Desensitization of AMPA receptors and AMPA-NMDA receptor interaction: an in vivo cyclic GMP microdialysis study in rat cerebellum.

1. Desensitization is an important characteristic of glutamate receptors of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) type. 2. Stimulation of N-methyl-D-aspartate (NMDA) or AMPA receptors in cerebellum results in increased production of cyclic GMP. We have investigated AMPA receptor desensitization in vivo by monitoring extracellular cyclic GMP during intracerebellar microdialysis in conscious unrestrained adult rats. 3. Local infusion of AMPA (10 to 100 microM) caused dose-related elevations of cyclic GMP levels. The effect of AMPA was prevented by the non-NMDA receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX) and by the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine (L-NOARG). 4. In the absence of AMPA, DNQX lowered the basal levels of cyclic GMP whereas the NMDA receptor channel antagonist dizocilpine (MK-801) was ineffective. 5. Cyclothiazide, a blocker of AMPA receptor desensitization, potentiated the cyclic GMP response to exogenous AMPA. Moreover, cyclothiazide (100-300 microM) produced on its own dose-dependent elevations of extracellular cyclic GMP. The cyclothiazide-induced response was prevented not only by DNQX but also by MK-801. 6. While the cyclic GMP response elicited by AMPA was totally insensitive to MK-801, the response produced by AMPA (10 microM) plus cyclothiazide (30 microM) was strongly attenuated by the NMDA receptor antagonist (30 microM). 7. The results suggest that (a) AMPA receptors linked to the NO-cyclic GMP pathway in the cerebellum can undergo desensitization in vivo during exposure to exogenous AMPA; cyclothiazide inhibits such desensitization; (b) AMPA receptors (but not NMDA receptors) are 'tonically' activated and kept in a partly desensitized state by endogenous glutamate; (c) if cyclothiazide is present, activation of AMPA receptors may permit endogenous activation of NMDA receptors.