Radek_2012_J.Pharmacol.Exp.Ther_343_736

Nicotinic acetylcholine receptor (nAChR) agonists improve sensory gating deficits in animal models and schizophrenic patients. The aim of this study was to determine whether the novel and selective alpha7 nAChR full agonist 5-(6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl)-1H-indole (ABT-107) improves sensory gating deficits in DBA/2 mice. Sensory gating was measured by recording hippocampal-evoked potential P20-N40 waves and determining gating test/conditioning (T/C) ratios in a paired auditory stimulus paradigm. ABT-107 at 0.1 mumol/kg (average plasma concentration of 1.1 ng/ml) significantly improved sensory gating by lowering T/C ratios during a 30-min period after administration in unanesthetized DBA/2 mice. ABT-107 at 1.0 mumol/kg was ineffective at 30 min after administration when average plasma levels were 13.5 ng/ml. However, the 1.0 mumol/kg dose was effective 180 min after administration when plasma concentration had fallen to 1.9 ng/ml. ABT-107 (0.1 mumol/kg) also improved sensory gating in anesthetized DBA/2 mice pretreated with alpha7 nAChR-desensitizing doses of nicotine (6.2 mumol/kg) or ABT-107 (0.1 mumol/kg) itself. Moreover, repeated b.i.d. dosing of ABT-107 (0.1 mumol/kg) was as efficacious as a single dose. The acute efficacy of ABT-107 (0.1 mumol/kg) was blocked by the nAChR antagonist methyllycaconitine, but not by the alpha4beta2 nAChR antagonist dihydro-beta-erythroidine. These studies demonstrate that ABT-107 improves sensory gating through the activation of nAChRs, and efficacy is sustained under conditions of repeated dosing or with prior nAChR activation with nicotine.