Intrahippocampal infusions of K-ATP channel modulators influence spontaneous alternation performance: Relationships to acetylcholine release in the hippocampus

One mechanism by which administration of glucose enhances cognitive functions may be by modulating central ATP-sensitive potassium (K-ATP) channels. K-ATP channels appear to couple glucose metabolism and neuronal excitability, with channel blockade increasing the likelihood of neurosecretion. The present experiment examined the effects of glucose and the direct K-ATP channel modulators glibenclamide and lemakalim on spontaneous alternation performance and hippocampal ACh release. Rats received either artificial CSF vehicle or vehicle plus drug for two consecutive 12 min periods via microdialysis probes (3 mm; flow rate of 2.1 μl/min) implanted in the left hippocampus. During the second 12 min period, rats were tested for spontaneous alternation performance. Dialysate was simultaneously collected for later analysis of ACh content. Both glucose (6.6 mM) and glibenclamide (100 μM) significantly increased alternation scores compared with those of controls. Conversely, lemakalim (200 μM) significantly reduced alternation scores relative to those of controls. Simultaneous administration of lemakalim with either glucose or glibenclamide resulted in alternation scores not significantly different from control values. All drug treatments enhanced hippocampal ACh output relative to control values. The results demonstrate that K-ATP channel modulators influence behavior when administered directly into the hippocampus, with channel blockers enhancing and openers impairing spontaneous alternation performance, thus supporting the hypothesis that glucose enhances memory via action at central K-ATP channels. That lemakalim, as well as glibenclamide and glucose, increased hippocampal ACh output suggests a dissociation between the effects of K-ATP channel modulators on behavior and hippocampal ACh release.