Effects of amphetamine on the plus-maze discriminative avoidance task in mice

RATIONALE: The contradictory amphetamine effects on memory could be due to different protocols of amphetamine administration or the well-known anxiogenic effect of the drug. OBJECTIVE: The effects of different protocols of administration of amphetamine were investigated on mice tested in the plus-maze discriminative avoidance task (DAT), which provides simultaneous information about memory and anxiety. METHODS: Acutely pre- or post-training, 0.3, 1.0, or 3.0 mg/kg amphetamine-treated, 10-day chronically 3.0 mg/kg amphetamine-treated, 0.3 mg/kg amphetamine plus 0.25 mg/kg scopolamine and 3.0 mg/kg amphetamine plus 3.0 mg/kg tacrine-treated mice were conditioned to choose between two enclosed arms (one of which was aversive) while avoiding two open arms. Learning/memory was evaluated by the percentage time in the aversive enclosed arm (PTAV), and anxiety by the percentage time in the open arms (PTO). RESULTS: Given acutely before conditioning, amphetamine significantly decreased PTO in training, suggesting an anxiogenic effect, and significantly increased PTAV in the test, suggesting an amnestic action. Given acutely after the conditioning, no action of this drug on memory was found. After repeated treatment, the anxiogenic effect disappeared, while the amnestic effect remained. While no effects of subeffective doses of amphetamine and scopolamine co-administration were detected, tacrine attenuated the amnestic effect of amphetamine. CONCLUSIONS: Amphetamine has different effects on DAT when given pre- or post-training. While acute pre-training amnestic action is temporally correlated with an anxiogenic effect, there is tolerance to the anxiogenic but not to the amnestic effect after repeated administration. Because this acute amnestic effect of amphetamine is attenuated by tacrine, a possible relationship with cholinergic system cannot be discarded as a mechanism to amphetamine-induced amnesia in DAT.     

Temporal and pharmacological parameters of puromycin-induced amnesia

Mice were trained in step-down passive avoidance behavior. Bitemporal injections of puromycin (PM) were given either immediately or delayed until 24 hrs after training. PM produced a marked amnesia in both cases during retention testing 3 days later. The amnesia persisted during a second retention test 6 days after training. Of all the antibiotics, only PM is effective as an amnestic agent when injections are delayed 24 or more hours after training. Cycloheximide (CXM) was also injected bitemporally immediately after training. However, CXM produced a weaker amnestic effect even though it produced a much greater inhibition of cerebral protein synthesis, more rapidly, and of longer duration. In an effort to attenuate the amnesia produced by PM, in separate experiments, the mice were injected with combined injections of PM and CXM (bitemporally); mice were also given combined injections of PM (bitemporally) and amphetamine (subcutaneously). The amnesia produced by immediate injections of PM was not attenuated by either CXM or amphetamine. However, the amnesia produced by delayed injections of PM was attenuated by both CXM and amphetamine. These results suggest that delayed injections of PM (24 hours after training) block the e expression or retrieval of memory. This study also supports the contention that puromycin has two separate effects on memory with different temporal parameters depending on when the drug is injected relative to initial training.     

梓醇改善东莨菪碱诱导的学习记忆障碍及机制研究

目的研究梓醇对由东莨菪碱所致小鼠空间学习记忆障碍的影响和机制。方法小鼠随机分为4组:正常组、模型组(东莨菪碱,2 mg.kg-1)、奥拉西坦组(阳性药物,105mg.kg-1)和梓醇治疗组(9 mg.kg-1),采用水迷宫测试小鼠空间学习记忆功能。于实验前30 min腹腔注射东莨菪碱诱导小鼠学习记忆障碍模型,记录小鼠逃避潜伏期时间。水迷宫测试毕,处死小鼠,分离大脑皮质和海马,匀浆取上清液测大脑皮质和海马中乙酰胆碱(acetylcholine,ACh)和脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)的含量。结果①各组实验前逃避潜伏期无差异;给药东莨菪碱前后差异有显著性。②组间比较,与正常组比较,东莨菪碱导致记忆障碍;与东莨菪碱组比较,阳性药物奥拉西坦和梓醇治疗组逃避潜伏期明显缩短,ACh和BDNF含量明显增加(P<0.05)。结论小鼠注射东莨菪碱成功诱导学习记忆机能障碍模型。梓醇改善东莨菪碱诱导的学习和记忆障碍,其机制可能与促进BDNF表达,增加脑ACh含量有关。     

