Amnesia In Animals Research Articles

Polarity directed solvent extracts from Bukiniczia Cabulica (Boiss.) Lincz. ameliorate scopolamine induced amnesia: HPLC-DAD polyphenolics analysis, cholinesterase, COX2, BACE1 inhibitory, anti-amyloid, antioxidant, molecular docking and behavioral correlates

Medicinal plants and polyphenolics of the family Plumbaginaceae have ethnomedicinal relevance in the management of neurological disorders. The current study was aimed to assess protective potentials of Bukiniczia cabulica (Boiss.) Lincz. against scopolamine induced amnesia. Quantitative polyphenolics assessment of the crude extract (Bc.Cme) was performed using HPLC-DAD analysis. In vitro cholinesterase (AChE/BChE), cyclooxygenase-2 (COX2) inhibitory and antioxidant (DPPH/ABTS) studies were performed following standard protocols. Spatial memory and neurocognitive benefits of the samples were tested in amnesic animals using Shallow Water Maze (SWM), Elevated Plus Maze (EPM), Y-Maze paradigms. The BACE1 inhibitory and anti-amyloid (Aβ) studies were performed using western blotting technique in amnesic animals. Binding affinity of the identified compounds against the target enzymes were evaluated via MOE software. A total of thirteen bioactive polyphenols including syringic acid (129.9 ± 0.9 mg/g), 4-Caffeoylquinic Acid (67.6 ± 0.3 mg/g), qurecetin-3-O-rutinoside (33.6 ± 0.5 mg/g), quercetin-3-feruloyl sophoroside (16.9 ± 0.3 mg/g), quercetin pentosyl hexoside (14.0 ± 0.3 mg/g), isorhamnetin-3-caffeoyl-7-glucoside (15.6 ± 0.5 mg/g), quercetin-3-(p-coumaroyl diglucoside)-7-glucoside (11.8 ± 0.3 mg/g), procyanidin trimer (10 ± 0.2 mg/g), were quantified. The Bc.Cme was found highly active against both AChE/BChE with IC50 values of 23.1 and 42.62 ug/ml respectively. In a DPPH and ABTS radical scavenging assay Bc.Cme considerable radicals scavenging activity. Further, Bc.Cme effectively inhibited COX-2 enzyme with IC50 value of 74.3 ug/ml. The Bc.Cme offered protection against scopolamine induced amnesia in various behavioral models. The BACE1 enzyme was inhibited significantly as compared to amnesia group animals and a considerable decline in Aβ load was observed in Bc.Cme treated animals. Affinity was observed for the identified compounds against target enzymes.

Beneficial Effect of Atomoxetine Treatment on Scopolamine-Induced Cognitive Impairments and Molecular Changes in Rats

Objective: Atomoxetine is a noradrenaline re-uptake inhibitory drug that is currently used in the pharmacological treatment of attention deficit/hyperactivity disorder in children, adolescents, and adults. Based on the findings that noradrenergic system is closely associated with learning and memory processes, dysfunction of this system might contribute to the pathophysiology of cognitive disorders. Therefore, atomoxetine, which alters the noradrenergic neurotransmission in the synaptic cleft, has a potential to modulate learning and memory functions in various areas of the central nervous system. In the present study, it was aimed to investigate the effects of atomoxetine treatment on the cognitive impairments in amnesic animals using behavioral and immunohistochemical methods. Method: Male Sprague-Dawley rats (adult, weighing 250-300 g) were used in the experiments. Atomoxetine at doses of 3 or 6 mg/kg (i.p.) was administered to the rats for 14 days. Experimental amnesia was induced in the animals by applying scopolamine (0.5 mg/kg, i.p.) injection. Following the treatment protocol, Morris water maze and passive avoidance tests were conducted to assess spatial and emotional learning and memory parameters of rats, respectively. Piracetam (300 mg/kg daily for 14 days) was used as reference drug in these experiments. In addition, motor performances of the animals were evaluated by activity cage and Rota-rod tests. Subsequent to behavioral tests, rats were euthanized and immunohistochemical analyses were performed to determine the alterations in the BDNF and NGF levels in the hippocampi of the animals. Results: In the Morris water maze test, amnesic rats found the hidden platform slower and spent less time in the target quadrant compared to the healthy controls. On the other hand, atomoxetine treatments significantly decreased the escape latencies, and also increased the target quadrant time values of the amnesic animals at both doses. Data obtained from the passive avoidance test showed that second transition latency values of the amnesic rats were significantly shortened with respect to the control animals; while atomoxetine treatment prolonged these shortened values significantly. It was observed that atomoxetine did not alter motor coordination or spontaneous locomotor activities of animals. Moreover, this drug increased the BDNF and NGF levels in the hippocampal sub-regions which were diminished by scopolamine administration. Conclusions: The obtained findings showed that atomoxetine treatment significantly improved the impaired learning and memory performances of the rats induced by scopolamine administration. Furthermore, anti-amnesic effects of this drug were concomitant with increased neurotrophic factors levels in the hippocampal brain regions. These results suggest a notable therapeutic potential of this drug in the treatment of dementia and several cognitive disorders; however, it should be underlined they are needed to be confirmed by well-designed clinical trials.

