Crucial role of kainate receptors in mediating striatal kainate injection-induced decrease in acetylcholine M 1 receptor binding in rat forebrain

Abstract

We investigated the roles of kainate-, α-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 ∼20%), [ 3H]MK-801 (up to ∼90%) and [ 3H]pirenzepine (up to ∼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 ∼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).