The enhancement of retention induced by vasopressin in mice may be mediated by an activation of central nicotinic cholinergic mechanisms.

Immediate post-training subcutaneous administration of lysine vasopressin (LVP, 0.003-1.00 microgram/kg) enhanced retention, whereas the vasopressin antagonist AAVP (0.01-0.30 microgram/kg) impaired it, in male Swiss mice tested 48 h after training in an inhibitory avoidance task. Both effects were dose-dependent. Neither LVP nor AAVP affected response latencies in mice not given the footshock on the training trial. The simultaneous administration of AAVP at a dose (0.01 microgram/kg) which had no effect on retention shifted the dose-response curve of LVP to the right. Nicotine (1.0-30.0 micrograms/kg, sc), a central nicotinic cholinergic agonist, also facilitated retention in a dose-related manner without affecting the retention performance of unshocked mice. The effect of nicotine was prevented by the central acting nicotinic cholinergic receptor antagonist mecamylamine (5 mg/kg, sc.). In contrast, neither hexamethonium (5 mg/kg, sc), a peripheral acting nicotinic receptor blocker, nor atropine (0.5 mg/kg, sc) or methylatropine (0.5 mg/kg, sc), two anticholinergic drugs which are known to act on muscarinic cholinergic receptors, prevented the effect of post-training nicotine. The effects of LVP and nicotine were time-dependent, suggesting that both treatments enhanced retention by influencing post-training processes involved in memory storage. Low doses of nicotine (1.50 microgram/kg, sc) or the central anticholinesterase physostigmine (35 micrograms/kg, sc) and LVP (0.003 microgram/kg, sc), which had no effect on retention when administered alone, produced a synergistic interaction when given together following training. The influence of LVP (0.03 microgram/kg, sc) on retention was prevented not only by AAVP (0.01 microgram/kg, sc) but also by mecamylamine (5 mg/kg, sc), whereas the effects of nicotine (10.0 micrograms/kg, sc) were prevented only by mecamylamine. These results suggest that the enhancement of retention induced by vasopressin is probably due to an activation of central nicotinic cholinergic mechanisms which are critical for memory formation.     

Facilitation of inhibitory avoidance by hypertonic saline is reversed by a vasopressin and a nicotinic antagonist

Hypertonic saline (1 ml of 0.25, 0.50, and 1.00 M NaCl, ip) facilitated retention of a one-trial, step-through inhibitory avoidance task when injected into male Swiss mice 10 min after training, as indicated by retention performance 48 h later. A similar result was obtained after a subcutaneous injection of lysine vasopressin (LVP, 0.03 microgram/kg). Neither hypertonic saline nor LVP modified latencies to step-through of mice that had not received a footshock during training. The enhancement of retention produced both by hypertonic saline and by LVP was prevented by the vasopressin receptor antagonist AAVP (0.01 microgram/kg, sc) given after training, but 10 min before the treatments. The effect of hypertonic saline was also prevented by the central acting cholinergic nicotinic receptor antagonist mecamylamine (5 mg/kg, sc). On the contrary, neither hexamethonium (5 mg/kg, sc), a peripheral acting nicotinic receptor blocker, nor atropine (0.5 mg/kg, sc) or methylatropine (0.5 mg/kg, sc), two anticholinergic drugs which are known to act on cholinergic muscarinic receptors, prevented the effect of post-training hypertonic saline. These results suggest that a peripheral osmotic stimulus, probably through an endogenous release of vasopressin, may be behaviorally significant, and are consistent with the view that vasopressin may modulate the activity of central cholinergic nicotinic mechanisms which are critical for the behavioral change observed.     