DNA methylation inhibition participates in the anterograde amnesia key mechanism through the suppression of the transcription of genes involved in memory formation in grape snails

The study of the amnesia mechanisms is of both theoretical and practical importance. The mechanisms of anterograde amnesia are the least studied, due to the lack of an experimental model that allows studying this amnesia type molecular and cellular mechanisms. Previously, we found that conditional food aversion memory reconsolidation impairment in snails by NMDA glutamate receptor antagonists led to the amnesia induction, in the late stages of which (>10 days) repeated training did not cause long-term memory formation. In the same animals, long-term memory aversion to a new food type was formed. We characterized this amnesia as specific anterograde amnesia. In the present work we studied the role of epigenetic DNA methylation processes as well as protein and mRNA synthesis in the mechanisms of anterograde amnesia and memory recovery. DNMT methyltransferase inhibitors (iDNMT: zebularine, RG108 (N-Phthalyl-1-tryptophan), and 5-AZA (5-Aza-2'-deoxycytidine)) were used to alter DNA methylation. It was found that in amnesic animals the iDNMT administration before or after shortened repeated training led to the rapid long-term conditional food aversion formation (Ebbinghaus saving effect). This result suggests that amnestic animals retain a latent memory, which is the basis for accelerated memory formation during repeated training. Protein synthesis inhibitors administration (cycloheximide) before or immediately after repeated training or administration of RNA synthesis inhibitor (actinomycin D) after repeated training prevented memory formation under iDNMT action. The earlier protein synthesis inhibitor effect suggests that the proteins required for memory formation are translated from the pre-existing, translationally repressed mRNAs. Thus, we have shown for the first time that the anterograde amnesia key mechanism is DNMT-dependent suppression of the transcription of genes involved in memory mechanisms. Inhibition of DNMT during repeated training reversed these genes expression blockade, opening access to them by transcription factors synthesized during training from the pre-existing mRNAs.

Neuroprotective Effect of Green Synthesized Iron Oxide Nanoparticles Using Aqueous Extract of Convolvulus Pluricaulis Plant in The Management of Alzheimer’s Disease

To evaluate the neuroprotective effect of green synthesized iron oxide nanoparticles using aqueous extract of whole plant of Convolvulus pluricaulis (CPIO) in scopolamine induced amnesia model. CPIO were orally tested at the dose of 100 mg/kg, 200 mg/kg and 400 mg/kg for neuroprotective effect in scopolamine induced amnesia mice. In addition, neurobehavioral studies were carried out using elevated plus maze, Morris water maze to evaluate learning and memory in mice in normal and scopolamine induced amnesia mice. CPIO 400 mg/kg showed a significant improvement in learning and memory in the normal and scopolamine induced amnesia mice in exteroceptive models. Significant differences were observed in lipid peroxidation, catalase and acetylcholinesterase by 400 mg/kg of CPIO treated amnesic animals, when compared with untreated and scopolamine group animals. The highest dose of CPIO exhibited significant neuroprotective effect in normal and scopolamine induced amnesia mice. They also showed significant improvement in learning and memory in exteroceptive and interoceptive models and so might be of value in Alzheimer’s treatment.

