Comparative effects of the α7 nicotinic partial agonist,S 24795, and the cholinesterase inhibitor,donepezil, against aging-related deficits in declarative and working memory in mice

Introduction The comparative effects of a newly described specific α7 nAChR partial agonist, S 24795, and a cholinesterase inhibitor, donepezil, currently used as a symptomatic Alzheimer’s disease treatment were studied in two mouse models of aging-related memory deficits. Materials and methods We employed radial arm-maze paradigms assessing short-term working memory (STWM, experiment A) and mnemonic flexibility, a cardinal property of long-term declarative (LTDM, experiment B). Both compounds were administered daily at 0.3 and 1 mg/kg subcutaneously (∼3 weeks). Results In the STWM experiment, vehicle-treated aged mice displayed a severe and persistent deficit in the retention of successive arm visits in comparison to younger controls. S 24795 at 1 mg/kg (trends at 0.3 mg/kg) and donepezil at 0.3 mg/kg (but not 1 mg/kg) exerted beneficial effects on this deficit: The performance of aged mice treated with these drugs remarkably increased across the testing days and almost reached young adult performance level. In the critical test trials of memory flexibility (i.e., LTDM), in experiment B, S 24795 at 1 mg/kg (trends at 0.3 mg/kg) and donepezil at the dose of 1 mg/kg (but not 0.3 mg/kg) improved aged mice performance. Conclusion This preclinical demonstration that S 24795 restored specific age-related memory deficits with as much efficacy as donepezil adds to recent literature in highlighting the potential interest of an α7 nAChR drug as a symptomatic AD therapeutic.     

Improvement of episodic contextual memory by S 18986 in middle-aged mice: comparison with donepezil

Introduction This study compared the effects of S 18986, a positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors, to those of donepezil a cholinesterase inhibitor on memory impairments induced by ageing in a contextual serial discrimination (CSD) task in middle-aged mice. Materials and methods The CSD task involved the learning of two consecutive discriminations in a four-hole board, each performed on two different floors. This model has been developed to study simultaneously different forms of memory in mice (i.e., episodic-like vs semantic-like forms of memory). We showed that placebo-middle-aged mice (14–15 months old) and placebo-aged subjects (19–20 months old) exhibited a severe memory deficit for the first but not the second discrimination, which was due to an increase in interference, as compared with placebo-treated young mice (5 months old). Middle-aged mice were given (9 days) per os administration of either donepezil, S 18986, or placebo. Results and discussion Both 0.3 mg/kg donepezil and 0.1 mg/kg S 18986 reversed the deficit of middle-aged mice through a significant increase in contextually correct responses and in parallel a tendency to reduce interfering responses. Conclusion Overall, S 18986 emerges as having a beneficial impact on contextual memory processes in middle-aged mice.     

Combined effects of acute stress and amphetamine on serial memory retrieval pattern in mice

Introduction  This study investigated the dose–effect of amphetamine on contextual serial (contextual serial discrimination (CSD)) and serial (serial discrimination (SD)) memory in acutely stressed versus nonstressed C57 Bl/6 Jico mice. Materials and methods  Memory was first evaluated in nonstress condition. Mice learned two consecutive discriminations (D1 and D2) in a four-hole board involving either distinct (CSD) or identical (SD) internal contextual cues. All mice received i.p. injections of vehicle before acquisition and vehicle or amphetamine 20 min before the memory retrieval phase occurring 24 h after acquisition. Results  Results showed that: (1) vehicle group expressed in both tasks a similar memory retrieval pattern, D2 being better retrieved than D1; (2) 2 mg/kg amphetamine significantly enhanced D1 but not D2 performance in both tasks, whereas 4 mg/kg amphetamine enhanced D2 but not D1 retrieval. Thus, amphetamine more specifically modulates serial order memory retrieval in a context-independent manner. In a further step, we studied the effect of an acute stress (electric foot shocks 5 min before retrieval) specifically on D1 performance of the CSD task in 2 mg/kg amphetamine-treated mice. Immediately after testing, blood was sampled to measure plasma corticosterone levels. Results showed that acute stress significantly improved D1 performance in vehicles but blocked the memory-enhancing effect of 2 mg/kg amphetamine, as compared to the nonstress condition. However, statistical analysis failed to evidence a significant interaction between treatments and conditions (stress vs nonstress) on corticosterone levels, contrary to another vigilance-enhancing drug, modafinil (Béracochéa, Psychopharmacology 196:1–13, 2008).     

