Modafinil facilitates performance on a delayed nonmatching to position swim task in rats

Modafinil is a wake-promoting drug approved by the FDA for the treatment of narcolepsy. Recent evidence suggests that modafinil may improve learning and memory processes. To further evaluate possible cognitive properties associated with modafinil, male Sprague-Dawley rats were tested in a delayed nonmatching to position (DNMTP) task. A modified water maze allowed animals to make one of two choices for the location of the escape platform. Each trial consisted of two swims. On the information swim (IS), only one choice was open to the animal for escape. One minute later, a choice swim (CS) presented the animal with two choices with the escape platform in the opposite position. There were 10 trials per day for 10 days. Rats received 0, 30, 55, or 100 mg/kg ip of modafinil 30 min prior to testing. Locomotor activity was also assessed. Animals that received 55 and 100 mg/kg made significantly more correct choices, indicating that higher doses of modafinil learned the task faster than did controls. While animals that received 100 mg/kg did exhibit an enhancement of locomotor activity, this effect did not result in more efficient goal-directed behavior. The evidence is consistent with previous research showing that modafinil facilitates cognitive processes.     

The effects of atipamezole, an alpha-2 antagonist, on the performance of young and aged rats in the delayed nonmatching to position task.

The present experiments were undertaken to study whether pharmacological activation of the noradrenergic system would improve age-related deficits in short-term memory. Thus, we investigated the effects the single dose administration (0.1, 0.3, 0.9 and 2.7 mg/kg, subcutaneously) or atipamezole, a specific alpha-2 adrenoceptor antagonist, had on the performance of young and aged rats in a delayed nonmatching to position task. After substantial training, aged rats made more errors at longer delays (4-30 seconds) than did young rats, although the percent correct responses at short delays (0-2 seconds) did not differ between young and aged rats. Atipamezole (0.1-0.9 mg/kg) did not improve the performance of young and aged rats in this task. Moreover, the highest dose (2.7 mg/kg) used increased the number of omissions and increased the latency to collect food pellets, indicating disruption of the performance of rats in this task. According to the present results, alpha-2 antagonist (administered peripherally at a single dose), which increases the release of noradrenaline, did not improve age-related deficit in short-term memory in rats.     

Effects of transient cerebral ischemia in gerbils on working memory performance in the delayed nonmatching to position task using a T-maze.

To examine the working memory performance, gerbils were tested in the delayed nonmatching to position task using a T-maze, and the effects of cerebral ischemia on the performance were examined. There were no significant differences between gerbils and rats in the alternation performance without delay and with the interrun intervals ranging from 10 to 810 sec. These data suggest that this task is useful for assessing working memory in gerbils as well as in rats. Scopolamine (0.1 and 0.2 mg/kg) impaired the working memory performance in both species. Bilateral occlusion of the common carotid arteries for 5 min severely impaired the choice accuracy in the gerbils 1 to 3 days after the operation. This memory impairment was observed even at the shortest interval. One month after the operation, partial behavioral recovery was observed in the ischemic gerbils, in spite of a marked loss of the pyramidal cells in the hippocampus CA1 sector. These data indicate that the working memory performance is highly vulnerable to the cerebral ischemia and that the ischemic operation transiently but severely impairs the acquisition process of the working memory in gerbils.     

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.     

Scopolamine differentially disrupts the behavior of male and female Wistar rats in a delayed nonmatching to position procedure

Evidence is available that pharmacological interference with the cholinergic system may disrupt behavior in experimental procedures designed to investigate learning and memory processes. Recently it has been suggested that the cholinergic system may be sexually dimorphic. The present experiment was designed to investigate whether or not manipulation of the cholinergic system differentially affected memory processes in both sexes. Male and female Wistar rats were exposed to a delayed nonmatching to position procedure and were challenged with increasing doses of scopolamine hydrobromide (a central and peripheral muscarinic receptor blocker) and scopolamine methyl bromide (which does not pass the blood-brain barrier). Response accuracy decreased in both sexes as the delay interval duration increased. Behavioral differences between saline-treated males and females were not observed. Response accuracy decreased dose-dependently after subjects were injected with scopolamine hydrobromide. Response accuracy also decreased after treatment with scopolamine methyl bromide, but to a smaller extent. Males showed less accurate responding after treatment with either drug than females. These results provide behavioral evidence for the hypothesis that cholinergic functioning may differ between the sexes.     