COGNITIVE-ENHANCING PROPERTIES OF MORINDA LUCIDA (RUBIACEAE) AND PELTOPHORUM PTEROCARPUM (FABACEAE) IN SCOPOLAMINE-INDUCED AMNESIC MICE.

Background:Cognitive disorders associated with aging have been successfully managed by African traditional medical practitioners using various plants. This study evaluated the cognitive enhancing potentials of Morinda lucida (L) Rubiaceae and Peltophorum pterocarpum (DC) ex. K Heyne in scopolamine induced amnesic animals.Materials and Methods:The anti-amnesic activity of the ethyl acetate extracts of Morinda lucida and Peltophorum pterocarpum at doses of 4 mg/kg, 6 mg/kg and 8 mg/kg were assessed in scopolamine induced amnesic mice using Morris water maze test model. Effect of the extracts on the histology of the hippocampus was also evaluated.Results:The ethyl acetate extract of Morinda lucida and Peltophorum pterocarpum ameliorated scopolamine induced memory deficit in the animals under study. There was no effect of the extract on the histology of the hippocampus. However, there was an increase in the density of cells in the hippocampus of treated group as compared to the untreated.Conclusion:Morinda lucida and Peltophorum pterocarpum showed considerable enhancement of cognition in scopolamine induced amnesic mice.

Bacopa monniera alleviates Nω-nitro- l-arginine-induced but not MK-801-induced amnesia: A mouse Morris water maze study

N-methyl- d-aspartate (NMDA) receptor and nitric oxide syntheses are the emerging target sites for development of novel drug molecules because their modulation affects the long term potentiation (LTP) process. NMDA receptor antagonists and nitric oxide synthase inhibitors induce amnesia in animals and therefore have been employed for evaluation of efficacy of several novel antiamnesic agents. Bacopa monniera Linn (syn. Brahmi) is commonly used in the ancient Indian medical system for improvement of memory deficit. We have earlier described the involvement of GABAergic and cholinergic system to account for the antiamnesic effects of B. monniera on diazepam- and scopolamine-induced amnesia. In extension to our previous study this study was designed to investigate the downstream mechanism of B. monniera by evaluation of its effect on MK-801 (an NMDA receptor antagonist) and N ω-nitro- l-arginine ( l-NNA) (a nitric oxide inhibitor) induced memory deficit. We used a Morris water maze scale and compared the degree of reversal of amnesia induced by the two agents. Male Swiss albino mice were subjected to a Rota-rod muscle incoordination test followed by water maze tasks. Our data revealed that l-NNA and MK-801 produced anterograde and retrograde amnesia and B. monniera significantly attenuated the l-NNA-induced anterograde amnesia, partially reversing l-NNA-induced retrograde amnesia. On the other hand, B. monniera neither attenuated the MK-801-induced anterograde amnesia nor improved retrograde amnesia caused by it.

Involvement of GABA-B receptors of the dorsal hippocampus in the inhibition of morphine-induced amnesia by morphine sensitization

Results Morphine-induced amnesia was reversed in morphinesensitized mice which had previously received once daily injections of morphine for 3 days. The inhibition of morphine-induced amnesia in animals that had previously received the 3-days morphine treatment was significantly decreased by once daily injections of the different doses of GABA-B receptor agonist, baclofen prior to s.c. injections of morphine. Amnesia induced by pre-training morphine had no significant change in mice which had previously received once daily injections of CGP35348 plus an ineffective dose of morphine for 3 days. Conclusions The present results indicate that GABA-B receptors of the dorsal hippocampus may play an important role in the inhibition of morphine-induced amnesia by morphine sensitization.