Comparative effects of the dopaminergic agonists piribedil and bromocriptine in three different memory paradigms in rodents

The potential memory-enhancing properties of two dopamine agonists currently used in patients with Parkinson's disease, piribedil (1, 10 mg/kg/day, subcutaneously) and bromocriptine (5 mg/kg/day, subcutaneously), were evaluated in three experiments. Although piribedil (10 mg/kg) and bromocriptine equally enhanced spontaneous object recognition in young adult rats (experiment A), only piribedil displayed beneficial effects against aging-related memory impairments in two radial-maze experiments in mice. First (experiment B), a two-stage paradigm of spatial discrimination was used to assess relational/declarative memory in aged mice; piribedil (1 and 10 mg/kg) selectively and significantly improved the performances of aged mice in the critical tests for relational/declarative memory, whereas bromocriptine had no effect. Second, in a novel working memory task (experiment C), vehicle- or bromocriptine-treated aged mice displayed, compared with (vehicle) younger controls, a severe and persistent deficit in short-term retention of successive arm-visits, performing close to chance whichever the retention interval. Performances of piribedil (10 mg/kg) group remarkably improved across testing-days and reached young adults' level. The restoration of specific mnemonic impairments, in aged mice, highlights the memory-enhancing properties of piribedil. The efficacy of this drug in treating cognitive impairment of Parkinson's disease should now be assessed in more specific models.This work was published in an abstract form: ECNP Abstracts, 2005 (P8060 & P8065).     

Stress modulation of the memory retrograde-enhancing effects of the awakening drug modafinil in mice

Purpose This study investigated the dose–effect relationship of modafinil administration on contextual memory processes, in parallel with the measurements of plasma corticosterone levels in acutely stressed mice. Materials and methods Memory was first evaluated in normal (nonstressed) mice either in contextual (CSD) or spatial (SSD) tasks. Thus, C57 Bl/6 Jico mice learned two consecutive discriminations (D1 and D2) in a four-hole board. The discriminations occurred on either distinct (CSD) or identical (SSD) floors (internal contextual cues). All mice received a vehicle intraperitoneal injection before learning and were injected 24 h later (20 min before the test session) either with vehicle or modafinil. Results Results showed that modafinil-treated mice behaved similarly as vehicles in the spatial SSD task, whereas in contrast, memory of the first-learned discrimination (D1) in the CSD task was enhanced by a 32- but not a 16-mg/kg modafinil dose. Hence, we studied the effect of a pretest acute stress (electric footshocks) specifically on D1 performance in modafinil-treated subjects. Immediately after behavioral testing, blood was sampled to measure plasma corticosterone levels. Conclusions Results showed that: (1) stress significantly improved performance in vehicles, (2) stress decreased the efficiency threshold of modafinil, as performance was enhanced at the low dose (16 mg/kg), whereas this enhancement was obtained for the high dose (32 mg/kg) under nonstress conditions, (3) the performance was impaired at the high (32 mg/kg) dose, and (4) modafinil significantly reduced the magnitude of the stress-induced corticosterone secretion, mainly at the dose of 32 mg/kg.     

The cannabinoid CB1 receptor antagonist SR141716A attenuates the memory impairment produced by Δ9-tetrahydrocannabinol or anandamide