The effects of exifone, a new agent for senile memory disorder, on two models of memory in the mouse

The effects of exifone (ADLONE), hexahydro-2,3,4,3',4',5'-benzophenone, were tested in two models of memory in the mouse: habituation of exploratory activity and antagonism of amnesia induced by scopolamine in a passive avoidance task. In the first model, mice which had received exifone (128 and 256 mg/kg IP) 30 minutes before a 3 minute exposure to a staircase exploratory test showed a more marked decrease in exploratory activity in the same apparatus 24 hours later (habituation) than a control group indicating improved memory. Similar results were obtained with piracetam (512 mg/kg, IP). In the second model exifone (512 mg/kg PO), administered 60 minutes before both the learning and retention trials of a standard step-through passive avoidance, task partially antagonized the amnesia induced by 10 mg/kg scopolamine IP administered immediately after the learning trial. Similar results were obtained with piracetam (800 mg/kg PO). Taken together these results suggest that exifone facilitates memory function in simple rodent models in a manner consistent with its supposed therapeutic effects in man.     

Effects of bifemelane hydrochloride (MCI-2016) on experimental amnesia (passive avoidance failure) in rodents

To further predict the possible activity on memory disorders, the effect of MCI-2016 (bifemelane hydrochloride) was examined using the passive avoidance (PAR) failure technique as an experimental model of amnesia. The amnesia was produced either by post training treatments of electroconvulsive shock (ECS), scopolamine (mice) and cycloheximide or by pre-test injection of scopolamine (rats). In ECS-PAR failure model, the retention test was carried out 3 hr (3 hr experiment) or 24 hr (24 hr experiment) after ECS. MCI-2016 showed a significant improvement when administered just after ECS (3 hr experiment, 30 mg/kg, i.p.) or 0.5 hr before the retention test (24 hr experiment, 10-30 mg/kg, i.p.). Cahopantenate was only active in the 3 hr experiment (500 mg/kg, i.p.), and piracetam was rather active in the 24 hr experiment (60 mg/kg, i.p.). MCI-2016 (30 mg/kg, i.p.) prevented the scopolamine-induced PAR-failure. In this model, physostigmine (0.3 mg/kg, i.p.) exhibited a tendency to improve the failure. In another scopolamine-induced PAR failure model in mice, all of the test drugs showed a significant improvement at different dose levels. The effect of MCI-2016 (25-100 mg/kg, p.o.) was superior to those of piracetam, aniracetam and choline chloride. Higher doses of MCI-2016 were required to improve the cycloheximide-induced PAR failure. Considering the experimental conditions and results, it may be suggested that MCI-2016 ameliorates the amnesia possibly through its influence on memory consolidation and retrieval processes.     

Alleviation of scopolamine amnesia by different retrieval enhancing treatments

Mice were trained in a one-way active avoidance task to a criterion of 9/10 avoidances. Immediately following training they were injected with scopolamine hydrochloride (1 mg/kg SC) or with saline. Retention was assessed 3 days after training by 5 test trials on which the UCS was not present. Thirty min prior to the test, groups were injected with different doses of arecoline, d-amphetamine sulphate or with saline. Other scopolamine-treated mice were exposed to the CS or the UCS 24 hr prior to the test. The scopolamine-induced amnesia was attenuated by both 0.5 and 1.0 mg/kg arecoline and by 2.0 mg/kg d-amphetamine. Retention was also improved by exposure to the CS and the UCS. These data show that scopolamine amnesia can be alleviated by treatments which activate retrieval processes.     