Facilitating effects of SR 57746A on short-term memory in an operant delayed alternation task in aged rats

The effects of SR 57746A during acquisition and on stabilized performance of a delayed alternation task in a Skinner Box (Model E 10.10, Coulbourn Instruments, Lehigh Valley, PA) were investigated in aged rats (22–26 months old). Test sessions consisted of repeated trials during which animals were first presented with a single lever (left or right) followed several seconds later by two levers. A press on the lever opposite to that presented previously (delayed alternation) was rewarded. The number of correct responses and the reaction times to the one- and two-lever presentations were recorded. SR 57746A (0.3 and 3 mg/kg p.o.) was first evaluated during the acquisition of the delayed alternation, given before each of 10 daily acquisition sessions to different groups of aged animals. The imposed delay was 5 sec. Afterward, training continued without drug until asymptotic performance was reached. Rats were then given repeated drug test sessions during which different intervals (5, 10, and 20 sec) were presented in a random order. During this phase, both young and aged animals received all the different treatments (SR 57746A at 0.3, 1, and 3 mg/kg and vehicle p.o.). Aged animals showed clear deficits during both acquisition and stabilized performance phases. SR 57746A, particularly at the highest dose tested (3 mg/kg p.o.), clearly increased response accuracy of aged animals both during acquisition of the delayed alternation and during stabilized performance. In the latter phase, the facilitation of response accuracy was observed only in conditions (10 sec retention delay) where aged animals showed a deficit compared with young animals. SR 57746A did not affect response accuracy during stabilized performance in young animals at any delay. The drug-induced increase in response accuracy in aged animals occurred at a dose of SR 57746A (3 mg/kg p.o.) that lengthened reaction times, particularly simple reaction times, during both acquisition and stabilized performance and also lengthened reaction times in young animals during the stabilized performance phase. These results suggest that SR 57746A specifically attenuates age-related short-term memory impairment in rats. © 1995 Wiley-Liss, Inc.     

Adrafinil disrupts performance on a delayed nonmatching-to-position task in aged beagle dogs

Previous studies in humans and dogs have reported beneficial effects of adrafinil on specific cognitive functions. The effects in dogs are limited to a single study examining discrimination learning. We wanted to further explore the cognitive effects of adrafinil in dogs. The purpose of the present study was to determine the effect of oral administration of adrafinil on visuospatial function in dogs. Eighteen aged beagle dogs were tested on a delayed nonmatching-to-position (DNMP) task 2 h following one of three possible treatments; 20 mg/kg of adrafinil, 10 mg/kg of adrafinil or a placebo control. All dogs were tested under each treatment for eight test sessions. A 2-day washout period was given between treatments and the order of treatments was varied. Treatment with 20 mg/kg of adrafinil produced a significant impairment in working memory as indicated by an increase in the number of errors over the 8-day test period. The disturbance of memory functions from adrafinil could be a result of increased noradrenergic transmission in the prefrontal cortex.     

Clonidine enhances delayed matching-to-sample performance by young and aged monkeys

Clonidine, an alpha-2 noradrenergic agonist, has been shown to alter cognitive performance in humans and animals. Included among the evidence are studies which differ in their conclusions regarding the question of whether clonidine administration improves delayed response (DR) performance by nonhuman primates. The present results indicated that clonidine administration to both young and aged monkeys results in a modest performance improvement as measured by one of the commonly employed versions of DR performance-delayed matching-to-sample (DMTS). The clonidine-induced enhancement of DMTS had a duration of at least 24 h in both age groups.     