 The administration of Δ⁹-tetrahydrocannabinol (THC), the principle psychoactive ingredient in marijuana, or the endogenous cannabinoid anandamide, has been shown to impair recent memory. The purpose of the present investigation was to determine if the cannabinoid CB₁ receptor antagonist SR141716A could attenuate THC- or anandamide-induced memory impairment, and to assess the effects on memory of SR141716A alone. Memory was assessed in rats well-trained in a two-component instrumental discrimination task, consisting of a conditional discrimination, and a non-match-to-position to assess recent or working memory. SR141716A (0.0–2.0 mg/kg) had no effect on either the conditional discrimination or the non-match-to-position. However, SR141716A (0.0–2.0 mg/kg) attenuated the memory impairment produced by THC (2.0 or 4.0 mg/kg) as indexed by an enhancement of performance in the non-match-to-position. When administered to rats pretreated with anandamide (2.0 mg/kg), SR141716A (0.0–2.5 mg/kg) impaired performance in the conditional discrimination at the highest dose. This was interpreted as a deficit in some capacity unrelated to memory (e.g., motor impairment). However, lower doses of SR141716A (0.1 and 0.5 mg/kg) attenuated the anandamide-induced impairment of performance in the non-match-to-position without affecting the conditional discrimination. This is the first report that the memory impairment produced by anandamide can be attenuated by a cannabinoid antagonist; results suggest that anandamide-induced memory disruption is mediated by CB₁ receptors. Received: 25 June 1997 / Final version: 7 February 1998     

Differential effects of total sleep deprivation on contextual and spatial memory: modulatory effects of modafinil

The aim of the present work was to investigate in mice the effects of a total 10-hr sleep deprivation on contextual (episodic-like) and spatial (reference) memory tasks. For that purpose, mice learned two consecutive discriminations (D1 and D2) in a 4-hole board involving either identical (Serial Spatial Discrimination, SSD) or distinct (Contextual Serial Discrimination, CSD) internal contextual cues. In a second step, we intended to assess the corrective effect of modafinil on memory impairments generated by sleep deprivation. Sleep deprivation was triggered through an alternative platform apparatus (water box), previously validated using EEG recording and spectral analysis.We showed that a 10-hr total sleep deprivation impaired the CSD task but not the SSD one. Moreover, the impairment of contextual memory in sleep-deprived animals was dose-dependently corrected by modafinil. Indeed, modafinil administered after the sleep deprivation period and 30 min before the test session restored a memory retrieval pattern identical to non sleep-deprived animals at the doses of 32 and 64 mg/kg, however not at 16 mg/kg.Results hereby evidence that the vigilance-enhancing drug modafinil is able to restore the contextual memory performance at a low dose as compared to other memory tasks, possibly by an enhancement of hippocampal activity known to be both involved in the processing of contextual information and impaired following our sleep deprivation procedure.     

Effects of positive modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors in a benzodiazepine-induced deficit of spatial discrimination in mice

Imbalance between GABAergic and glutamatergic neurotransmission has been recently hypothesized to trigger memory decline related either to ageing or to Alzheimer's disease (AD). Thereby, benzodiazepine-induced anterograde amnesia has been construed as a model of hippocampal-related cognitive dysfunctions. Since spatial memory is altered both by ageing and by benzodiazepines such as alprazolam, we investigated the pharmacological sensitivity of alprazolam-induced deficit in a delayed spatial discrimination (SD) task, notably with positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors. We showed that alprazolam (0.1?mg/kg intraperitoneally) induced memory impairments as compared with vehicle-treated mice. The oral administration of modulators of AMPA receptors (IDRA-21: 10?mg/kg; S18986: 3 and 10?mg/kg) reversed the alprazolam-induced deficits. This study is first to show evidence that reference treatments of AD, such as memantine (a NMDA receptor antagonist) at 3?mg/kg per os (po) and donepezil (an acetylcholinesterase inhibitor) at 1?mg/kg po, also reversed the alprazolam-induced amnesia. Given such results, the SD task emerges as a valuable novel task to screen pro-cognitive compounds. Thus, we highlight the efficacy of modulators of AMPA-type glutamate receptors to counteract alprazolam-induced spatial deficits. These results could be viewed alongside the imbalance between excitation and inhibition observed during normal and pathological ageing.     

Involvement of nitric oxide in pioglitazone memory improvement in morphine-induced memory impaired mice

Introduction

Pioglitazone, a PPAR‐γ agonist, which is clinically used in treating diabetic patients, has been recently reported to have crucial roles in improving cognition and memory performance. Since the mechanisms involved in the neuroprotective effect of pioglitazone are not entirely understood, the current study was designed to investigate the possible interaction of pioglitazone with morphine in memory-impaired mice and the probable role of nitric oxide (NO) in this effect.

