Scopolamine in rats impairs acquisition but not retention in a 14-unit T-maze

To follow up a previous report noting that scopolamine impaired acquisition performance of young rats in a shock-motivated 14-unit T-maze, the present study assessed the effects of muscarinic antagonism on retention aspects of the same task. The broader objective was to further the investigation of possible defects in cholinergic neurotransmission that might underlie the age-related impairements previously observed in this task. Young (3-month) male F-344 rats were given preliminary training to criterion in one-way active avoidance in a straight runaway. Then on the first day of complex maze training, each rat received 5 acquisition (AQ) trials followed by a second 10-trial retention (RET) session conducted the following day. Subjects were assigned to one of eight groups receiving an intraperitoneal injection of either scopolamine hydrochloride (1.0 mg/kg) or saline as follows: (a) 30 min prior to training on the first day (PRE-AQ); (b) 30 min prior to training on both the first and second day (PRE-AQ-RET); (c) immediately after completing the trial on the first day (POST-AQ); (d) 30 min prior to testing on the second day (PRE-RET). Dependent measures included errors, alternation errors, run time, number of shocks, and total shock received. On the first day of maze training, all performance measures except for alternation errors were significantly higher for the two acquisition groups (PRE-AQ and PRE-AQ-RET) compared to all other groups which did not differ significantly. While on the second day the PRE-AQ group recovered on all measures to levels comparable to other groups, the PRE-AQ-RET group remained impaired throughout training on all performance measures and appeared to maintain an alternation strategy for maze acquisition. Retention aspects of this task appeared unaffected as none of the other groups differed significantly in performance. Thus, further evidence of a scopolamine-induced cognitive impairment in acquisition of this task was noted but was manifested only when given throughout training. These results suggest that the dose of scopolamine used impaired encoding processes while leaving storage and retrieval mechanisms intact.     

石杉碱甲和乙促进小鼠的空间辨别学习和记忆

石杉碱甲和乙是从石杉科石杉属植物蛇足石杉[Huperzia scrrata(Thunb.)Trev.]中分得的二个新生物碱。“Y”迷宫实验表明,ip Hup-A 0.075～0.125 mg/kg或Hup-B 0.4～0.8mg/kg,均能明显促进小鼠的空间辨别学习,并能显著预防CO₂产生的短时识别障碍,促进记忆保持和记忆再现。ig Hup-A 0.1～0.3 mg/kg或Hup-B 0.8 mg/kg也有促进学习的作用。促进作用Hup-A>Phys>Hup-B。剂量与效应曲线呈倒U型。     

Phencyclidine disrupts long- but not short-term memory within a spatial learning task

In the first experiment rats with 1, 2, 3 or 4 mg/kg phencyclidine (PCP), or saline injections were tested for acquisition or retention of a cheese board spatial task (dry land version of a water maze). Results indicate that relative to controls or rats with injections of 1 and 2 mg/kg PCP, rats with 3 or 4 mg/kg PCP injections were impaired in acquisition and retention of the task as measured by increased distances traveled to find the correct food location. This impairment was primarily observed in between days but not within days performance. In the second experiment rats with 4 mg/kg PCP or saline injections were tested for memory performance of a delayed spatial matching-to-sample task. Results indicate that relative to controls rats with 4 mg/kg PCP injections were not impaired at either 1–5 or 30 s delays. It is suggested that PCP through its blocking action of the NMDA receptor mediates long- but not short-term memory for spatial location information as well as the ability to retrieve previously learned spatial location information.     

Age-dependent effects of neonatal methamphetamine exposure on spatial learning

Neonatal rats exposed to (+)-methamphetamine (MA) display spatial learning and reference memory deficits in the Morris water maze. In separate experiments the emergence and permanence of these effects were determined. Twenty litters were used in each experiment, and two male/female pairs/litter received saline or MA (5 mg/kg four times a day) on postnatal days (P) 11-20. In experiment 1, one MA and one saline pair from each litter began testing on either P30 or P40, whereas in experiment 2, testing began on P180 or P360. Animals received trials in a straight swimming channel and then in the Morris maze (acquisition, reversal, and reduced platform phases). In both experiments, MA-treated groups showed impaired learning in the platform trials and impaired reference memory in the probe trials, which were largely independent of age. The P30 and P40 MA impairments were seen on acquisition and reduced platform trials but not on reversal. In the probe trials, MA effects were seen during all phases. The P180 and P360 MA-induced deficits were seen in all phases of the platform trials. In probe trials, deficits were only seen during the reversal and reduced platform phases. The results demonstrate that neonatal MA treatment induces spatial learning and reference memory deficits that emerge early and persist until at least 1 year of age, suggesting permanence.     