Effects of San-Yu-Tang on the Cycloheximide-Induced Amnesia in Rats

The effects of San-Yu-Tang (SYT)on cycloheximide (CXM)-induced amnesia were assessed by passive avoidance in rats. Oral SYT administration (0.5 or 1g/kg for 1 week) significantly prolonged step-through latency in the amnesic animals. This beneficial effect of SYT on CXM-induced amnesia was enhanced by 8-OH-DPAT (a partial agonist of the 5-HT(subscript 1A) receptor), but reduced by scopolamine (a muscarinic antagonist) and p-chloroamphetamine (a 5-HT releaser) and baclofen (a GAGA(subscript B) receptor antagonist). These results suggest that SYT enhances memory functions in amnesic rats, at least in part, by increasing the activity of the muscarinic and GABA(subscript B) receptors, and decreasing the activity of the serotoninergic system.

Perirhinal cortex lesions produce variable patterns of retrograde amnesia in rats

Two experiments examined the contribution of the perirhinal cortex (PRh) to retrograde memory for the location of a platform in a water maze. In a previous study, we found that electrolytic lesions of the PRh produced retrograde amnesia, without a temporal gradient, for water-maze problems acquired 4 weeks and 2 days before surgery [Behav. Brain. Res. 114 (2000) 119]. In Experiment 1, we used the same mixed design as in our previous report (time of learning was a within-subjects factor), but PRh lesions were made by aspiration. Contrary to our earlier report, these PRh rats displayed good retention of both platform locations. Combined, these findings indicate that the lesion method may contribute importantly to the pattern of deficits observed. Experiment 2 was conducted similar to Experiment 1, except that a completely between-subjects design was used (time of learning was a between-subjects factor). Rats that received PRh lesions approximately 2 days after the last training session displayed impaired retention of the platform’s location, whereas rats that received PRh lesions 4 weeks after training did not. This finding of a temporally graded retrograde amnesia is consistent with our earlier report, and further suggests that the involvement of the PRh in the retention of water-maze problems is time-limited. However, also consistent with our earlier report, the PRh-lesioned rats in Experiment 2 that displayed a retention deficit rapidly reacquired the task. This finding, combined with the negative findings in Experiment 1, suggests that the contribution of the PRh to retrograde memory for platform locations is subtle and may not be due to impaired spatial memory abilities. Additionally, the conflicting results of Experiments 1 and 2 underscore the importance of the design employed in studies of retrograde amnesia in animals.

Brain neurotransmitter receptor binding and nootropic studies on Indian Hypericum perforatum Linn.

The high affinity binding sites for serotonin and benzodiazepine in the frontal cortex, for dopamine in the striatum and muscarinic cholinergic receptors in the hippocampus were investigated in the brains of Charles Foster rats treated for 3 days. Transfer latency on elevated plus maze (TL), passive and active avoidance behaviour (PA and AA) and electroconvulsive shock (ECS) induced amnesia were also studied. Pilot studies indicated that single dose administration of Indian Hypericum perforatum (IHp) had little or no acute behavioural effects and hence the extract of IHp was administered orally at two dose levels (100 and 200 mg/kg, p.o.) once daily for 3 consecutive days, while piracetam (500 mg/kg, i.p.), a clinically used nootropic agent, was administered acutely to rats as the standard nootropic agent. Control rats were treated with an equal volume of vehicle (0.3% carboxymethyl cellulose). The results indicate that IHp treatment caused a significant decrease in the binding of [3H] spiroperone (DA-D2 receptor) to the striatum and an increase in the binding of [3H] ketanserin (5-HT2A receptor) and [3H] flunitrazepam (BDZ receptor) to the frontal cortex in rats. Preliminary pharmacological studies with IHp extract indicate the presence of two major behavioural actions, namely, antidepressant and anxiolytic. The present findings tend to elucidate the mechanism of earlier observations, the downregulation of the dopamine D2 receptor being consonant with anxiolytic and the upregulation of 5-HT2A and BDZ receptors being consonant with antidepressant activity. Piracetam when given alone, shortened the TL on days 1, 2 and 9 day and also antagonized the amnesic effects of ECS on the TL significantly, whereas IHp antagonized the amnesia produced by ECS. IHp had no significant effect per se on the retention of the PA in rats but produced a significant reversal of ECS induced PA retention deficit. Piracetam showed a significant facilitatory effect per se on PA retention and also reversed the ECS induced impaired PA retention. In the AA test, piracetam facilitated the acquisition and retention of AA in rats but IHp had no effect per se. Both the doses of IHp and piracetam significantly attenuated the ECS induced impaired retention of AA. These results indicate a possible nootropic action of IHp in amnesic animals, which was comparable qualitatively to piracetam.

