Positive allosteric modulation of cholinergic receptors improves spatial learning following cortical contusion injury in mice.

We examined benzyl quinolone carboxylic acid (BQCA), a novel M1 muscarinic positive allosteric modulator, for improving memory and motor dysfunction following cerebral cortical contusion injury (CCI). Adult mice received unilateral motorsensory cortical CCI or sham injury. BQCA (5, 10, 20mg/kg, i.p.x2/day x 3-4 weeks) or vehicle (Veh) were administered, and weekly evaluations undertaken using a battery of motor tests, as well as the Morris Water Maze. Thereafter, cerebral metabolic activation was investigated in awake animals during walking with [¹⁴C]-2-deoxygIucose autoradiography, comparing CCI mice previously treated with BQCA (20 mg/kg) or vehicle. Relative changes in local cerebral glucose uptake (rCGU) were evaluated in 3D-reconstructed brains using statistical parametric mapping. CCI resulted in mild hyperactivity in the Open Field, and modest significant motor deficits, as well as significantly decreased spatial learning at 3 weeks. BQCA in CCI mice resulted in significantly improved spatial recall during the third week, with minimal effects on motor outcomes. CCI significantly decreased rCGU in the ipsilesional basal ganglia-thalamocortical circuit and in somatosensory regions, with relative increases noted contralaterally, as well as in the cerebellum. Significant decreases in rCGU were noted in subregions of the ipsilesional hippocampal formation, with significant increases noted contralesionally. BQCA compared to vehicle treated mice showed modest, though significantly increased rCGU in motor regions, as well as a partial reversal of lesion-related rCGU findings in subregions of the hippocampal formation. rCGU in ipsilesional posterior CA1, demonstrated a significant inverse correlation with the latency to find the submerged platform. BQCA at 20mg/kg had no significant effect on general motor activity, body weight or acute motor, secretory, or respiratory symptoms. Results suggest that BQCA is a candidate compound to improve learning and memory function following brain trauma, and may not suffer the associated CNS side effects typically associated with even modest doses of other cholinergic enhancers.