The effects of -cycloserine and MK-801 on the performance of rats in two spatial learning and memory tasks

The present study was undertaken to investigate the effects of modulation of the (NMDA) receptor on learning and memory. Thus, the performance of rats treated with -cycloserine, a partial agonist at the glycine recognition site of the NMDA receptor complex, and MK-801, a noncompetitive NMDA receptor antagonist, either alone or concurrently were assessed in radial arm maze and water maze tasks. Administration of MK-801 (0.1 mg/kg, i.p.) impaired acquisition in the water maze (increased escape latency and distance) and working memory in the radial arm maze (increased re-entries) in rats. Moreover, in the radial arm maze, MK-801 disrupted locomotion (increased latencies and decreased arm entries per minute) and impaired the acquisition of reference memory (increased number of errors) performance of rats. -Cycloserine (0.03, 0.3, 1.0, 3.0, 10 mg/kg, i.p.) had no effects on acquisition or memory performance of control or MK-801-treated rats in either of these tasks. However, -cycloserine (0.03, 0.3, 3.0 mg/kg) reversed the MK-801-induced disruption in locomotion. Furthermore, 3.0 mg/kg -cycloserine increased behavioral activity and also decreased the time needed to complete the task in control animals. To conclude, our results suggest that the consequences of NMDA receptor modulation on learning and memory processes and sensorimotor functions may be functionally different or have distinct anatomical locations.     

Nefiracetam (DM-9384): effect on eyeblink classical conditioning in older rabbits

The nootropic compound nefiracetam was evaluated in 88 older rabbits in a 750-ms delay paradigm of eyeblink classical conditioning (EBCC). Rabbits (mean age=28.7 months) were assigned in groups of eight to one of six conditions in experiment 1: paired tone conditioned stimulus (CS)-corneal airpuff unconditioned stimulus (US) presentations and 1, 3, or 10 mg nefiracetam/kg or sterile saline vehicle; explicitly unpaired CS and US presentations and 3 mg nefiracetam/kg or sterile saline vehicle. Animals in the paired conditions received 10 daily sessions of 90 paired trials and animals in the unpaired conditions received 10 daily sessions of 180 unpaired CS and US presentations. The six conditions in experiment 2 were 5, 10, and 15 mg nefiracetam/kg and vehicle in 15 sessions of paired presentations; 10 mg nefiracetam/kg and vehicle in 15 sessions of unpaired conditioning. In both experiments 1 and 2, acquisition measured by trials to learning criterion was significantly faster at the 10 mg/kg dose of nefiracetam. In the repeated measures analyses comparing six doses in the paired conditions, all dependent measures [percentage conditioned responses (CRs), CR amplitude, and response latency] indicated significantly better conditioning in rabbits treated with 10 mg nefiracetam/kg, but this dose did not increase motor responding or responding in the unpaired condition. Nefiracetam facilitated acquisition of EBCC in older rabbits. EBCC is performed poorly by older humans and is seriously impaired in Alzheimer's disease. These preclinical data in an animal model with clear parallels in humans suggest that nefiracetam may prove effective as a cognition enhancer in clinical trials.     

Task-dependent effects of the antidepressant/antipanic drug phenelzine on memory

 Phenelzine (PLZ) is a non-selective monoamine oxidase (MAO) inhibitor commonly used to treat depression and panic disorder. In addition to increasing levels of biogenic amines in the brain, PLZ elevates brain levels of the amino acid gamma-aminobutyric acid (GABA; Baker et al. 1991; present study). Given the extensive evidence implicating biogenic amines and GABA in mnemonic processes, PLZ may affect learning and memory. To investigate this possibility, male Sprague-Dawley rats were given PLZ sulfate (15 or 30 mg/kg, based on free base weight) 2 h prior to training in a continuous multiple trial inhibitory avoidance (CMIA) and spatial water maze task. Retention was assessed 48 h later. The results indicated that PLZ enhanced CMIA and impaired water maze retention performance. Compared to control rats, rats given PLZ took significantly longer to re-enter the shock compartment and swam longer distances before reaching the escape platform on the retention tests. These effects of PLZ did not appear to be the result of PLZ-induced changes in acquisition or retrieval processes, activity levels, or footshock sensitivity. Combined, these findings indicate that PLZ influences memory in a task-dependent manner. These differential effects of PLZ may be the result of contrasting influences of GABA and biogenic amines on memory. Received: 10 June 1998 / Final version: 3 September 1998     

