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 functio ns 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 pr esent experiment examined the effects of glucose and the direct K-ATP chann el modulators glibenclamide and lemakalim on spontaneous alternation perfor mance and hippocampal ACh release. Rats received either artificial CSF vehi cle or vehicle plus drug for two consecutive 12 min periods via microdialys is probes (3 mm; flow rate of 2.1 mul/min) implanted in the left hippocampu s. During the second 12 min period, rats were tested for spontaneous altern ation performance. Dialysate was simultaneously collected for later analysi s of ACh content. Both glucose (6.6 mM) and glibenclamide (100 muM) signifi cantly increased alternation scores compared with those of controls. Conver sely, lemakalim (200 muM) 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 chan nel modulators influence behavior when administered directly into the hippo campus, with channel blockers enhancing and openers impairing spontaneous a lternation performance, thus supporting the hypothesis that glucose enhance s memory via action at central K-ATP channels. That lemakalim, as well as g libenclamide and glucose, increased hippocampal ACh output suggests a disso ciation between the effects of K-ATP channel modulators on behavior and hip pocampal ACh release.