Idazoxan increases perforant path-evoked EPSP slope paired pulse inhibition and reduces perforant path-evoked population spike paired pulse facilitation in rat dentate gyrus

Abstract

Norepinephrine, acting via β-adrenoceptors, enhances the perforant path-evoked potential in dentate gyrus. Using systemic idazoxan to increase norepinephrine, and paired perforant path pulses to probe early inhibition, previous investigators reported that idazoxan increased initial spike amplitude and increased somatic feedback inhibition. Here, feedback inhibition was re-examined in idazoxan-treated (5 mg/kg) rats under urethane anesthesia. To control for initial increased spike amplitude after idazoxan, evoked potentials were matched, pre- and post-idazoxan, on initial population spike. Input–output current profiles were also compared pre- and post-idazoxan. Saline- and timolol-filled micropipettes permitted evaluation of a contribution of local β-adrenoceptors. As previously observed, initial spike amplitude was potentiated by idazoxan. Comparable spike potentiation was not seen on the timolol micropipette. Paired pulse inhibition of spike amplitude apparently increased, but input–output curve comparisons revealed a loss of feedback facilitation rather than an increase in feedback inhibition. Initial EPSP slopes were depressed after idazoxan in input–output curve data. EPSP slope feedback ratios were significantly reduced following idazoxan.These data suggest idazoxan has multiple effects on perforant path input to the dentate gyrus. Spike potentiation following idazoxan has previously been shown to depend on intact norepinephrine input. Here, the reduction in spike potentiation on the timolol pipette is consistent with other evidence that norepinephrine-mediated potentiation of the perforant path-evoked potential is dependent on local β-adrenoceptor activation. The input–output data suggest a decrease in feedback facilitation after idazoxan is likely to account for the apparent increase in feedback inhibition previously reported. Decreased EPSP slope ratios with similar paired pulse intervals have been reported in novel environments. Since exposure to novel environments activates locus coeruleus neurons, norepinephrine may mediate the change in EPSP slope inhibition reported in awake rats.In summary, these results are consistent with the hypothesis that idazoxan potentiates granule cell responses to perforant path input in the dentate gyrus via increases in norepinephrine that lead to β-adrenoceptor activation, and, further, that idazoxan reduces paired pulse feedback spike facilitation and enhances EPSP slope, but not spike, feedback inhibition.