Effects of nicotine on spatial learning in C57BL mice

In the present study, the effects of nicotine on spatial memory in C57BL/6J mice was evaluated. Mice were trained in a water maze during four daily sessions of three trials each. In the first experiment, nicotine (0.7 and 0.35 mg/kg) or saline was administered once daily for 4 days, 15 min before the start of daily training: an impairment of performance of the water maze was observed in the group treated with 0.7 mg/kg of nicotine. In the second experiment, nicotine (0.7 and 0.35 mg/kg) or saline was administered from the 5 days prior to the beginning of the task and during the 4 days of acquisition. The results indicated an improvement in the rate of learning in the 9-day nicotine treated groups. The comparison between 4-day and 9-day treated groups revealed that the group receiving 0.35 mg/kg of nicotine for 9 days displayed significantly shorter latencies than all the other groups, while the group receiving 0.7 mg/kg of nicotine for 4 days performed significantly worse than all the other groups. The most noteworthy result is that nicotine was more effective after a more prolonged administration than when administered only during the training days.     

Drug discrimination in rats: evidence for amphetamine-like cue state following chronic haloperidol

Two groups of male Sprague-Dawley rats were trained to discriminate which of two levers to press for milk reinforcement on a VI-20 sec schedule of reinforcement on the basis of whether they were injected intraperitoneally with d-amphetamine (0.50 mg/kg or 1.50 mg/kg) or saline 15 min prior to daily 30 min training sessions. Following acquisition of the discrimination, dose-response functions were generated for both training-dose groups during 5 min test sessions. All subjects were then injected with 1.0 mg/kg of haloperidol for ten consecutive days and retested on either saline or intermediate doses of amphetamine on days 1, 2, 4 and 7 following the final haloperidol injection. The results indicated that chronic haloperidol enhanced the discriminative stimulus properties of amphetamine in both training groups. More importantly, when tested on saline, subjects in both training groups made significantly more responses on the d-amphetamine lever than observed prior to chronic haloperidol. On the basis of linear regression analysis of the dose-response curves it was shown that rats in both groups responded as though they had been injected with 0.18 mg/kg of d-amphetamine. In a second experiment this increase in amphetamine-lever responding when animals were tested with saline following chronic haloperidol was replicated and in addition it was observed that chronic amphetamine had the opposite effect on this measure.     

Memory and performance effects of single and 3-week administration of diazepam

The effects of diazepam on several cognitive and performance tasks were investigated in 30 healthy volunteers randomly assigned to three groups: A chronic group received diazepam for 21 days; an acute group received placebo during the same period, except at session 4 when they received diazepam; and a third group received placebo only at the sessions. Diazepam was given orally in a dose of about 0.2 mg/kg. Behavioral sessions were conducted before treatment (practice), after one administration (session 2), after 19 days (session 3), after 20 days (session 4), and 7 days following withdrawal (session 5). A single administration of diazepam produced significant memory impairment in both immediate and delayed free recall. Reduced memory performance was the result of impaired acquisition rather than reduced retention. Comparison of the chronic and acute groups in sessions 3 and 4 and analysis of the performance of the chronic group over sessions indicated the development of some tolerance to the memory impairment with continued administration. No residual memory effects were apparent following withdrawal. No other cognitive or psychomotor functions differed among the three treatment groups.     

Effects on retention of posttraining amphetamine injections in mice: Interaction with pretraining experience

These experiments examined the effects of d-amphetamine on retention of one-trial inhibitory (passive) avoidance training in mice. Water-deprived mice were pretrained to lick from a water spout at the end of a darkened compartment. Footschock was administered during licking after 4, 6, or 7 days of pretraining. Retention performance (latency to lick) was measured 24 h after training. The effects on memory of posttraining amphetamine varied not only with amphetamine dose but also with the amount of pretraining. In animals pretraining for 7 days, 0.3 and 1.0 mg/kg but not 0.03, 0.1, or 3.0 mg/kg posttraining amphetamine significantly enhanced later retention performance. In mice pretrained for 6 days, 1 mg/kg amphetamine also enhanced retention performance. However, in mice pretrained for only 4 days, 1 mg/kg amphetamine impaired later retention performance. These results are consistent with the view that posttraining treatments may affect memory storage processes by interacting with training-related arousal levels.     