Involvement of central cholinergic mechanisms in the effects of oxytocin and an oxytocin receptor antagonist on retention performance in mice

Oxytocin (OT, 0.10 microg/kg, sc) impaired retention of a one-trial step-through inhibitory avoidance task when injected into male Swiss mice 10 min after training, as indicated by retention performance 48 h later. In contrast, the immediate post-training administration of the putative oxytocin receptor antagonist d(CH(2))(5)[Tyr(Me)(2), Thr(4), Thy-NH(9)(2)] OVT (AOT, 0.30 microg/kg, sc) significantly enhanced retention performance. Neither OT nor AOT affected response latencies in mice not given footshock on the training trial, and neither the impairing effects of OT nor the enhancing effects of AOT were seen when the training-treatment interval was 180 min, suggesting that both treatments influenced memory storage. The effects of OT (0.10 microg/kg, sc) on retention were prevented by AOT (0.03 microg/kg, sc) given immediately after training, but 10 min prior to OT treatment. The central acting anticholinesterase physostigmine (35, 70, or 150 microg/kg, i.p.), but not its quaternary analogue neostigmine (150 microg/kg, i.p.), reversed the impairment of retention performance induced by OT, whereas low subeffective doses of the centrally active muscarinic cholinergic antagonist atropine (0.5 mg/kg, i.p.) or the central acting nicotinic cholinergic antagonist mecamylamine (5 mg/kg, i.p.), but not methylatropine (0.5 mg/kg, i.p.) or hexamethonium (5 mg/kg, i.p.) prevented the enhancement of retention performance caused by AOT. We suggest that oxytocin negatively modulates the activity of central cholinergic mechanisms during the posttraining period that follows an aversively motivated learning experience, leading to an impairment of retention performance of the inhibitory avoidance response.     

Effects of the nicotinic receptor blocker mecamylamine on radial-arm maze performance in rats

Lesions of cholinergic neurons have been found by many investigators to impair choice accuracy in the radial arm maze. Because muscarinic receptor blockers, such as scopolamine, have also repeatedly been found to impair choice accuracy in the radial-arm maze, it has generally been thought that the critical effect of cholinergic lesions is the deafferentation of muscarinic receptors. The possible involvement of nicotinic receptors in the cholinergic bases of cognitive performance in the radial-arm maze has not been as well investigated. The present study examined the effects of the blockade of nicotinic receptors on performance of female Sprague-Dawley rats in the radial-arm maze. Acute administration of the the nicotinic receptor blocker, mecamylamine (10 mg/kg) was found to significantly impair radial-arm maze choice accuracy. This dose also caused a significant increase in response latency in the maze. The effect on choice behavior but not locomotor speed seemed to be due to the central effects of mecamylamine, because administration of the peripheral nicotine receptor blocker, hexamethonium (20 mg/kg), did not impair choice accuracy, even though it did increase response latency to a similar degree as the 10-mg/kg dose of mecamylamine. Lower doses of mecamylamine (2.5 and 5 mg/kg) did not impair choice accuracy. These results indicate that central nicotinic as well as muscarinic cholinergic receptors are involved with cognitive functioning.     

Mecamylamine prevents the enhancement of retention induced by lysine vasopressin in mice

Lysine vasopressin (0.03 microgram/kg, sc) enhanced retention of a one-trial, step-through inhibitory avoidance task when injected into male Swiss mice immediately post-training, as indicated by retention performance 48 h later. A low dose of the vasopressin antagonist, AAVP (0.01 microgram/kg, sc), did not significantly affect retention, whereas a higher dose (0.03 microgram/kg, sc) impaired retention. Neither lysine vasopressin nor AAVP modified latencies to step-through of mice that had not received a footshock during training. The simultaneous injection of AAVP (0.01 microgram/kg, sc) prevented the enhancement of retention induced by lysine vasopressin. The influence of lysine vasopressin on retention was antagonized by the simultaneous administration of mecamylamine (5 mg/kg, sc) but not by hexamethonium (5 mg/kg, sc), atropine (0.5 mg/kg, sc), or methylatropine (0.5 mg/kg, sc). A modulatory role of vasopressin on the activity of central cholinergic nicotinic mechanisms which participate in memory formation is suggested.     

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.     