Materials and methods

All the experiments were performed in passive avoidance and Y-maze paradigms. To induce memory impairment, mice were administered morphine (1, 3 and 10 mg/kg, s.c.) immediately before the training trial. Pioglitazone (20, 40 and 80 mg/kg, p.o.) was gavaged 2 h prior to the training trial. Further, an NO synthase inhibitor, L-NAME (10 mg/kg, i.p.), or an inducible NO synthase inhibitor, aminoguanidine (100 mg/kg, i.p.) was administered 30 min before the training trial to determine the possible involvement of NO in the restorative effect of pioglitazone.

Results

1) Morphine dose dependently impaired the acquisition of spatial memory and passive avoidance task. 2) Treatment with pioglitazone significantly improved the memory performance in morphine-treated mice in both tests. 3) In the passive avoidance task, L-NAME, but not aminoguanidine, altered the effect of pioglitazone on morphine-induced memory impairment. 4) In Y-maze discrimination, the memory improving effect of pioglitazone was reversed by both NO synthase inhibitors, L-NAME and aminoguanidine.

Discussion

Our results demonstrate that the pioglitazone improving effect on the morphine-induced impairment of memory acquisition is at least in part through the NO pathway. It is suggested that in short term spatial recognition memory, both inducible and constitutive NO synthases are involved, but in the long term fear memory, only the constitutive NO synthases indicated a prominent role in the anti‐amnestic effect of pioglitazone on morphine-induced memory impairment.     

Some characteristics of amnesia induced by FLA-63 an inhibitor of dopamine beta hydroxylase.

The amnesic effects of FLA-63, a potent dopamine-beta-hydroxylase (DBH) inhibitor, were investigated in a food motivated spatial discrimination task. Groups of C57BL/6J mice were injected with either 5 mg/kg, 15 mg/kg, 25 mg/kg, 35 mg/kg or physiological saline 4 hr prior to training. Amnesia was observed 24 hr following training at all dose levels except 5 mg/kh. The performance deficit was specific to memory of the discrimination and not the result of state-dependency. Training conditions which produce an increase in habit strength prevented the amnestic effects of FLS-63. Spontaneous recovery of memory occurred 48 hr following drug administration. Recovery from amnesia was also induced by injections of a monoamine oxidase inhibitor, pargyline, administered 2 hr prior to the retention test. These data suggest that amnesia induced by norpinephrine (NE) depletion is the result of impairment of mechanisms necessary for memory retrieval.     

The cannabinoid receptor agonist WIN 55,212-2 facilitates the extinction of contextual fear memory and spatial memory in rats

Rationale Previous studies demonstrated that pharmacological blockade of CB1 cannabinoid receptors decreases the extinction of conditioned fear and spatial memory in rodents. However, the effects of CB1 cannabinoid receptor activation in this response remain unclear.Objectives To evaluate the effects of the cannabinoid agonist WIN 55,212-2 (WIN) and the cannabinoid antagonist SR 147778 (SR) on the extinction of contextual fear memory in rats 24 h or 30 days after fear conditioning.Methods For fear conditioning, rats were placed in the conditioning chamber for 3 min and received a 1-s electric foot shock (1.5 mA). Retrieval testing consisted of a 3-min exposure to the conditioning chamber and extinction training consisted of successive 9-min exposures at 24-h intervals. Rats were also evaluated in the open field and water maze reversal task.Results The administration of SR (1.0 mg/kg, i.p.) and WIN (0.25 mg/kg, i.p.) before extinction training disrupted and facilitated, respectively, the extinction of 24 h contextual fear memory. These effects were not related to any disturbance in memory retrieval, unconditioned freezing expression, or locomotor activity. WIN (0.25 mg/kg, i.p.) also facilitated the extinction of 30-day-old contextual fear memory, while the prior administration of SR (0.2 mg/kg, i.p.) antagonized this response. The facilitative effect of WIN on memory extinction does not seem to be specific for contextual fear memory because it was also observed in the water maze reversal task.Conclusions These results suggest cannabinoid receptor agonists as potential drugs to treat anxiety disorders related to the retrieval of aversive memories.Part of this study was presented at the 18th European College of Neuropsychopharmacology Congress, Amsterdam, The Netherlands, 22–26 October 2005.     