D-ribose-L-cysteine enhances memory task,attenuates oxidative stress and acetyl-cholinesterase activity in scopolamine amnesic mice

d -Ribose-l -cysteine (DRLC) is an analogue of cysteine that has been shown to boost cellular antioxidant capacity by enhancing intracellular biosynthesis of glutathione (GSH). Deficiency of GSH has been implicated in the pathogenesis of Alzheimer's disease (AD), a neurodegenerative disorder associated with loss of memory. Thus, the use of antioxidants to prevent or retard the progression of memory deteriorations in persons with AD has been the focus of intense investigations. This study was carried out to evaluate the effects of DRLC on memory and scopolamine-induced amnesia, acetyl-cholinesterase activity, and oxidative stress in mice. Male Swiss mice were given oral administration of saline (10 ml/kg), DRLC (25, 50, and 100 mg/kg) or donepezil (1 mg/kg) 30 min before testing for memory performance using Y-maze and object recognition models. Another set of mice were also pretreated orally with saline, DRLC (25, 50, and 100 mg/kg) or donepezil (1 mg/kg) but in combination with scopolamine (3 mg/kg, i.p.) daily for 7 days. Thirty minutes after treatment on Day 7, memory function was then evaluated. The brain levels of acetyl-cholinesterase and oxidative stress parameters were assayed. DRLC significantly (p < .05) enhanced memory performance and attenuated scopolamine-induced amnesia. Increased acetyl-cholinesterase activity and oxidative stress, as shown by decreased antioxidant substrates (glutathione and catalase) and elevated malondialdehyde contents in mice with scopolamine amnesia were also attenuated by DRLC. Our findings suggest that inhibition of oxidative stress and acetyl-cholinesterase activity might contribute to the potential benefit of DRLC in persons with amnesia.     

Scopolamine inhibits cocaine-conditioned but not unconditioned stimulant effects in mice

RATIONALE: In animal models, cocaine cues contribute to the development of conditioned responses to the psychomotor stimulating and rewarding effects of the drug. OBJECTIVES: In the present study we investigated the effect of scopolamine, known to impair learning and memory, on cocaine-induced conditioned and unconditioned responses in Swiss Webster mice. METHODS: In the first experiment, mice were treated with saline/saline, saline/cocaine (20 mg/kg), scopolamine (1.0 mg/kg)/cocaine, or scopolamine/saline for 5 days. The treatments were paired with the locomotor activity test cage twice, on days 1 and 5. This allowed to determine: (a) the induction and expression of place-dependent sensitization (PDS) to the psychomotor-stimulating effect of cocaine and (b) place-dependent hyperlocomotion (PDH; i.e., conditioning) as defined by the response to saline injection in the test cage. In the second experiment, all injections were delivered in animals' home cage in order to induce place-independent sensitization (PIS) to cocaine and to avoid the development of PDH. In the third experiment, the effect of scopolamine (1.0 mg/kg) on the acquisition of cocaine-induced conditioned place preference (CPP) was investigated. RESULTS: Data from the first experiment suggest that pretreatment with scopolamine had no specific effect on the induction and expression of cocaine-induced PIS. However, scopolamine blocked cocaine-induced PDH. Results from the second experiment confirmed that scopolamine had no effect on the induction of PIS to cocaine. Results from the third experiment showed that scopolamine completely blocked cocaine-induced CPP. CONCLUSIONS: The finding that scopolamine blocked the conditioned behaviors, PDH and CPP, that develop after exposure to cocaine supports the hypothesis that cocaine cue reactivity in the paradigms tested is associated with learning and memory.     

Ganglioside GM1 attenuates scopolamine-induced amnesia in rats and mice

 Some experimental evidence suggests that the beneficial effects of monosialoganglioside GM1 on learning and memory could be related to an improving effect in central cholinergic function. The present study investigates the effects of GM1 on the memory impairment induced by scopolamine in rats or mice tested in passive (PA) and discriminative avoidance (DA) tasks, respectively. Wistar EPM-1 male rats and Swiss EPM-M1 male mice were treated daily IP with 50 mg/kg GM1 or saline for 7 or 14 days, respectively. Twenty-four hours after the last injection, GM1-treated animals received 1 mg/kg scopolamine (GM1-SCO) and saline-treated animals received 1 mg/kg scopolamine (SAL-SCO) or saline (SAL-SAL) IP. Twenty minutes later, the animals were submitted to PA or DA conditioning, and tests were performed 24 h later. The latency in entering the dark chamber of the PA apparatus (LD) presented by SAL-SCO rats was significantly decreased when compared to that presented by SAL-SAL animals. GM1-SCO animals showed an increased LD when compared to SAL-SCO animals and were not significantly different from SAL-SAL rats. GM1-SCO and SAL-SAL (but not SAL-SCO) mice spent significantly less time in the aversive enclosed arm of the discriminative avoidance apparatus when compared to the time spent in the non-aversive enclosed arm. The results are consistent with the interpretation that GM1 attenuates scopolamine-induced amnesia. Although not eliminating the participation of other transmitter systems, the present study indicates a possible role of central cholinergic transmission in the action of this compound on learning and memory. Received: 21 October 1997 / Final version: 8 June 1998     