Vasopressin modulates the activity of nicotinic cholinergic mechanisms during memory retrieval in mice

Lysine vasopressin (0.03 micrograms/kg, sc) enhanced retention test performance on a one-trial step-through inhibitory avoidance task when injected into male Swiss mice 20 min before the retention test. Tests were done 48 h following training. A low dose of the vasopressin antagonist AAVP (0.01 microgram/kg, sc, 20 min prior to testing) did not significantly affect retention test performance, whereas a higher dose (0.03 microgram/kg, sc) impaired it. Neither lysine vasopressin nor AAVP when given prior to testing modified latencies to step-through of mice that had not received a footshock during training. The simultaneous administration of AAVP (0.01 microgram/kg, sc) prevented the enhancement of retention test performance induced by lysine vasopressin. The influence of lysine vasopressin on retention test performance was antagonized by the simultaneous administration of mecamylamine (5 mg/kg, sc) but not by hexamethonium (5 mg/kg, sc), atropine (0.5 mg/kg, sc), or methylatropine (0.5 mg/kg, sc). A modulatory role of vasopressin on the activity of central cholinergic nicotinic mechanisms which probably operate at the time of testing is suggested.     

Nicotinic-dopaminergic relationships and radial-arm maze performance in rats

Accurate performance on the radial-arm maze is dependent upon the integrity of nicotinic-cholinergic, muscarinic-cholinergic, and dopaminergic systems. Pharmacological blockade of these systems with mecamylamine, scopolamine, or haloperidol impairs choice accuracy in the maze. We have previously demonstrated that the performance deficit caused by muscarinic blockade is enhanced by coadministration of the nicotinic antagonist, mecamylamine, and is diminished by coadministration of the dopamine antagonist, haloperidol. In the present study, it was found that the choice accuracy deficit produced by nicotinic blockade is enhanced, not antagonized, by coadministration of haloperidol. Thus, although both nicotinic and muscarinic cholinergic systems are involved in radial-arm maze performance and antagonists of these receptors are additive in the deficits they cause, nicotinic and muscarinic interactions with dopaminergic systems are opposite in nature.     

Blood glucose and brain function: interactions with CNS cholinergic systems

We recently found that glucose injections attenuate amnesia and hyperactivity produced by scopolamine, a muscarinic antagonist. The present study examined whether glucose would augment behavioral effects produced by a muscarinic agonist, physostigmine. In experiment I, doses were first determined for which neither glucose (10 mg/kg) nor physostigmine (0.05 mg/kg) altered scopolamine-induced hyperactivity. However, combined glucose-physostigmine injections significantly reduced scopolamine hyperactivity. Experiment II evaluated the effects of glucose on physostigmine-induced tremors. Glucose (10, 100, and 250 mg/kg) or saline injections were given 20 min before physostigmine injections (0.4 or 0.05 mg/kg). Observations of glucose effects on the severity of physostigmine-induced tremors were then obtained at 5-min intervals for 25 min after physostigmine injections. Glucose (100 mg/kg) significantly facilitated the onset of tremors when injected before either dose of physostigmine, and augmented (at 100 and 250 mg/kg) tremor severity when injected before the lower dose of physostigmine. These findings indicate that glucose can facilitate the actions of a cholinergic agonist on two behaviors, locomotor activity and tremors, adding support to the view that circulating glucose levels can modulate central cholinergic function. More generally, the results provide additional evidence that circulating glucose levels can influence brain function.     

Scopolamine-induced deficits in spontaneous alternation performance: attenuation with lateral ventricle injections of glucose.

This experiment determined whether centrally administered glucose can attenuate scopolamine-induced deficits in spontaneous alternation performance. All rats were surgically prepared with indwelling cannulae directed at the lateral ventricle. Thirty min prior to alternation tests, rats received systemic (ip) injections of saline or scopolamine (3 mg/kg). Ten or thirty min prior to training, the rats also received a direct injection into the lateral ventricle of either artificial cerebrospinal fluid (CSF) or glucose (3 micrograms in 1 microliter). Scopolamine significantly impaired spontaneous alternation performance relative to controls. Additional treatment with ICV glucose 30 min, but not 10 min prior to testing, significantly attenuated the scopolamine-induced deficit. These results add support to the view that glucose acts directly on brain systems to attenuate behavioral effects of cholinergic antagonists.     

