Maximizing the effect of an α7 nicotinic receptor PAM in a mouse model of schizophrenia-like sensory inhibition deficits

Positive allosteric modulators (PAMs) for the alpha 7 nicotinic receptor hold promise for the treatment of sensory inhibition deficits observed in schizophrenia patients. Studies of these compounds in the DBA/2 mouse, which models the schizophrenia-related deficit in sensory inhibition, have shown PAMs to be effective in improving the deficit. However, the first published clinical trial of a PAM for both sensory inhibition deficits and related cognitive difficulties failed, casting a shadow on this therapeutic approach. The present study used both DBA/2 mice, and C3H Chrna7 heterozygote mice to assess the ability of the alpha 7 PAM, PNU-120596, to improve sensory inhibition. Both of these strains of mice have reduced hippocampal alpha 7 nicotinic receptor numbers and deficient sensory inhibition similar to schizophrenia patients. Low doses of PNU-120596 (1 or 3.33 mg/kg) were effective in the DBA/2 mouse but not the C3H Chrna7 heterozygote mouse. Moderate doses of the selective alpha 7 nicotinic receptor agonist, choline chloride (10 or 33 mg/kg), were also ineffective in improving sensory inhibition in the C3H Chrna7 heterozygote mouse. However, combining the lowest doses of both PNU-120596 and choline chloride in this mouse model did improve sensory inhibition. We propose here that the difference in efficacy of PNU-120596 between the 2 mouse strains is driven by differences in hippocampal alpha 7 nicotinic receptor numbers, such that C3H Chrna7 heterozygote mice require additional direct stimulation of the alpha 7 receptors. These data may have implications for further clinical testing of putative alpha 7 nicotinic receptor PAMs. (C) 2015 Elsevier B.V. All rights reserved.