Scopolamine and Pavlovian fear conditioning in rats: dose-effect analysis.

Muscarinic-cholinergic antagonism produces learning and memory deficits in a wide variety of hippocampal-dependent tasks. Hippocampal lesions produce both acquisition deficits and retrograde amnesia of contextual fear (fear of the place of conditioning), but do not impact fear conditioning to discrete cues (such as a tone). In order to examine the effects of muscarinic antagonism in this paradigm, rats were given 0.01 to 100 mg/kg of scopolamine (or methylscopolamine) either before or after a fear conditioning session in which tones were paired with aversive footshocks. Fear to the context and the tone were assessed by measuring freezing in separate tests. It was found that pretraining, but not post-training, scopolamine severely impaired fear conditioning; methylscopolamine was ineffective in disrupting conditioning. Although contextual fear conditioning was more sensitive to cholinergic disruption, high doses of scopolamine also disrupted tone conditioning. Scopolamine did not affect footshock reactivity, but did produce high levels of activity. However, hyperactivity was not directly responsible for deficits in conditioning. It was concluded that scopolamine disrupts CS-US association formation or CS processing, perhaps through an attenuation of hippocampal theta rhythm.     

Cholinergic influence on memory stages: A study on scopolamine amnesic mice

Objectives:

The study was planned to determine cholinergic influence on different stages of memory - acquisition, consolidation and recall in scopolamine-induced amnesia (memory impairment) in mice.

Materials and Methods:

To study acquision, consolidation and recall stages of memory, we administered scopolamine (0.75, 1.5 and 3 mg/kg ip) 30 minutes and five minutes prior to first trial acquisition and consolidation and 30 minutes prior to second trial recall of passive avoidance (PA) test, respectively, in separate groups. Tacrine (5 mg/kg po) and rivastigmine (5 mg/kg po) were administered one hour prior to first trial in separate groups which received scopolamine (3 mg/kg ip) 30 minutes and five minutes prior to first trial where as the control group received vehicle only.

Results:

In the control group, there was a significant (P < 0.01) increase in transfer latency time (TLT) in the second trial compared to first indicating successful learning. In scopolamine treated groups, administering scopolamine 30 minutes or five minutes prior to first trial did not show any significant (P > 0.05) change in TLT whereas mice treated with scopolamine 30 minutes prior to second trial showed significant (P < 0.01) increase in TLT in second trial as compared to the first. Both tacrine and rivastigmine administration in scopolamine treated mice showed significant (P < 0.05-0.01) increase in TLT in second trial as compared to first trial while the rivastigmine treated group showed greater percentage retention compared to tacrine treated group.

Conclusion:

Results show that acquisition and consolidation are more susceptible to the scopolamine effects than recall. Thus, it may be concluded that cholinergic influence is more on acquisition and consolidation as compared to recall.     

Asymmetrical dissociation of learning between scopolamine and Wy 4036, a new benzodiazepine tranquilizer

Summary Hungry rats, trained to drink milk rapidly in a small test chamber, received a single electric shock 30 min after injections of either scopolamine, a new benzodiazepine tranquilizer (Wy 4036), or saline. One week later, subgroups were tested for conditioned suppression of the drinking response under all drug conditions, according to a factorial design. Conditioned suppression transferred from saline to both drugs, across the same drug, and from scopolamine to Wy 4036, but not from the drugs to saline or from Wy 4036 to scopolamine. All groups tested under Wy 4036 showed supernormal suppression. The pattern of asymmetrical transfer was explained by a hypothetical neural conditioning model. The supernormal suppression caused by Wy 4036 was attributed to enhanced retrieval of the memory of the shock experience.     

