Cognitive enhancing effects of an AMPA receptor positive modulator on place learning in mice

This study presents an in vivo investigation of the arylpropylsulfonamide alpha-amino-3-hydroxy-5methyl-4-isoxazole propionic acid (AMPA) receptor positive modulator (R,R)-N,N-(2,20-[biphenyl-4-40-diyl]bis[propane-2,1-diyl])dimethanesulfonamide (PIMSD). The pharmacokinetics of the drug were examined in male C57BL/6J mice and the drug concentration in blood plasma determined after subcutaneous injection of 1 mg/kg b.w. This analysis revealed a rapid increase of the plasma concentration, peaking within 30 min after administration with a T-1/2 of approximately 30 min and a peak plasma concentration of about 2 mu M. Analysis of brain tissue homogenates also indicated blood-brain barrier permeability of the compound. Cognitive enhancing effects of the drug were then studied on place learning in male C57BL/6J mice in a water maze. In order to elucidate the potential positive effects of PIMSD on spatial learning the muscarinergic antagonist scopolamine was utilized, which is known to impair spatial learning ability. The mice were divided into four groups and subjected to two sequential subcutaneous injections administered 25 min prior to behavioural testing: (1) vehicle/vehicle; (2) PIMSD/vehicle; (3) scopolamine/vehicle; (4) PIMSD/scopolamine. PIMSD at a dose of 3 mg/kg b.w. was able to partially reverse the impairment given by 0.5 mg/kg b.w. scopolamine. These results suggest that arylpropylsulfonamides such as PIMSD may have a therapeutic use in the enhancement of cognitive function and support the hypothesis that AMPA receptor potentiation is one mechanism that can be targeted for diseases of cognitive impairment. (C) 2011 Elsevier B.V. All rights reserved.