Detecting drug effects on short-term memory function using a combined delayed matching and non-matching to position task

Operant delayed non-matching-to-position (DNMTP) and delayed matching-to-position (DMTP) have become standard techniques to investigate drug effects on short-term memory function in rats. However, these two tasks are normally conducted in isolation. Using two standard drugs, the 5HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), and the muscarinic antagonist scopolamine, this study looked at a two-choice operant task that essentially involved a mixed DNMTP/DMTP paradigm. Thus, DNMTP trials were interspersed with DMTP trials in a random sequence for the duration of a session. 8-OH-DPAT (0.03 mg/kg) slightly but significantly improved response accuracy in a delay-dependent fashion during DMTP but not DNMTP trials. The highest dose of 8-OH-DPAT (0.1 mg/kg) impaired accuracy during DNMTP trials independent of delay and had no significant effect during DMTP trials. Scopolamine (0.1 mg/kg) produced delay-dependent deficits in accuracy during DMTP trials but delay-independent impairments during DNMTP trials. Because both 8-OH-DPAT and scopolamine produced delay-dependent effects with DMTP trials types and either had no effect (8-OH-DPAT) or produced delay-independent impairments (scopolamine) during DNMTP trials types, it is suggested that DMTP trials had a greater dependence on short-term working memory function than DNMTP trials that probably relied more on positional (mediating) strategies for solving the task. Therefore, we believe that this mixed DNMTP/DMTP task offers greater potential for more reliable and discerning interpretation of data regarding short-term memory function in rodents than either of the paradigms performed in isolation.     

Contrasting effects of vasopressin,desglycinamide-vasopressin and amphetamine on a delayed matching to position task in rats

The effects of peripherally injected arginine vasopressin (AVP: 0–25 g/kg), its desglycinamide analogue (DGAVP: 0–25 g/kg), which is practically devoid of pressor activity, and d-amphetamine (AMP: 0–1.25 mg/kg) were studied using a delayed (0–32 s) matching to position task (Dunnett 1985). A limited hold for responding (20 s) was in operation. This task enables an accurate assessment of forgetting in rats. AVP reliably improved per cent correct performance, and this effect was substantiated by accuracy indices derived from signal detection theory (TSD). DGAVP, however, was inactive, suggesting that the parent peptide's pressor properties were responsible for its beneficial effects. AMP disrupted performance in a dose-related manner, and was the only substance to alter a TSD bias index (responsivity index, RI), indicating a degree of response repetition at the highest dose. These results are consistent with some earlier reports, and suggest that AVP may enhance memory by peripheral action, while AMP disrupts performance. Closer inspection of the data, however, suggested that the peptide reduced general responsiveness. A new index to measure bias (Sahgal 1987) suggested that AVP-treated subjects restricted their sample and choice responses to one side of the operant chamber, thereby achieving a spuriously high detection rate with few errors of commission (incorrect responses). It is concluded that AVP does not, after all, improve performance: on the contrary it has detrimental effects, and produces errors of omission (failure to respond).     

5-HT1A receptor agonists improve the performance of normal and scopolamine-impaired rats in an operant delayed matching to position task