Long-Lasting Antiamnesic Effect of a Novel Anticholinesterase Inhibitor (MF268)

In the present study a short (120 min) and long-lasting (360 min) antagonism of scopolamine-induced amnesia in rats was investigated in an eight-arm radial maze, by (3a S, 8a R)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indol-5-ol[8-(cis2,6-dimethyl-morpholin-4-yl)octyl]-carbamate L-bitartrate hydrate (MF268), a new cholinesterase inhibitor. Upon completing the training session, the rats were orally administered increasing doses of MF268 (2, 3, 6, 7, and 8 mg/kg) 60 min prior to SC injection of scopolamine (0.25 mg/kg). Following a further 60 min the rat was placed in the maze. The reversal of scopolamine-induced impairment was characterized by an inverted U-shaped dose–response curve. A significant reduction in the number of errors, and time taken to complete the maze was observed with a dose of 6 mg/kg. The compound improved memory retention without affecting scopolamine-induced hypermotility. When the same dose was administered 360 min prior to the test a significant reduction in the number of amnesic animals was observed, whereas no cognitive improvement was detected when either 1-Benzil-4-[(5,6-dimethoxy-1-indanon)-2-yl]-methyl piperidine hydrochloride (E2020) (0.25 mg/kg) or tacrine (0.5 mg/kg) were administered 360 min prior to the test. The kinetics of whole-brain cholinesterase confirmed the long-lasting activity for MF268. A clinical relevance for the use of MF268 in AD treatment is suggested.

An inverted U-shaped curve for heptylphysostigmine on radial maze performance in rats: comparison with other cholinesterase inhibitors

The potential of heptylphysostigmine tartrate (pyrrolo [2,3b] indol-5-ol, 3,3a,8,8a-hexahydro-1,3a,8-trimethylheptylcarbamate [ester, (3aS-cis)]) (MF201), a new second-generation cholinesterase inhibitor, to antagonize scopolamine-induced amnesia in rats was assessed in an 8-arm radial maze. Upon completing the training session, the rats were orally administered increasing doses of MF201 (2, 3, 4, 6 and 8 mg/kg) 60 min prior to a s.c. injection of scopolamine (0.25 mg/kg). 9-Amino-1,2,3,4-tetrahydroamino-acridine hydrochloride hydrate (tacrine) (0.25, 0.37, 0.5, 1 and 2 mg/kg), 1-benzil-4-[(5,6-dimethoxy-1-indanon)-2-yl]-methyl piperidine (E2020) (0.125, 0.18, 0.25 and 0.5 mg/kg) and physostigmine (0.15, 0.25, 0.5 and 1 mg/kg) were orally administered and rats were tested in the same task. As previously described, scopolamine induced an impairment in radial maze performance, measured in terms of total number of errors, total time taken to complete the task and the percentage of amnesic animals. The reversal of scopolamine-induced impairment was characterized by the presence of an inverted U-shaped dose-response curve. A significant antagonistic effect was achieved with a dose (mg/kg) of 0.25 for E2020, 0.5 for tacrine and physostigmine and 3, 4 and 6 for MF201, the latter manifesting a broader spectrum of activity (3–6 mg/kg). While the maximal active doses restored the scopolamine-induced modified pattern of arm entry, they were ineffective in reducing hypermotility, suggesting the drugs have a specific effect on cognitive function.