State dependent and/or direct memory retrieval by morphine in mice

Mice were trained in step-down and step-through type passive avoidance learning tasks and given retention tests. Pre-training administration of morphine impaired retention, the effect recovering completely after an additional injection of the same dose of morphine given 30 min before the retention test. Amnesia produced by scopolamine, cycloheximide and electroconvulsive shock was also reversed by pre-test morphine. Pre-test saline also reversed the morphine-induced memory impairment to some extent, indicating that the recovery may partially be due to the state dependent effect. Thus, it is demonstrated that pre-test morphine not only state dependently but also directly reversed memory impairment in mice.     

Effects of acute doses of oxiracetam in the scopolamine model of human amnesia

The scopolamine model of amnesia has been used to test the pharmacodynamic efficacy of oxiracetam in 12 healthy volunteers. The subjects were divided into four experimental groups, according to a double-blind cross over incomplete randomized block design. After a baseline neuropsychological examination, each subject received in two separate sessions one of the following treatments, as acute oral doses: oxiracetam 800, 1600, 2400 mg or placebo. One hour after treatment scopolamine hydrobromide (0.5 mg) was given subcutaneously. The cognitive performance was tested before and 1, 2, 3 and 25 h after scopolamine administration. Scopolamine caused a deterioration of performance of verbal episodic memory, semantic memory and attention tests. In comparison to placebo, oxiracetam improved the overall test performance, with a statistically significant difference at the dose of 1600 mg on delayed recall of word lists, and showed dose-related antagonism of scopolamine-induced effects also on semantic memory and attention. The efficacy of an acute dose of oxiracetam in reducing scopolamine-induced cognitive impairment supports the potential usefulness of this pharmacological model of amnesia for studying the effects of cognition enhancers in humans.     

Effects of pretraining on subsequent cycloheximide induced amnesia

In the first experiment, mice were trained on a passive avoidance (PA) task, given one extinction trial, and then were injected with cycloheximide or saline shortly before retraining on the PA task. On a subsequent test trial, the performance of the cycloheximide group was inferior to the saline group, but superior to a cycloheximide group not given the pretraining experience. In the second experiment, one group of mice was given cycloheximide before each of two training sessions while another group received cycloheximide before the first training session and saline before the second. The group given cycloheximide before each training session was amnesic for both sessions to an equal degree, while the other group was amnesic for only the first session. The final test performance of the latter group was similar to that of a saline group not given any pretraining experience. These data seem to indicate that pretraining has limited effect on subsequent cycloheximide induced amnesia, and that such amnesia is the result of impaired memory formation rather than impaired memory retrieval.     

Pharmacological studies on sufoxazine (Y-8894). (I) Effects on experimental amnesia in mice

The effects of sufoxazine on various experimental amnesia models were studied using passive avoidance behavior in mice. Sufoxazine had no influence on learning and memory in intact mice. Sufoxazine, administered either immediately after CO2 exposure or 30 min prior to the acquisition trial, improved CO2 induced amnesia. It also improved both electroconvulsive shock (ECS) induced amnesia (administered immediately after the amnestic treatment) and scopolamine induced amnesia (administered immediately after the acquisition trial). The anti-depressant drugs, imipramine and desipramine had no ameliorative activity in any of these experimental amnesia models. These results suggest that sufoxazine improves amnesia experimentally induced by various methods.     

Anti-amnesic effect of dimemorfan in mice

(1) Dimemorfan, an antitussive for more than 25 years, has previously been reported to be a relative high-affinity ligand at sigma-1 (sigma(1)) receptor with the K(i) value of 151 nM. (2) To test whether dimemorfan has anti-amnesic effects similar to a sigma(1) receptor agonist, this study examined its effects on scopolamine- and beta-amyloid peptide-(25-35)-induced amnesia in mice. (3) Dimemorfan (10-40 mg kg(-1), i.p.) administered 30 min before the training trial, immediately after the training trial, or 30 min before the retention test significantly improved scopolamine (1 mg kg(-1), i.p.)- or beta-amyloid peptide-(25-35) (3 nmol mouse(-1), i.c.v.)-induced amnesia in a step-through passive avoidance test. Dimemorfan (5-40 mg kg(-1), i.p.) pretreatment also attenuated scopolamine (8 mg kg(-1), i.p.)-induced amnesia in a water-maze test. And, these anti-amnesic effects of dimemorfan, like the putative sigma(1) receptor agonist (+)-N-allylnormetazocine ((+)-SKF-10047), were antagonized by a sigma receptor antagonist haloperidol (0.25 mg kg(-1), i.p.). (4) These results indicated that dimemorfan has anti-amnesic effects and acts like a sigma(1) receptor agonist.     