A series of experiments examined the effects of 5-HT_1A ligands alone and in combination with the muscarinic antagonist scopolamine on short term working memory in the rat. The behavioural paradigm was a discrete trial, operant delayed matching to position task, with delays of 0, 5, 15 and 30 s. The 5-HT_1A ligands tested were the full agonist, 8-OH DPAT (0, 0.1, 0.3 and 1 mg/kg), the partial agonist, ipsapirone (0, 1, 3 and 10 mg/kg), and the purported antagonist, NAN 190 (0, 1, 2, and 4 mg/kg). 1-PP (0, 0.1, 0.3, 1 mg/kg), the major metabolite of ipsapirone, was also tested. The lowest dose of 8-OH DPAT significantly improved matching accuracy at the longest delay, whereas the highest dose impaired matching accuracy and increased the latency to respond. Ipsapirone also significantly improved the accuracy of performance at a dose of 3 mg/kg, but the doses of 1 and 10 mg/kg did not significantly affect performance. NAN-190, at the highest dose tested (4 mg/kg), impaired matching accuracy, whereas the two lower doses did not significantly affect performance. The highest dose also increased the latency to respond. 1-PP had no effect on performance. Scopolamine HBr (0.14 mg/kg) caused a delay dependent impairment in matching accuracy, and had no effect on missed trials or the latency to respond. Low doses of 8-OH DPAT (0.1 and 0.3 mg/kg) significantly attenuated the scopolamine induced accuracy impairment, whereas 1 mg/kg 8-OH DPAT potentiated the impairment. Ipsapirone (3 mg/kg) also significantly improved the performance of scopolamine impaired rats. NAN-190 increased the latency to respond and reduced the number of nose pokes made during the delays in scopolamine-treated rats, and tended to potentiate the scopolamine-induced accuracy impairment. 1-PP did not affect the performance of scopolamine treated rats. Taken together, these results suggest that modulation of 5-HT_1A receptors influences short term spatial working memory in the rat.     

Effects of physostigmine on memory test performance in normal volunteers

The effects of an intraveneous infusion of physostigmine (0.94 mg infused over 60 min) on performance in memory tests were studied in 12 young subjects. Drug effects were modest and are discussed in relation to results of physostigmine studies in Alzheimer patients.     

Effects of drugs of abuse and scopolamine on memory in rats: delayed spatial alternation and matching to position

 Drugs of abuse produce amnestic effects in humans and laboratory animals in a variety of tasks. Generally, only a few compounds have been examined in any particular procedure. It was the goal of the present studies to examine drugs of abuse of different pharmacological classes in rats responding under two behavioral schedules historically employed as experimental models of memory: spatial alternation and matching to position. One group of rats responded under a single-response spatial-alternation baseline with a 10-s delay and another group responded under a matching-to-position baseline with delay values of 3, 10 and 30 s. Performance under the spatial-alternation baseline was characterized by low variability and >90% accuracy. Under the matching-to-position baseline, saline control percent accuracy was >95% at 3 s, >85% at 10 s and >70% at 30 s. Under spatial alternation cocaine, d-amphetamine, pentobarbital, diazepam, phencyclidine, scopolamine and methscopolamine produced significant (P<0.05) effects on accuracy, whereas only cocaine, d-amphetamine, pentobarbital and phencyclidine disrupted accuracy under the matching-to-position baseline. These results suggest that spatial alternation may be a more sensitive baseline for determining drug effects on working memory in the rat. Received: 16 April 1997 / Final version: 25 November 1997     

Effects of benzodiazepine receptor ligands on the performance of an operant delayed matching to position task in rats: opposite effects of FG 7142 and lorazepam

The effects of a series of benzodiazepine (BZ) receptor ligands, ranging from a full agonist through to partial inverse agonists, were examined on short term working memory in the rat. The behavioural paradigm used was a discrete trial, operant delayed matching to position task, as originally described by Dunnett (1985), with delays of 0, 5, 15 and 30 s. The benzodiazepine receptor (BZR) full agonist lorazepam (0.25, 0.375 and 0.5 mg/kg) dose and delay dependently impaired matching accuracy. Lorazepam also increased the latency to respond and decreased the number of nose pokes made into the food tray during the delays. In contrast, the BZR partial agonist ZK 95 962 (1, 3, 10 mg/kg) did not affect matching accuracy, but did increase the speed of responding. The BZR antagonist ZK 93 426 (1.25, 5, 25 mg/kg) had no effects in this paradigm. The BZR weak partial inverse agonists Ro 15-4513 (0.1, 1 and 10 mg/kg) and ZK 90 886 (1, 3 and 10 mg/kg) did not affect accuracy of performance. However, both of these drugs increased the latency to respond and decreased nose poke responses. These motoric effects were particularly strong following 10 mg/kg Ro 15-4513. This shows that the effects of drugs on the accuracy of responding and on the speed of responding can be dissociated. The BZR partial inverse agonist FG 7142 had effects on matching accuracy that were dependent upon dose. The lowest dose of FG 7142 (1 mg/kg) significantly improved accuracy, whereas the highest dose (10 mg/kg) impaired accuracy. This impairment induced by FG 7142 (10 mg/kg) was accompanied by an increase in the latency to respond and a decrease in the number of nose pokes. Taken together, these results show that the accuracy of delayed matching performance can be modulated in opposite ways by the BZR full agonist lorazepam and a low dose of the BZR partial inverse agonist, FG 7142.     

