Abstract
Nicotinic acetylcholine receptor (nAChR) agonists improve sensory gating deficits in animal models and in schizophrenic patients. The aim of this study was to determine whether the novel and selective α7 nAChR full agonist 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 T:C ratios in a paired auditory stimulus paradigm. ABT-107 at 0.1 μmol/kg (average plasma concentration 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 μmol/kg was ineffective at 30 min after administration when average plasma levels were 13.5 ng/ml. However, the 1.0 μmol/kg dose was effective 180 min after administration when plasma concentration had fallen to 1.9 ng/ml. ABT-107 (0.1 μmol/kg) also improved sensory gating in anesthetized DBA/2 mice pretreated with α7 nAChR desensitizing doses of nicotine (6.2 μmol/kg), or ABT-107 (0.1 μmol/kg) itself. Moreover, repeated BID dosing of ABT-107 (0.1 μmol/kg) was as efficacious as a single dose. The acute efficacy of ABT-107 (0.1 μmol/kg) was blocked by the nAChR antagonist methyllycaconitine (MLA), but not by the α4β2 nAChR antagonist dihydro-β-erythroidine (DHβE). These studies demonstrate that ABT-107 improves sensory gating through activation of nAChRs, and that efficacy is sustained under conditions of repeated dosing, or with prior nAChR activation with nicotine.
- Received June 29, 2012.
- Revision received September 13, 2012.
- Accepted September 13, 2012.
- The American Society for Pharmacology and Experimental Therapeutics