Comparative effects of alpha-2 receptor agents and THA on the performance of adult and aged rats in the delayed non-matching to position task

The present study investigated the effects of dexmedetomidine (an alpha-2 adrenoceptor agonist), atipamezole (an alpha-2 adrenoceptor antagonist) and tacrine (an inhibitor of acetylcholinesterase) on the performance of adult and aged rats in a delayed non-matching to position task assessing spatial short-term memory. Most of the aged rats were impaired in the pretraining phases and in the acquisition of the non-delayed version of the task. After a substantial training period of the delayed version of the task, both adult and aged rats reached their asymptotic level of performance. Both adult and aged rats showed a decline in the percent correct responses at the longest delays in this task, and a delay independent decrease in the percent correct responses across the delays (0–30 s) was found in the group of aged rats (25-month-old) as compared to the adults (10-month-old). Dexmedetomidine (0.3, 1.0 or 3.0 µg/kg), atipamezole (0.03, 0.3 or 3.0 mg/kg) and tacrine (1.0 or 3.0 mg/kg) did not increase the percent correct responses in adult or aged rats. The highest doses of dexmedetomidine and tacrine decreased behavioural activity of rats during this short-term memory testing. Atipamezole (0.03 mg/kg) increased behavioural activity of rats. The results suggest that acute, systemic administrations of alpha-2 drugs or an anticholinesterase do not improve short-term memory in rats.     

Beneficial effects of galantamine on performance in the object recognition task in Swiss mice: deficits induced by scopolamine and by prolonging the retention interval

Episodic memory has been found to be impaired in several neuropsychiatric disorders. The object recognition task (ORT), introduced by Ennaceur and Delacour [Ennaceur A., Delacour J. A new one-trial test for neurobiological studies of memory in rats: 1. Behavioral data. Behav Brain Res 1988; 31: 47-59.], is a method to measure a specific form of episodic memory in rats and mice. It is based on the spontaneous behavior of rodents and can be considered as a retention test completely free of reference memory components. Therefore, the ORT has been increasingly used as an experimental tool in assessing drug effects on memory and investigating the neural mechanisms underlying learning and memory. In the present study, the main goal was to evaluate the effects of galantamine in Swiss mice in the ORT on scopolamine-induced deficits and with different retention intervals. Mice had a good object recognition memory at the 15 min retention intertrial interval (ITI). Object discrimination was absent at the longer intervals (1 h, 4 h and 24 h). Galantamine (10 mg/kg, administered s.c., 30 min prior to acquisition) partially reversed effects of scopolamine (0.63 mg/kg, administered s.c., 30 min prior to acquisition) and normalized performance to control levels. A lower dose of galantamine (0.63 mg/kg) was also investigated when two different retention intervals (15 min and 1 h) were used. Galantamine (0.63 mg/kg) had no adverse effects. Solvent-treated mice in the 1 h ITI condition did not discriminate between the novel and the familiar object (discrimination index was equal to zero), while galantamine (0.63 mg/kg)-treated mice attained a good object recognition memory performance. In conclusion, galantamine was shown to possess memory-enhancing effects in two conditions that reduced object discrimination: scopolamine-induced deficits and when a longer retention interval was used.     

Characteristics of learning and memory impairment induced by delta9-tetrahydrocannabinol in rats

We investigated the characteristics of delta9-tetrahydrocannabinol (THC)-induced impairment of learning and memory using an 8-arm radial maze task, a water maze, a visual discrimination task with 2 figures and a passive avoidance test in rats. THC (6 mg/kg, i.p.) impaired spatial memory in the standard task of the 8-arm radial maze. THC (4-6 mg/kg, i.p.) selectively impaired working memory in a reference and working memory task of the 8-arm radial maze. Even at a dose of 10 mg/kg, THC did not impair spatial memory in the water maze. In addition, THC at a dose of 6 mg/kg, which had inhibitory effects in the 8-arm radial maze, did not affect performance in the visual discrimination task. These results indicate that at low doses (2-6 mg/kg), THC may not produce visual function abnormalities. THC impaired retrieval (6 mg/kg, i.p.) as well as acquisition (10 mg/kg, i.p.) in the passive avoidance test. The consolidation process was also impaired by i.c.v. injection (100 microg), but not i.p. injection (6-10 mg/kg) of THC. These results suggest that THC-induced impairment of spatial memory is based on the selective impairment of working memory through its effects on acquisition and retrieval processes.     