Propranolol blocks chronic risperidone treatment-induced enhancement of spatial working memory performance of rats in a delayed matching-to-place water maze task

Rationale Atypical antipsychotics improve cognitive function, including working memory, in schizophrenia. Some atypical antipsychotics have been reported to activate the locus coeruleus and induce beta-adrenoceptor antagonist sensitive c-Fos-like immunoreactivity in the prefrontal cortex. Materials and methods The present study investigated the effects of chronic treatment of rats with risperidone (1 mg kg⁻¹ day⁻¹ s.c.), clozapine (10 mg kg⁻¹ day⁻¹ s.c.), or acidified saline vehicle control for 2, 4, or 8 weeks on spatial working memory performance in a delayed matching-to-place water maze task with a 60-s inter-trial retention interval with and without acute challenge with propranolol (10 mg/kg i.p.). Results Treatment with risperidone for 8 weeks, but not 2 or 4 weeks, significantly improved working memory performance. In contrast, treatment with clozapine for up to 8 weeks did not improve working memory. Acute challenge with propranolol blocked the improvement in working memory produced by chronic treatment with risperidone, but had no significant effect on performance in saline- or clozapine-treated animals. Conclusions The delayed matching-to-place water maze task may prove valuable in the investigation of the behavioural pharmacology of the cognitive effects of antipsychotic drugs. These data suggest that beta adrenoceptors may contribute to the cognitive effects of chronic treatment with atypical antipsychotics.     

Contrasting effects of the competitive NMDA antagonist CPP and the non-competitive NMDA antagonist MK 801 on performance of an operant delayed matching to position task in rats

The effects of the competitive NMDA antagonist CPP and the non-competitive NMDA antagonist MK 801 (dizolcipine) on short term working memory in the rat were investigated. The behavioural paradigm used was discrete trial, operant delayed matching to position, as originally described by Dunnett (1985), with delays of 0, 5, 15 and 30 s. These delays generated an orderly forgetting curve in control rats, with matching accuracy decreasing from approximately 100% at 0-s delay to approximately 75% at 30-s delay. Intraperitoneal (IP) administration of CPP (10 mg/kg) produced a markeddelay dependent impairment in performance, suggesting a specific effect on short term working memory. This effect was accompanied by a minor decrease in the speed of responding, and a slight increase in the number of missed trials. Lower doses of CPP had no significant effects on either matching accuracy or sedation. In contrast, IP administration of MK 801 (0.1 and 0.2 mg/kg) caused a markeddelay independent impairment in the accuracy of delayed matching performance, suggesting a non-specific disruption of performance. A lower dose (0.05 mg/kg) of MK 801 had no significant effect on matching accuracy. The two lower doses of MK 801 increased the number of nose pokes made during the delays and tended to increase the speed of responding, suggesting a stimulant-like action. The highest dose of MK 801 had the opposite effects and also decreased the number of trials completed. The results with CPP therefore support the hypothesized role of NMDA receptors in learning and memory, and the contrasting effects of these two NMDA antagonists support previous suggestions of different behavioural effects resulting from administration of competitive and non-competitive NMDA antagonists.     

