Prepulse inhibition of the startle reflex and response to antipsychotic treatments in two outbred mouse strains in comparison to the inbred DBA/2 mouse

Abstract

CF-1 mice with naturally low PPI may be useful for testing typical and atypical antipsychotics while Black Swiss mice only responded to a typical antipsychotic. DBA/2 mice remain the only strain with naturally low PPI that responds to marketed antipsychotics, as well as to compounds with novel mechanisms of action. Thus, DBA/2 mice may be the strain of choice for screening novel chemical entities for their ability to increase PPI.

CEP-26401 (Irdabisant), a Potent and Selective Histamine H3 Receptor Antagonist/Inverse Agonist with Cognition-Enhancing and Wake-Promoting Activities

“…DBA/2 mice demonstrate naturally poor PPI that is reliably increased with antipsychotics and the H 3 R antagonists ABT-239, thioperamide, and ciproxifan (Browman et al, 2004;Fox et al, 2005;Flood et al, 2011). CEP-26401 administration in this model increased the average percentage of PPI after doses of 10 and 30 mg/kg i.p.…”

“…Wake times (min/h) were measured from the end of period of enhanced wake (3, 3.5, and 5.5 though the estimated H 3 R occupancy at effective doses of CEP-26401 was low, rodent models of short-term memory are particularly sensitive to the effects of H 3 R antagonists Medhurst et al, 2007) with a small percentage of occupancy (as low as Ͻ10%) producing efficacy in cognition models (Miller et al, 2009). Effects in preclinical models of PPI suggest that compounds of various classes, including H 3 R antagonists may have utility in the treatment of schizophrenia (Browman et al, 2004;Fox et al, 2005;Flood et al, 2011). However, whereas the DBA/2 mouse PPI model is sensitive to H 3 R antagonists, other preclinical models relevant to schizophrenia do not robustly respond to H 3 R antagonists (Burban et al, 2010;Flood et al, 2011).…”

“…Male DBA/2NCrl mice (19 -27 g; 7-9 weeks; Charles River Laboratories, Inc.) were administered CEP-26401 or vehicle (saline) and risperidone or vehicle [5% dimethyl sulfoxide (DMSO; Sigma-Aldrich)/10% polyethylene glycol 400 (PEG400; Hampton Research, Aliso Viejo, CA)/85% sterile water] intraperitoneally 30 min before testing. The PPI procedure for light phase testing in SR-LAB ABS Startle Reflex Systems (San Diego Instruments, San Diego, CA) was as described previously (Flood et al, 2011). In brief, after a 5-min acclimation period of 65-dB background white noise, mice received five conditioning trials consisting of a startle pulse (120 dB, 40 ms).…”

“…Post hoc pairwise comparisons versus the vehicle-treated group were made by using Bonferroni t tests. Compound exposures in plasma and brain for CEP-26401 and risperidone alone and in combination were assessed in DBA/2 mice at the end of the PPI experiments corresponding to 1 h after compound administrations, according to methods described previously (Flood et al, 2011).…”

Baseline prepulse inhibition expression predicts the propensity of developing sensitization to the motor stimulant effects of amphetamine in C57BL/6 mice

“…This admittedly is based on a correlative approach, which is certainly insufficient by itself to support a causative link. Yet, our emphasis on a single mouse strain here suffered less confounding differences than models based on inter-strains comparison, such as that between DBA/2 and C57BL/6 mice (Flood et al 2011;Singer et al 2009), or the alternative approach of selective breeding pioneered by Hadamitzky et al (2007), which produced separate rat lines with divergent PPI performance as heritable traits. In contrast, the use of inbred mice here minimizes genetic variation and emphasizes instead subtle environmental influences.…”