Subchronic memantine administration on spatial learning, exploratory activity, and nest-building in an APP/PS1 mouse model of Alzheimer's disease

Glutamate neurotoxicity has been proposed to be involved in Alzheimer pathogenesis, with clinical data supporting succesful treatment with the NMDA receptor antagonist memantine. In the present study, the effects of subchronic memantine administration were assessed on spatial and non-spatial learning as well as exploratory activity and nest-building in APP/PS1 mutant mice. Memantine (10 mg/kg, i.p.) was better than placebo during the reversal phase of left-right discrimination, though equivalent to saline for Morris water maze and passive avoidance learning. The drug had no effect on non-learned behaviors in elevated plus-maze exploration and nest-building. These results support a specific action of the NMDA receptor antagonist on behavioral flexibility in mutant mice with amyloid pathology.     

The neurosteroid pregnenolone sulfate reduces learning deficits induced by scopolamine and has promnestic effects in mice performing an appetitive learning task

The effects of the neurosteroid pregnenolone sulfate (PS) on learning as well as on scopolamine-induced learning deficits were studied in Swiss mice using an appetitively reinforced Go-No Go visual discrimination task. Subcutaneous (SC) administration of scopolamine (0.3–3 mg/kg) after the first session of training dose-dependently impairs learning during the following sessions in this task. Moreover, intracerebroventricular (ICV) administration of PS (0.01–10 nmol) dose-dependently blocks learning deficits induced by scopolamine (3 mg/kg), with the most potent effects at the dose of 0.5 nmol PS. In addition to antagonizing the amnestic effects of scopolamine, PS (0.5 nmol ICV) has a memory-enhancing effect, when administered alone after the first training session. Scopolamine (3 mg/kg SC) also produced substantial deficits on retrieval performance in the Go-No Go visual discrimination task, and caused motor disturbances, when administered 15 min before testing. PS (0.5 nmol ICV) also reduced scopolamine-induced deficits on retrieval but had no effect on scopolamine-induced motor impairments in the traction reflex test. Such a rapid effect of PS on memory processes may be mediated via NMDA and/or GABA_A receptors.     

Disruptive effects of the prototypical cannabinoid Δ⁹-tetrahydrocannabinol and the fatty acid amide inhibitor URB-597 on go/no-go auditory discrimination performance and olfactory reversal learning in rats

The effects of Δ?-tetrahydrocannabinol (Δ?-THC; 0.3, 1, 3 and 10 mg/kg), and the fatty acid amide hydrolysis inhibitor URB-597 (0.1 and 0.3 mg/kg), on auditory and olfactory go/no-go discrimination tasks were examined in rats. The aims were to assess (i) whether simple olfactory and auditory discrimination tasks are sensitive to cannabinoid interference and (ii) whether manipulation of endogenous cannabinoid levels with URB-597 might have adverse effects on perceptual and cognitive functions. Thirsty rats were trained to nose poke at a 'sniff port', where odours were briefly presented. After one odour (S+, lemon), licks made at an adjacent tube were rewarded with water, whereas licks after a second odour (S-, strawberry) were unrewarded. In an analogous auditory task, nose pokes produced an auditory S+ (beep) or S- (white noise). Δ?-THC and URB-597 impaired performance on the auditory but not the olfactory discrimination task. Auditory performance was still affected on the day after Δ?-THC (3 and 10 mg/kg) and URB-597 (0.3 mg/kg) exposure. Δ?-THC and URB-597 markedly impaired olfactory discrimination reversals without disrupting acquisition of the original discrimination. Rimonabant (CB1 antagonist; 3 mg/kg) reversed all Δ?-THC and URB-597 effects on auditory discriminations and olfactory discrimination reversals. These results confirm impairment of cognitive flexibility (reversal learning) by cannabinoids and show remarkable sensitivity of auditory discrimination performance to Δ?-THC and the augmented endocannabinoid signalling produced by URB-597.     

