Crucial role of kainate receptors in mediating striatal kainate injection-induced decrease in acetylcholine M(1) receptor binding in rat forebrain.
We investigated the roles of kainate-, alpha-amino-3-hydroxy-5-methylisoxazol-4-propionate (AMPA)- and N-methyl-D-aspartate (NMDA)-receptors in mediating striatal kainate injection-induced decrease in the binding of acetylcholine M(1) receptors in rat forebrain. After unilateral intrastriatal injection of kainate (4 nmol), the bindings of [3H]kainate (10 nM), [3H]MK-801 (4 nM) and [3H]pirenzepine (4 nM) to the rat ipsilateral forebrain membranes declined, reaching the lowest on day 2 to 4 and recovering on day 8. Saturation binding studies, performed on day 2 post-injection, showed that kainate (1, 2, 4 nmol) dose-dependently decreased B(max) and K(d) of the three ligands. (+)-5-Methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801), a selective NMDA receptor channel blocker, antagonised (from a dose of 4 nmol) kainate-induced decreases in the bindings of [3H]kainate (up to approximately 20%), [3H]MK-801 (up to approximately 90%) and [3H]pirenzepine (up to approximately 70%). In contrast, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a selective non-NMDA receptor antagonist, almost completely abolished (from a dose of 12 nmol) kainate-induced decreases in the bindings of all the three ligands (up to approximately 95-98%). Cyclothiazide, a selective potentiator that enhances AMPA receptor-mediated responses, significantly enhanced (from a dose of 4 nmol) kainate-induced decrease in the binding of [3H]kainate but not that of [3H]pirenzepine or [3H]MK-801. In summary, these results indicate that striatal kainate injection-induced decrease in the binding of acetylcholine M(1) receptors in rat forebrain is dependent on activation of kainate receptors and, to a certain extent, a consequent involvement of NMDA receptors. These and previous studies provide some evidence showing that kainate receptors might play a crucial role in regulating excitatory amino acids (EAA)-modulated cholinergic neurotransmission in the central nervous system (CNS).
Jin
S
S
Department of Pharmacology, Faculty of Medicine, The National University of Singapore, MD2, 18 Medical Drive, 117597, Singapore, Singapore. phcjinsy@nus.edu.sg
Yang
J
J
Lee
W L
WL
Wong
P T
PT
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007608:Kainic Acid / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D010890:Pirenzepine / Q000378:metabolism; D016548:Prosencephalon / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000187:drug effects* / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D016291:Dizocilpine Maleate; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D007608:Kainic Acid; D010890:Pirenzepine; D043643:Receptor, Muscarinic M1; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D011976:Receptors, Muscarinic; D016194:Receptors, N-Methyl-D-Aspartate