毒扁豆碱对大鼠的镇痛效应及静脉注射毒扁豆碱与蛛网膜下腔注射吗啡的相互作用(英文)

目的 :观察在术后不同阶段静脉注射胆碱酯酶抑制剂毒扁豆碱对鼠痛阈的影响 ,以及静注毒扁豆碱和蛛网膜下腔注射吗啡的药物相互作用。方法 :6组SD大鼠 ,置入蛛网膜下腔和股静脉导管。采用辐射热刺激诱发的鼠腿撤退试验测痛阈 ,测试分别于术后 1～ 3h和术后 3d进行。动物分别接受静注毒扁豆碱、蛛网膜下腔注射吗啡及两者联合给药。比较术后 1～ 3h和 3d各种药物对痛阈的影响、联合给药与单独给药对痛阈的影响。药物的镇痛效应以最大可能效应的百分比 ( %MPE)表示。结果 :毒扁豆碱术后 1～ 3h静注导致 %MPE明显提高 ;毒扁豆碱与吗啡的联合给药效应在术后早期更明显 ;小剂量联合给药的镇痛作用明显大于双倍剂量单独给药的镇痛作用 ;联合给药的测得效应值明显大于估计叠加效应值。结论 :胆碱酯酶抑制剂毒扁豆碱在术后早期产生镇痛作用 ;静注毒扁豆碱与蛛网膜下腔注射吗啡的联合给药呈协同效应。     

Working and reference memory in rats in the three-panel runway task following dorsal hippocampal lesions.

Using a three-panel runway task, the influence of dorsal hippocampal lesions on working and reference memory in rats was investigated. Despite 20 postoperative training sessions, rats with hippocampal lesions were unable to perform the working memory task. In the acquisition process of the reference memory task, however, there was no significant difference between hippocampal- and sham-lesioned rats. On the other hand, rats trained preoperatively with a working memory procedure, and then subjected to hippocampal lesions, showed more errors (pushes made on the two incorrect panels of the three panel-gates located at four choice points) than did sham-lesioned rats. The increase in working errors induced by hippocampal lesions was not reduced during 10 subsequent re-training sessions. Hippocampal lesions had no effect on retention of the reference memory performance. The increase in working errors in hippocampal-lesioned rats was significantly reduced by treatment with the cholinesterase inhibitor physostigmine at 0.1 mg/kg and the cholinergic activating drug minaprine at 10 mg/kg. These findings suggest that lesions of the dorsal hippocampus selectively impair the ability to carry out the working memory task whether rats are trained preoperatively or postoperatively, and that the working memory loss in hippocampal-lesioned rats is mediated by lowering of the cholinergic function.     

阿魏酸钠对老年大鼠学习记忆能力改善作用及机制

<正>阿尔采末病(AD)是一种慢性原发、进行性脑变性病,病因复杂,发病机制尚不清楚,但有研究表明,AD患者认知功能下降与突触素(SYP)的丢失存在相关性。另有研究表明,神经生长因子(NGF)可促进海马内突触的重建来提高SYP的表达从而改善AD大鼠的学习记忆能力[1]。NGF必须与其特异性高亲和力受体酪氨酸激酶受体A(TrkA)结合才能     

Benzodiazepine receptor ligands have no specific action on working memory in a delayed conditional discrimination task in rats

We investigated effects of benzodiazepine (BDZ) receptor ligands on working memory in a delayed conditional discrimination (DCD) task. The BDZ receptor full agonist midazolam (0.1-1.0mg/kg) dose-dependently impaired performance independent of delay, indicating no specific effect on working memory. The non-sedative BDZ receptor partial agonist bretazenil (0.06-0.6mg/kg), the inverse agonist beta-CCM (0.05-0.45mg/kg), the partial inverse agonist FG 7142 (0.5-5.0mg/kg), the antagonist flumazenil (1-10mg/kg), and the antagonist ZK 93 426 (1-10mg/kg) did not significantly affect performance. It is concluded that BDZ ligands do not affect working memory in a positively-motivated DCD task. Midazolam also impaired performance in the no-delay condition, suggesting loss of stimulus control, possibly through an attentional impairment.