Concussion-induced retrograde amnesia in rats

Three experiments were conducted to investigate the characteristics of retrograde amnesia (RA) induced by concussion in rats. In Experiment 1, rats receiving experimental concussion shortly after training in a single punishment trial exhibited severe forgetting on a retention test 48 h later. In the second experiment, rats receiving a concussion within 6 h after training showed severe RA, while those receiving concussion one day to five days after training exhibited progressively weaker amnesia. In Experiment 3, amnesic animals in one group received pretest noncontingent foot shock as a reminder treatment. This pretest cue significantly increased the cross-through latency, thus indicating a reduction in the memory deficit resulting from concussion. These results suggest that experimental concussion can be an effective method to induce retrograde memory loss in rats; that the RA caused by concussion is time-dependent; and that concussion-induced RA can be alleviated by a pretest cue,indicating that the underlying mechanism of concussion-induced RA is more likely to be a retrieval deficit than a consolidation failure.

Lack of the development of morphine tolerance in experimental amnesia: role of arginine vasopressin

The development of tolerance to morphine analgesia in amnesic model mice and the role of arginine vasopressin (AVP) in the underlying mechanism was examined. Hypoxia, brain ischemia, scopolamine and electroconvulsive shock (ECS) manipulation caused amnesia in the step-through type passive avoidance learning test performed at 24 h after the training trial. The amnesic state lasted for at least 3 days and recovered to naive control level on the 20th day after each manipulation. In all amnesic groups, radioimmunoassayable AVP content in hypothalamus was decreased, in particular, the reduction was significant in hypoxia and ischemia induced amnesic animals, then recovered to the control level by 20 days after each treatment. Daily morphine, 10 mg/kg, s.c. easily resulted in the development of tolerance to the analgesic effect in control animals. however, such treatment failed to develop tolerance in amnesic model animals, leaving the analgesic effect unchanged to the control levels. Daily pretreatment with i.c.v. AVP, dose-dependently reinstated the development of tolerance in amnesic model mice. When morphine injection was started from 20 days after the amnesia inducing treatment, tolerance developed as in a similar pattern as in control animals. Thus, amnesic model mice are deficient in brain AVP levels, and consequently, a certain level of AVP in the hypothalamus is required for maintaining the normal function such as the development of tolerance to morphine and the recovery from amnesia.

Strength of scopolamine-induced amnesia as a function of time between training and testing

Variations in the strength of scopolamine-induced amnesia as a function of age of the habit were studied in Swiss Webster mice. Animals were trained in an active avoidance task to a criterion of 9/10 avoidances and immediately following training injected with scopolamine hydrochloride (1.0 mg/kg) or saline. Retention of the avoidance learning was evaluated by testing different groups of animals 1, 3, 7, 10, 14, and 28 days following training. The retention test consisted of five trials in which the CS but not the UCS was presented. Results indicated that saline-treated mice exhibited near-perfect retention up to 14 days post-training with forgetting beginning to be apparent at 28 days. Scopolamine treatment produced strong amnesia in animals tested 1 and 3 days post-training but normal retention in animals tested 7 and 10 days after learning. The amnesia abruptly reappeared at 14 days after which time it remained stable. The marked similarity of the scopolamine retention curve to changes in the strength of memory of discrimination learning in undertrained rats reported by Deutsch suggested that scopolamine resulted in the storage of a weak memory of the avoidance response. To explore this idea further we trained mice to a criterion (4/5) which would result in a weak avoidance response and tested different groups 1, 3, 10, 14, and 28 days following learning. Results showed that strength of the memory of avoidance learning increased up to 10 days and then decreased abruptly at 14 days thus replicating the general shape of the retention curve produced by injecting scopolamine following strong training. These data suggest that scopolamine disrupts processes essential for the formation of durable memories.

The performance of amnesic subjects on tests of experimental amnesia in animals: delayed matching-to-sample and concurrent learning

A group of amnesic Korsakoff subjects and a group of alcoholic controls were trained on a test of visual recognition, delayed matching-to-sample with trial unique stimuli. This test was modelled on comparable tasks used in the development of animal models of human amnesia. It was found that the Korsakoff subjects were severely impaired when the task difficulty was increased by lengthening the retention delay beyond 10 sec or by increasing the number of items intervening between sample presentation and test. The amnesic subjects were also impaired on the acquisition of a set of concurrent visual discriminations. These results bear clear similarities to those obtained from experimental amnesic syndromes in monkeys.

