The M1 muscarinic agonist CI-1017 facilitates trace eyeblink conditioning in aging rabbits and increases the excitability of CA1 pyramidal neurons

The M1 muscarinic agonist CI-1017 was administered intravenously to aging r abbits on a daily basis before and during hippocampally dependent trace eye blink conditioning sessions. Circulating levels of CI-1017 were significant ly related to the drug dose. The drug was found to significantly increase t he rate and amount of learning in a dose-dependent manner with no significa nt effects on the amplitude, area, or latency of conditioned responses. The re was no evidence of pseudoconditioning at the highest drug concentration, and the minimally effective dose produced only mild and temporary hypersal ivation as a side effect. CI-1017 (10 mu M) was also found to increase the excitability of CA1 pyramidal neurons recorded from hippocampal slices from young and aging naive rabbits as measured by changes in spike-frequency ad aptation and the postburst afterhyperpolarization. These biophysical change s were reversed with either atropine (1 mu M) or pirenzepine (1 mu M). Thes e results suggest that M1 agonists ameliorate age-related learning and memo ry impairments at least in part by reducing the afterhyperpolarization and spike-frequency adaptation of hippocampal pyramidal neurons and that M1 ago nists may be an effective therapy for reducing the cognitive deficits that accompany normal aging and/or Alzheimer's disease.