YM796, a novel muscarinic agonist, improves the impairment of learning behavior in a rat model of chronic focal cerebral ischemia

We studied effects of YM796, a novel muscarinic agonist, on behavioral, histological and regional cerebral blood flow changes in the chronic phase after focal cerebral ischemia in rats. YM796 (0.03, 0.1, 0.3 and 1 mg/kg) was administered orally once a day from the 7th to the 13th day after the permanent occlusion of left middle cerebral artery. On the 7th day, rats were trained in one-trial step-through passive avoidance task 45 min after drug administration. Test trials were carried out on the 8th and 14th days. Neurological deficits, including hemiplegia and abnormal posture, were observed on the 7th and 14th days. After the completion of behavioral studies, the rats were decapitated and cerebral infarction was measured. Regional cerebral blood flow was also measured by the hydrogen clearance technique 7 days after MCA occlusion. YM796 (0.1 – 1 mg/kg) significantly (P < 0.05) attenuated the impairment of learning behavior in a dose-dependent manner without affecting spontaneous locomotor activity. The ameliorating effect of YM796 (0.3 mg/kg) on the impaired learning behavior was significantly (P < 0.05) suppressed by intracerebroventricular injection of pirenzepine (10 μg/rat), an M₁ antagonist. No significant difference in either neurological deficits or cerebral infarction was found between the vehicle- and YM796-treated groups. Further, YM796 (0.3 mg/kg) had little effect on the reduced blood flow in the ipsilateral frontal cortex 7 days after occlusion. These results suggest that YM796 improves the impaired learning behavior probably by activating central M₁ receptors in a rat model of chronic focal cerebral ischemia.