マウスにおけるプロリン特異性エンドペプチダーゼ阻害薬の抗健忘様効果

Based on the results of a previous report that prolyl endopeptidase (PPCE) inhibitors facilitated the acquisition of active avoidance response and retarded the extinction of the response, further studies were made on the effect of PPCE inhibitors on learning and the memory process. Using mice, tests were performed both in the light-dark discrimination Y-maze task and the lever-press task of the water reinforcement schedule, and mice were also tested in the acquisition and retention of one-trial "step-through" passive avoidance task. The effect of PPCE inhibitors were investigated both in control and electroconvulsive shock- or scopolamine-induced amnesic animals. Z-Pro-p, the most potent inhibitor among 5 compounds tested in this study, and arginine vasopressin (AVP) facilitated the learning process and retarded the extinction of the acquired response in all tests. Suc-Pro-p was also effective in the Y-maze and passive avoidance test. Thus, the effect of the test compounds were parallel with their in vitro activities as PPCE inhibitor. These results suggest that the anti-amnesic effect of PPCE inhibitors is partially attributable to their effect on the breakdown of the biologically active peptides which are involved in the memory process, such as AVP, in the brain.

P-49) - Effects of sufoxazine (Y-8894) on learning and memory in animals —— Investigation in intact and amnesic animals

P-49) - Effects of sufoxazine (Y-8894) on learning and memory in animals —— Investigation in intact and amnesic animals

Effects of cycloheximide, a protein synthesis inhibitor, on mouse brain catecholamine biochemistry

Cycloheximide (CXM), a protein synthesis inhibitor, has been shown to result in a marked inhibition of central catecholamine (CA) synthetic mechanisms at doses that cause amnesia in animals. Unlike other inhibitors of CA synthesis no significant depletion of whole brain NE or DA concentrations was observed 0.75, 1, 2, 3, 4, 6, 17, or 24 hours after administration of CXM (120 mg/kg) to C57BL/6J mice. In order to investigate the underlying basis of maintenance of CA levels in face of CA synthesis inhibition, the effects of CXM on in vitro release of 3H-NE was studied in mouse hypothalamic slices. CXM, in a dose related manner, significantly inhibited the potassium stimulated release of NE from hypothalamic slices. Anisomycin, another protein synthesis inhibitor, similarly inhibited NE release. These studies further document the effects of protein synthesis inhibitors on CA mechanisms and suggest that disruption of CA biochemistry may play a role in the amnesia observed after administration of protein synthesis inhibitors.

Clobazam: Induction of hyperlocomotion in a new nonautomatized device for measuring motor activity and exploratory behavior in mice: Comparison with diazepam and critical evaluation of the results with an automatized hole-board apparatus (?Planche � Trous?)

Clobazam, a 1,5-benzodiazepine, and diazepam, a 1,4-benzodiazepine, were tested for their influence on motor activity and exploratory behavior in mice in an automatized hole-board apparatus with two light beams (“Planche a trous”) and in a nonautomatized motility-exploration (MOTEX) device, designed by Weischer 1976. Clobazam at oral doses of 5 to 80 mg/kg caused a marked increase in locomotion (79% to 122%) under MOTEX conditions, whereas results with the hole-board device were inconsistent and misleading: Enhanced locomotion was represented as reduced motor activity in terms of light-beam crossings. Exploratory behavior was reduced by clobazam in both MOTEX and Planche a trous at ED50 values of 33 and 67 mg/kg orally (p.o.), respectively. Diazepam at oral doses of 1 to 10 mg/kg slightly but not significantly increased locomotion in MOTEX and reduced motor activity in the hold-board test (ED50 = 3.8 mg/kg). Exploratory behavior was inhibited under both conditions at ED50 values of 3.2 and 6.7 mg/kg p.o., respectively. The inability of a two light-beam system to properly examine locomotor activity (particularly when peripheral areas of the apparatus are favored by the animals) is considered the reason for misleading results obtained with clobazam in the hold-board test. The marked increase in locomotion induced by clobazam in a nonautomatized apparatus (MOTEX) is discussed in terms of disinhibitory effects in connection with the fact that clobazam does not induce amnesia in animals and man.