Involvement of hippocampal CA3 KATP channels in contextual memory

This paper evaluates the involvement of hippocampal ATP-sensitive potassium channels (K_ATP) in learning and memory. After confirming expression of the Kir6.2 subunit in the CA3 region of C57BL/6J mice, we performed intra-hippocampal pharmacological injections of specific openers and blockers of K_ATP channels. The opener diazoxide, the blocker tolbutamide, or a mixture of both, were bilaterally injected in the CA3 region before we subjected the animals to a fear conditioning paradigm. Diazoxide strongly impaired contextual memory of mice at both doses tested. This impairment was specifically reversed by co-injecting the blocker tolbutamide. Moreover, we studied the mnemonic abilities of mice deleted for the Kir6.2 subunit. These mice were backcrossed to C57BL/6J mice and tested in two learning paradigms. We found a significant impairment of contextual and tone memories in the Kir6.2 knock-out mice when compared with heterozygous or wild-type animals. Furthermore, these animals were also slightly impaired in a spatial version of the Morris water maze task. Our data suggest a specific involvement of hippocampal K_ATP Kir6.2/SUR1 channels in memory processes.     

Acute treatment with low doses of memantine does not impair aversive,non-associative and recognition memory in rats

Memantine is a non-competitive N-methyl-d-aspartate receptor antagonist, which has been employed in the clinic as a neuroprotective agent for the treatment of several dementias, particularly Alzheimer’s disease. In this study, we evaluated pharmacological effects of the acute administration of memantine on memory process. Memory retention scores were evaluated in normal adult Wistar rats injected with saline and memantine (2, 5, 10, and 20 mg/kg, IP) and then subjected to the step-down inhibitory avoidance task, habitation to an open-field apparatus, and object recognition task. The treatment with higher doses of memantine (10 and 20 mg/kg) injected 60 min before or immediately after training-session impaired acquisition and retention of aversive memory in the inhibitory avoidance task. In addition, higher doses of memantine injected 60 min before the first open-field exposure also impaired habituation during the second exposure to the apparatus. No significant differences were observed in the performance of rats treated with memantine, in all doses tested, compared to saline-treated rats in the object recognition task. Notably, we observed that at 5 mg/kg, memantine increased spontaneous locomotion and exploration in the rat open-field test. In conclusion, present findings support the view that memantine at lower doses did not affect memory formation in normal rats, but at high doses memantine, induce hyperlocomotion, which could bias the interpretation of the animal behavior assessed in memory tests.     

Cognitive dysfunction induced by sequential injection of amyloid-beta and ibotenate into the bilateral hippocampus; protection by memantine and MK-801

Aggregated 40-residue amyloid-beta peptide (beta40, 4 microg/microl), and 2 days later, ibotenate (NMDA receptor agonist, 0.3 microg/0.5 microl), were bilaterally injected into the hippocampus of rats. Five to six weeks after the beta40 injection, the rats showed learning deficits in the Morris water maze task and neuronal damage in the hippocampus, although the injection of beta40 or ibotenate alone did not result in cognitive deficits and hippocampal damage. Memantine (10, 20 mg/kg/day s.c. infusion for 6 weeks starting 24 h before the beta40 injection) significantly prevented learning deficits as measured for 4 days from 5 weeks after the beta40 injection, while a lower dose of memantine (5 mg/kg/day) and MK-801 (0.312, 0.624 mg/kg/day) did not have inhibitory effects on the learning deficits. The neuronal damage in the hippocampus, assessed as an elevation of the levels of the peripheral-type benzodiazepine-binding site (a gliosis marker for neuronal damage) produced by sequential intra-hippocampal injections of beta40 and ibotenate, at 6 weeks (39 days) after the beta40 injection, was significantly attenuated by memantine (10, 20 mg/kg/day) and MK-801 (0.624 mg/kg/day). These protective effects were also confirmed by histochemical examination (Cresyl violet staining of brain slices). In naive rats, MK-801 produced a significant learning impairment in the water maze task at a dose of 0.624 mg/kg/day, while memantine (20 mg/kg/day s.c. infusion) did not, although the beta40 plus ibotenate-induced hippocampal damage was lessened by both treatments. These results suggest that memantine and MK-801 exert protective effects on progressive neuronal damage, but that only memantine prevents memory impairment in hippocampal-lesioned rats, and that memantine may be a beneficial agent for the treatment of progressive cognitive dysfunction including Alzheimer's disease-type dementia.