Characterization of the cognitive effects of combined muscarinic and nicotinic blockade

Choice accuracy performance in the radial-arm maze is dependent upon the integrity of both the nicotinic and muscarinic cholinergic receptors. Pharmacological blockade of either of these subtypes of cholinergic receptors with mecamylamine or scopolamine impairs choice accuracy in the radial-arm maze. We have previously demonstrated that the performance deficit caused by muscarinic blockade is exacerbated in at least an additive fashion by coadministration of the nicotinic antagonist, mecamylamine. In the present study, it was found that mecamylamine and scopolamine act together in a greater than additive fashion in disrupting radial-arm maze choice accuracy. When doses of these drugs which do not by themselves cause significant impairments in choice accuracy are given together, they induce a pronounced impairment. Previous results have shown that the adverse effects of nicotinic blockade could be reversed by the dopaminergic D2 agonist LY 171555. In this study, this drug was found to attenuate the cognitive impairment caused by combined nicotinic and muscarinic blockade. On the other hand, the dopaminergic D1 antagonist SCH 23390 which has previously been shown to reverse the adverse effects of muscarinic blockade was not found in this study to attenuate the impairment of combined nicotinic and muscarinic blockade. Since combined nicotinic and muscarinic blockade approximates generalized cholinergic underactivation, treatments like LY 171555, which attenuate the adverse effects of this combined blockade, may be useful in treating syndromes like Alzheimer's disease, which are characterized by generalized cholinergic loss.     

Fetal Alcohol-Exposed Rats Exhibit Differential Response to Cholinergic Drugs on a Delay-Dependent Memory Task

Fetal alcohol exposure in human and rodents produces a number of cognitive deficits including impairments in learning and memory. Recent evidence in our laboratory has shown that fetal alcohol-exposed (FAE) rats respond differently to systemic administration of cholinergic drugs when tested for vigilance and locomotor activity. The present study examined the effects of muscarinic and nicotinic agonists and antagonists on memory performance in a delayed alternation task. Subjects were male offspring of Sprague-Dawley rats fed a 35% ethanol-derived caloric diet, pair-fed with sucrose, or chow-fed with lab chow during the last 2 weeks of gestation. Rats (3 months old) were food-deprived prior to training in the T-maze. Rats were first trained in the alternation task at no delay for five sessions. Rats were then trained at longer delays (20, 60, 180 s) until all groups showed similar performance for two consecutive sessions. Each animal was then tested following systemic injections of the cholinergic antagonists scopolamine and mecamylamine (60-s delay) and the cholinergic agonists pilocarpine and nicotine (180-s delay). Rats received saline injections on alternate days of testing. The results revealed that FAE rats exhibited no impairments in alternation performance at the no delay and 20-s delay, but showed impairments on both the 60- and 180-s delays during the initial sessions. However, with additional training, FAE rats showed performance similar to that of control groups at these delays. Following both pilocarpine and nicotine injections, control groups, but not the FAE group, showed significant memory enhancement in the alternation task. Following scopolamine injections, the FAE rats showed a significant impairment, while control groups showed a nonsignificant decrease in performance. All three groups showed impairments in the alternation task following administration of mecamylamine compared to saline treatment. These findings suggest that alterations in the cholinergic system in FAE rats may underlie some of the cognitive deficits observed with prenatal alcohol exposure.     

Effects of combined muscarinic and nicotinic blockade on choice accuracy in the radial-arm maze

Acetylcholine (ACh) systems have been found to be crucial for the maintenance of accurate cognitive performance. A great variety of studies have shown that the muscarinic ACh receptor blocker scopolamine impairs choice accuracy in the radial-arm maze. Recently, it has been found that the nicotinic ACh receptor blocker mecamylamine also impairs radial-arm maze choice accuracy. In the present study, we investigated the effects of combined administration of these two ACh blockers. Scopolamine (0.15 mg/kg) and mecamylamine (10 mg/kg) each moderately impaired choice accuracy. Combined treatment with scopolamine and mecamylamine significantly decreased choice accuracy relative to either drug alone. This combination treatment lowered choice accuracy to chance levels. These data show that nicotinic and muscarinic blockade have at least additive effects in producing an anterograde memory deficit. Concurrent blockade of these two components of ACh systems may provide a better animal model of cognitive impairments due to the loss of cholinergic neurons, such as Alzheimer's disease.     

