TONIC DESENSITIZATION OF HIPPOCAMPAL ALPHA-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLEPROPIONIC ACID RECEPTORS REGULATES 5-HYDROXYTRYPTAMINE RELEASE IN-VIVO

Strong evidence implicates glutamate as an excitatory neurotransmitter in the central nervous system. In the present study we have investigated the effects of different concentrations of the excitatory amino acid agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid on release of 5-hydroxytryptamine in rat hippocampus using in vivo microdialysis. Infusion of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid at 1 mu M led to an increase in dialysate 5-hydroxytryptamine. In contrast 100 mu M alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid decreased extracellular 5-hydroxytryptamine, collected in 30 min samples, and this decrease was sustained for several hours. alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor desensitization is well documented in vitro, and is reversed by the drug diazoxide. We therefore studied the possibility that this was occurring in hippocampus in vivo. Collection of dialysates at 5 min time intervals revealed a brief increase in dialysate 5-hydroxytryptamine in response to 100 mu M alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, although basal level of 5-hydroxytryptamine was below the level of detection. When 100 mu M agonist was co-infused with 500 mu M diazoxide, a substantial and prolonged increase in dialysate 5-hydroxytryptamine was seen. Diazoxide alone was observed to cause an increase in extracellular 5-hydroxytryptamine. Diazoxide is known to active ATP-dependent K+ channels, however, cromakalim (100 mu M), an activator of ATP-dependent K+ channels, reduced hippocampal 5-hydroxytryptamine release, suggesting that the effect of diazoxide is not the result of such an action. The non-N-methyl-D-aspartate receptor antagonist 6-cyano-7-nitroquinoxiline-2,3-dione reversed the effects of infusion of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid diazoxide, and the combination of the two drugs on 5-hydroxytryptamine release. When infused alone, the antagonist decreased dialysate 5-hydroxytryptamine. Collectively, these data indicate that desensitization of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors tonically controls hippocampal release of 5-hydroxytryptamine. This suggests that desensitization of these receptors plays a role in terminating glutamatergic transmission in vivo.