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 α7 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 α7 PAM, PNU-120596, to improve sensory inhibition. Both of these strains of mice have reduced hippocampal α7 nicotinic receptor numbers and deficient sensory inhibition similar to schizophrenia patients. Low doses of PNU-120596 (1 or 3.33mg/kg) were effective in the DBA/2 mouse but not the C3H Chrna7 heterozygote mouse. Moderate doses of the selective α7 nicotinic receptor agonist, choline chloride (10 or 33mg/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 α7 nicotinic receptor numbers, such that C3H Chrna7 heterozygote mice require additional direct stimulation of the α7 receptors. These data may have implications for further clinical testing of putative α7 nicotinic receptor PAMs.
Department of Psychiatry, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA. Electronic address: Karen.Stevens@ucdenver.edu.
Karen E
KE
Stevens
Department of Psychiatry, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
Lijun
L
Zheng
Department of Psychiatry, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
Kirsten L
KL
Floyd
Institute for Behavioral Genetics, University of Colorado, Boulder, Boulder, CO, USA.
Jerry A
JA
Stitzel
D000161:Acoustic Stimulation; D000818:Animals; D001307:Auditory Perception / Q000187:drug effects / Q000502:physiology; D002794:Choline / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D006579:Heterozygote; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D010671:Phenylurea Compounds / Q000494:pharmacology; D012559:Schizophrenia / Q000503:physiopathology*; D055139:Sensory Gating / Q000502:physiology*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists / Q000235:genetics / Q000502:physiology*
C508388:1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; C579166:Chrna7 protein, mouse; D007555:Isoxazoles; D010671:Phenylurea Compounds; D064569:alpha7 Nicotinic Acetylcholine Receptor; D002794:Choline
Auditory gating; C3H heterozygote Chrna7 null mutant mice; DBA/2 mice; PAM; PNU-120596; Positive allosteric modulator; Schizophrenia; Sensory inhibition; α7 Nicotinic receptor