The Effects of L-glucose on memory in mice are modulated by peripherally acting cholinergic drugs.

D-Glucose improves memory in animals and humans and in subjects with memory pathologies. To date, the accepted conclusion drawn from animal research is that D-glucose improves memory via alterations in central cholinergic systems. However, recent evidence suggests that a sugar which does not cross the blood-brain barrier also facilitates memory (Talley, Arankowsky-Sandoval, McCarty, & Gold, 1999). The present study examined the effects of peripherally administered L-glucose, a stereoisomer of D-glucose, in male mice. Intraperitoneal administration of L-glucose (300 mg/kg) before testing enhanced place learning in the Morris water maze. Mice injected with L-glucose had significantly shorter escape latencies than mice injected with saline (1 ml/kg). Effects were observed on both reference memory and working memory tasks. L-Glucose did not facilitate performance on either task when it was simultaneously administered with cholinergic antagonists that are excluded from the central nervous system. Thus, simultaneous administration of either methyl-scopolamine (0.3 mg/kg), a peripherally acting muscarinic receptor blocker, or hexamethonium (1 mg/kg), a peripherally acting nicotinic receptor blocker, reversed the effect of L-glucose on memory. These findings suggest that the memory effects of l-glucose may be mediated by facilitated acetylcholine synthesis and/or release in the peripheral nervous system.     

Effects of Posttraining Administration of Insulin 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 a 10-min period. The procedure was repeated twice within a 24-h interval. The difference in the exploratory activity between the first (training) and the second exposure (testing) to the chamber was taken as an index of retention of this habituation task. Posttraining intraperitoneal administration of insulin (8, 20, or 80 IU/kg) impaired retention in a dose-related manner, although only the dose of 20 IU/kg of insulin produced significant effects. Thus, the dose–response curve adopted a U-shaped form. Insulin (20 IU/kg) given to untrained mice did not modify their exploratory performance when recorded 24 h later. The effects of insulin on retention were time dependent, suggesting an action on memory storage. An ineffective dose (8 IU/kg) of insulin given together with an ineffective dose of a central acting muscarinic cholinergic antagonist atropine (0.5 mg/kg) or with a central acting nicotinic cholinergic antagonist mecamylamine (5 mg/kg) interacted to impair retention. 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, interacted with the subeffective dose of insulin on retention. The impairing effects of insulin (20 IU/kg) on retention were reversed by the simultaneous administration of physostigmine (70 μg/kg) but not neostigmine (70 μg/kg). We suggest that insulin impairs memory storage of one form of learning elicited by stimuli repeatedly presented without reinforcement, probably through a decrement of brain acetylcholine synthesis.     

Glucose and physostigmine effects on morphine- and amphetamine-induced increases in locomotor activity in mice

Recent findings indicate that glucose antagonizes several behavioral effects of cholinergic antagonists and augments those of cholinergic agonists. For example, scopolamine elicits increased locomotor activity, an action which is attenuated by glucose and by combined treatment with glucose and physostigmine at doses which are individually without effect. Opiate and catecholamine agonists, such as morphine and amphetamine, also elicit hyperactivity. The present study examined interactions of glucose and physostigmine with morphine- and amphetamine-induced hyperactivity. Mice received saline, morphine (10 mg/kg), or amphetamine (1 mg/kg) 50 min prior to testing, followed by saline, physostigmine (0.01, 0.05, 0.1, or 0.2 mg/kg), or glucose (10, 50, 100, or 500 mg/kg) administered 20 min prior to activity testing in an open field. Physostigmine significantly attenuated both morphine- and amphetamine-induced increases in activity, but higher doses were required to attenuate the effects of amphetamine. Like physostigmine, glucose significantly attenuated morphine-induced activity levels, but unlike physostigmine, glucose did not attenuate amphetamine-induced activity. Thus, the behavioral effects of morphine were more susceptible to modification by physostigmine and glucose than were the effects of amphetamine. The attenuation of morphine-induced hyperactivity demonstrates a similarity between glucose and cholinergic agonists, and also indicates that glucose may inhibit, directly or indirectly, opiate functions. More generally, these findings add to the evidence that circulating glucose levels selectively influence a growing list of behavioral and neurobiological functions.     

