Silvia R. Kopf

Memory-improving actions of glucose: Involvement of a central cholinergic muscarinic mechanism

Post-training intraperitoneal administration of alpha-D[+]-glucose (10-300 mg/kg) facilitated 24-h retention, in male Swiss mice, of a one-trial step-through inhibitory avoidance task. The dose-response curve was an inverted U. Glucose did not increase the retention latencies of mice that had not received a footshock during training. The effect of glucose (30 mg/kg, ip) on retention was time-dependent, which suggests that the drug facilitated memory storage. The memory facilitation induced by glucose (30 mg/kg, ip) was prevented by atropine (0.5 mg/kg, ip) administered after training, but 10 min prior to glucose treatment. In contrast, neither methylatropine (0.5 mg/kg, ip), a peripherally acting muscarinic receptor blocker, nor mecamylamine (5 mg/kg, ip) or hexamethonium (5 mg/kg, ip), two cholinergic nicotinic receptor antagonists, prevented the effects of post-training glucose on retention. Low subeffective doses of the central acting anticholinesterase physostigmine (35 micrograms/kg, ip), administered immediately after training, and glucose (10 mg/kg, ip), given 10 min after training, acted synergistically to improve retention. The effects of glucose (10 mg/kg, ip) were not influenced by the peripherally acting anticholinesterase neostigmine (35 micrograms/kg, ip). Considered together, these findings suggest that the memory facilitation induced by post-training administration of glucose could result from an enhancement of brain acetylcholine synthesis and/or its release that, in turn, might modulate the activity of muscarinic cholinergic mechanisms that are critically involved in memory storage.

Facilitation of memory storage by the acetylcholine M2 muscarinic receptor antagonist AF-DX 116

Post-training administration of the acetylcholine muscarinic M2 presynaptic receptor antagonist AF-DX 116 (0.1-10.0 mg/kg, ip), facilitated 48 h retention, in male Swiss mice, of a one-trial step-through inhibitory avoidance task. The dose-response curve was an inverted U. AF-DX 116 did not increase the retention latencies of mice that had not received a footshock during training. The influence of AF-DX 116 (1 mg/kg, ip) on retention was time-dependent, which suggests that the drug facilitated memory storage. The memory facilitation induced by AF-DX 116 (1 mg/kg, ip) was prevented by atropine (0.5 mg/kg, ip) administered after training, but 10 min prior to AF-DX 116 treatment. In contrast, neither methylatropine (0.5 mg/kg, ip), a peripherally acting muscarinic receptor blocker, nor mecamylamine (5 mg/kg, ip) or hexamethonium (5 mg/kg, ip), two cholinergic nicotinic receptor antagonists, prevented the effects of post-training AF-DX 116 on retention. Low subeffective doses of the central acting anticholinesterase physostigmine (35 micrograms/kg, ip), administered immediately after training, and AF-DX 116 (0.1 mg/kg, ip), given 10 min after training, acted synergistically to improve retention. The effects of AF-DX 116 (0.1 mg/kg, ip) were not influenced by the peripherally acting anticholinesterase neostigmine (35 micrograms/kg, ip). Considered together, these findings suggest that the activation of a muscarinic cholinergic presynaptic inhibitory mechanism, probably by increasing brain acetylcholine release, may modulate the activity of post-training processes involved in memory storage.

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 L-NG-nitroarginine methyl ester (L-NAME; 100 mg/kg). Retention (cut-off time, 300 s) was tested 48 h after training. The administration of L-NAME results in memory impairment for the inhibitory avoidance task. The effects of L-NAME (100 mg/kg, ip) on retention were reversed in a dose-related manner by the centrally acting anticholinesterase physostigmine (35, 70, or 150 microg/kg, sc) administered 30 min after the NOS inhibitor. Further, L-NAME (100 mg/kg, ip)-induced memory impairment was completely antagonized by the centrally acting muscarinic cholinergic agonist oxotremorine (OTM; 25, 50, or 100 microg/kg, sc) when given 30 min after L-NAME. The peripherally acting anticholinesterase neostigmine (150 microg/kg, sc) did not modify the memory-impairing effects of L-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.

The post-training memory enhancement induced by physostigmine and oxotremorine in mice is not state-dependent

Immediate post-training subcutaneous administration of either the centrally acting anticholinesterase physostigmine (35, 70, or 150 mu g/kg) or the centrally acting muscarinic cholinergic agonist oxotremorine (OTM; 25, 50, or 100 mu g/kg) significantly enhanced retention of male Swiss mice tested 48 h after training in a one-trial step-through inhibitory avoidance task (0.8 mA, 50 Hz, 1 s footshock). Neither physostigmine nor OTM affected latencies to step through in mice not given the footshock on the training trial, suggesting that the effects of both cholinomimetics on retention performance were not due to nonspecific actions on response test latencies. The peripherally acting anticholinesterase neostigmine (35, 70, or 150 mu g/kg) did not significantly influence retention latencies of either shocked or unshocked mice. The influences of physostigmine (150 mu g/kg) or OTM (100 mu g/kg) 30 min prior to the retention test did not affect the retention performance of mice given post-training injections of either saline, physostigmine (150 mu g/kg), or OTM (100 mu g/kg). Considered together, these findings indicate that the memory-enhancing effects of post-training administration of physostigmine or OTM are not state-dependent and are consistent with the view that the behavioral effects of the cholinomimetics drugs are mediated through an interaction with the neural processes underlying the storage of acquired information.

Glucose enhancement of memory is not state-dependent

Immediate post-training intraperitoneal administration of alpha-D[+]-glucose (10-300 mg/kg) significantly enhanced retention of male Swiss mice tested 24 h after training in an inhibitory avoidance task. The dose-response curve was an inverted U in this range of dose. However, of the doses tested, only 30 mg/kg was effective. Glucose did not affect response latencies in mice not given the footshock on the training trial, suggesting that the actions of glucose on retention performance were not due to nonspecific effects on response latencies. The influence of glucose (30 mg/kg) was time-dependent, which suggests that glucose facilitated memory consolidation processes. Administration of glucose (30 mg/kg) 2 or 10 min prior to the retention test did not affect the retention performance of mice given post-training injections of either saline or glucose (30 mg/kg). These findings indicate that the memory-enhancing effects of post-training administration of glucose are not state-dependent and are consistent with the view that the behavioral effects of glucose are mediated through an interaction with the neural or neurohumoral processes underlying the storage of acquired information.