Enhancement of the Post-training Cholinergic Tone Antagonizes the Impairment of Retention Induced by a Nitric Oxide Synthase Inhibitor in Mice

The present experiments examined the role of the central cholinergic system in the memory impairment induced by post-training administration of a nitric oxide synthase (NOS) inhibitor in mice. Male Swiss mice received a one-trial inhibitory avoidance training (0.8 mA, 50 Hz, 1-s footshock) followed immediately by an ip injection of the NOS inhibitor -N^G-nitroarginine methyl ester ( -NAME; 100 mg/kg). Retention (cut-off time, 300 s) was tested 48 h after training. The administration of -NAME results in memory impairment for the inhibitory avoidance task. The effects of -NAME (100 mg/kg, ip) on retention were reversed in a dose-related manner by the centrally acting anticholinesterase physostigmine (35, 70, or 150 μg/kg, sc) administered 30 min after the NOS inhibitor. Further, -NAME (100 mg/kg, ip)-induced memory impairment was completely antagonized by the centrally acting muscarinic cholinergic agonist oxotremorine (OTM; 25, 50, or 100 μg/kg, sc) when given 30 min after -NAME. The peripherally acting anticholinesterase neostigmine (150 μg/kg, sc) did not modify the memory-impairing effects of -NAME. These findings suggest that the memory impairment following post-training administration of a NOS inhibitor is mediated, at least in part, by a reduction of the activity of central muscarinic cholinergic mechanisms and are consistent with our previous view that nitric oxide may be involved in post-training neural processes underlying the storage of newly acquired information.     

Effects of Posttraining Administration of Glucose on Retention of a Habituation Response in Mice: Participation of a Central Cholinergic Mechanism

Male Swiss mice were allowed to explore a novel environment, provided by an open-field activity chamber, for 10 min. The procedure was repeated twice with a 24-h interval. The difference in the exploratory activity between the first (training) and the second (testing) exposures to the chamber was taken as an index of retention of this habituation task. Posttraining intraperitoneal administration of glucose (10–300 mg/kg) enhanced retention in a dose-related manner, although only the dose of 30 mg/kg of glucose produced significant effects. Thus, the dose–response curve adopted an inverted U-shaped form. Glucose (30 mg/kg) given to untrained mice did not modify their exploratory performance when recorded 24 h later. The effects of glucose on retention were time-dependent, suggesting an action on memory storage. The memory-improving actions of glucose were prevented by the simultaneous administration of both the central acting muscarinic cholinergic antagonist atropine (0.5 mg/kg) and by the central acting nicotinic cholinergic antagonist mecamylamine (5 mg/kg). In contrast, neither methylatropine (0.5 mg/kg), a peripherally acting muscarinic receptor blocker, nor hexamethonium (5 mg/kg), a peripherally acting nicotinic receptor blocker, prevented the effects of glucose on retention. Low subeffective doses of glucose (10 mg/kg) and the central anticholinesterase physostigmine (35 μg/kg), but not neostigmine (35 μg/kg), given together, act synergistically and facilitated retention. We suggest that glucose modulates memory storage of one form of learning elicited by stimuli repeatedly presented without reinforcement, probably through an enhancement of brain acetylcholine synthesis and/or its release.