynapticNMDA receptors causes release of DA, and of adenosine, which via A1 receptorsreduces the electrically evoked release of both DA and ACh. Thus adenosine may beable to limit the alterations in transmitter release induced by minor alterationsin energy metabolism, but not those induced by major insults. In summary, the present results confirm that in the striatum there are stimulatoryglutamate receptors of both the NMDA and non-NMDA type and inhibitory adenosine Alreceptors that regulate DA and ACh release in an antagonistic manner. The resultsalso indicate that these receptors are important under both physiological and pathophysiologicalconditions. Key words: striatum, dopamine, acetylcholine, adenosine receptors, glutamatereceptors. ISBN 91-628-2599-2