Impairment of spontaneous alternation performance by an NMDA antagonist: attenuation with non-NMDA treatments.

N-Methyl-D-aspartate (NMDA) receptor antagonists disrupt learning on a variety of tasks. Previous findings indicate that glucose, naloxone, and physostigmine ameliorate learning deficits produced by several treatments. The present experiment examines whether these agents also reverse the amnestic effects of NMDA receptor blockade. Mice were tested for spontaneous alternation performance in a Y-maze. The animals received either saline or the NMDA antagonist, NPC 12626 (35 mg/kg, IP), 50 min prior to testing and received an additional injection of saline, glucose, naloxone, or physostigmine 30 min prior to testing. NPC 12626 significantly decreased alternation scores. Glucose (250 mg/kg), physostigmine (0.01 mg/kg), and naloxone (1 mg/kg) reversed the effects of NPC 12626. Thus, impairments of learning after NMDA receptor blockade share with other amnestic conditions the susceptibility to attenuation by glucose, naloxone, and physostigmine.     

AF-DX 116, a Presynaptic Muscarinic Receptor Antagonist, Potentiates the Effects of Glucose and Reverses the Effects of Insulin on Memory

Male Swiss mice were tested 24 h after training in a one-trial step-through inhibitory avoidance task. Low subeffective doses of -(+)-glucose (10 mg/kg, ip), but not its stereoisomer -(−)-glucose (30 mg/kg, ip), administered immediately after training, and AF-DX 116 (0.3 mg/kg, ip), a presynaptic muscarinic receptor antagonist, given 10 min after training, interact to improve retention. Insulin (8 IU/kg, ip) impaired retention when injected immediately after training, and the effects were reversed, in a dose-related manner, by AF-DX 116 (0.3, 1.0, or 3.0 mg/kg, ip) administered 10 min following insulin. Since AF-DX 116 possibly blocks autoreceptors mediating the inhibition of acetylcholine release from cholinergic nerve terminals, the present data support the view that changes in the central nervous system glucose availability, subsequent to modification of circulating glucose levels, influence the activity of central cholinergic mechanisms involved in memory storage of an inhibitory avoidance response in mice.     

Differing time dependencies of object recognition memory impairments produced by nicotinic and muscarinic cholinergic antagonism in perirhinal cortex

The roles of muscarinic and nicotinic cholinergic receptors in perirhinal cortex in object recognition memory were compared. Rats' discrimination of a novel object preference test (NOP) test was measured after either systemic or local infusion into the perirhinal cortex of the nicotinic receptor antagonist methyllycaconitine (MLA), which targets alpha-7 (α7) amongst other nicotinic receptors or the muscarinic receptor antagonists scopolamine, AFDX-384, and pirenzepine. Methyllycaconitine administered systemically or intraperirhinally before acquisition impaired recognition memory tested after a 24-h, but not a 20-min delay. In contrast, all three muscarinic antagonists produced a similar, unusual pattern of impairment with amnesia after a 20-min delay, but remembrance after a 24-h delay. Thus, the amnesic effects of nicotinic and muscarinic antagonism were doubly dissociated across the 20-min and 24-h delays. The same pattern of shorter-term but not longer-term memory impairment was found for scopolamine whether the object preference test was carried out in a square arena or a Y-maze and whether rats of the Dark Agouti or Lister-hooded strains were used. Coinfusion of MLA and either scopolamine or AFDX-384 produced an impairment profile matching that for MLA. Hence, the antagonists did not act additively when coadministered. These findings establish an important role in recognition memory for both nicotinic and muscarinic cholinergic receptors in perirhinal cortex, and provide a challenge to simple ideas about the role of cholinergic processes in recognition memory: The effects of muscarinic and nicotinic antagonism are neither independent nor additive.     

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.