Effects of VA-045 on learning and memory deficits in traumatic brain injury (TBI)-induced retrograde and anterograde amnesic mice

1. No specific regimen has been developed to treat post-traumatic amnesia in man. In the present study, we examined the effects of (+)-eburnamenine-14-carboxylic acid (2-nitroxyethyl) ester (VA-045), a novel derivative of apovincaminic acid, on learning and memory deficits associated with a mild traumatic brain injury (TBI) in mice.
2. Two kinds of amnesia, TBI-induced retrograde amnesia (TRA) and anterograde amnesia (TAA), were produced by means of post- and pre-acquisition head injury, respectively, by a simple weight-drop device. A novel procedure of water-finding task was used to assess learning and memory functions.
3. Both TRA and TAA mice were dramatically impaired in the task performance, with prolonged latencies for finding and drinking in either retention test or retest, indicating that retention was impaired in TRA mice while learning and retention were impaired in TAA mice.
4. VA-045 administered 30 min post-trauma in TRA mice dramatically shortened the prolonged latencies for finding and drinking in both retention test and retest, indicating that VA-045 significantly improved the retention deficit observed in TRA mice.
5. VA-045 administered 30 min post-trauma in TAA mice dramatically attenuated the prolonged latencies for finding and drinking in both retention test and retest, indicating that VA-045 significantly improved the learning and retention deficits observed in TAA mice.
6. Administration of VA-045 30 min pre-trauma in normal mice markedly attenuated the delay of latencies for finding and drinking after trauma in both retention test and retest, which shows that VA-045 significantly prevented learning and retention deficits after TBI.
7. Motor activities were not significantly affected by either the TBI or the chemical treatment at the time of task examination in either experimental model.
8. It is concluded that VA-045 may have potential effects on learning and memory deficits observed in either TBI-induced retrograde or anterograde amnesia.

     

Dissociation of the effects of scopolamine and d-amphetamine on a spontaneous alternation task

The immediate and carry-over effects of scopolamine and d-amphetamine were evaluated in a free running Y-maze spontaneous alternation task. The immediate effect of scopolamine (1.0 mg/kg) or d-amphetamine (5.0 mg/kg) was to reduce alternation to chance or to levels significantly below chance (persereration), respectively. On a second, non-drug test day alternation decreased in saline treated animals, but increased among mice which received scopolamine on Day 1. In contrast, upon retesting in the non-drug state, the performance of animals initially treated with d-amphetamine resembled that of saline treated mice. Subsequent experiments revealed that these effects could not be attributed to drug effects on peripheral mechanisms, memory consolidation, residual drug action or drug dissociated learning. It was concluded that the behavioral effects of scopolamine and d-amphetamine are qualitatively different. Whereas scopolamine disrupts habituation, d-amphetamine induces perservation independently of any effects on habituation.     

Reversal of ECS-induced amnesia by post-ECS injections of amphetamine.

Water deprived rats were trained to drink from a water spout within an apparatus on each of 2 days. On the third day, passive avoidance of the spout was induced by giving the animal a 0.3 sec, 5 mA footshock after 1 lick at the spout. A test for retention of the avoidance learning was given 48 hr following training. ECS administered through cortical electrodes at 15 sec following the footshcok impaired retention. The amnesia was attenuated when amphetamine (1 mg/kg) was injected immediately but not at 6 hr following the ECS. In a second experiment, attentuation of amnesia by amphetamine was not found when the ECS occured at 4 sec instead of 15 sec following the footshock. The results are interpreted in terms of reactivation by amphetamine of a consolidation process that was interrupted by ECS.