Paradoxical sleep and memory: Long-term disruptive effects of anisomycin

The effects of the protein synthesis inhibitor Anisomycin (ANI) on Paradoxical Sleep (PS or REM sleep), slow wave sleep (SWS), and retention of one-trial inhibitory avoidance training was examined in mice in three separate experiments. In Experiment 1, mice injected with ANI 120 mg/kg and 210 mg/kg exhibited reductions in PS for 9 consecutive hours and ANI 40 mg/kg treated mice for 6 consecutive hours with no PS rebound in all three groups. ANI increased SWS commencing 3 hr postinjection, continuing for 9 consecutive hours and then returning to saline control levels. There were no significant differences between ANI-treated groups in the degree of SWS augmentation. In Experiment 2, Part A, ANI 120 mg/kg and 210 mg/kg but not ANI 40 mg/kg impaired retention measured 72 hr after training. In Experiment 2, Part B, ANI 120 mg/kg and 210 mg/kg induced amnesia from 3 to 9 hr post-training but ANI 40 mg/kg was effective only from 3 to 6 hr. In Experiment 3, the gradient of memory trace susceptibility to disruption by ECS was extended to 3 hr post-training in mice given immediate post-training injections of ANI 40 mg/kg. ANI 20 mg/kg and ANI 10 mg/kg alone or in combination with ECS was ineffective in extending the lability of the memory trace. The results of this study indicate that PS in the 3 hr period after aversively motivated training is not essential for memory processing. We suggest that memory stability and maintenance is dependent on PS occurring over a protracted time period.     

Effects of chronic intermittent and continuous amphetamine administration on acoustic startle

Acoustic startle was evaluated after mice were exposed to two different schedules of long-term amphetamine treatment. Under one schedule, mice received two daily subcutaneous injections of d-amphetamine for 7 consecutive days, whereas the other consisted of continuous administration of amphetamine via a subcutaneously implanted minipump. The enhanced acoustic startle observed after a test dose of d-amphetamine (3.0 mg/kg) was further facilitated when animals were exposed to long-term intermittent amphetamine administration. In contrast, the enhanced startle response to amphetamine was attenuated when mice received chronic continuous exposure to amphetamine. Possible behavioral and neurochemical mechanisms that may be involved in the development of tolerance after continuous amphetamine administration, and reverse tolerance after intermittent amphetamine treatment were discussed.     

Amnesia induced by short-term treatment with ethanol: attenuation by pretest oxotremorine

CD-1 mice were administered a series of tones paired with footshock in the closed arm of a Y maze. On a test session 8 days later the animals were tested for retention of the conditioned emotional response (CER). On the 2-min test session, the three arms of the maze were open and the number of entries into the arms was counted. Retention of the CER was measured by the decrease in the number of entries in comparison with animals trained with no footshock. Starting 24 hr after training, and continuing for the 7 days between training and testing, the animals in different groups received a daily IP injection of saline, 3.6 g/kg of ethanol, 150 micrograms/kg of the cholinergic muscarinic agonist oxotremorine, or ethanol plus oxotremorine. Retention was evaluated 24 hr after the last injection. Ethanol reduced retention of the conditioned emotional response. This effect was attenuated by oxotremorine (150 micrograms/kg) given IP 6 min prior to testing, but not by the same dose of oxotremorine given daily together with the ethanol treatment. Oxotremorine injections administered prior to the retention test also enhanced the retention performance of the control group. Daily oxotremorine administration had no effect. These findings suggest that ethanol weakened retention of the conditioned emotional response, that this effect was unrelated to acquisition or consolidation, and that the deleterious effect of the ethanol treatment can be attenuated by oxotremorine administered prior to the retention test.     

Blockade of the central effects of d-amphetamine sulfate by amantadine hydrochloride

Amantadine hydrochloride, unexpectedly, was found to block certain effects of d-amphetamine sulfate. In mice pretreated with amantadine, 150 mg/kg, d-amphetamine, 2 mg/kg or 5 mg/kg, failed to produce hyperactivity. This pretreatment also protected aggregated mice from the lethal effects of d-amphetamine, 30 mg/kg. Both d-amphetamine, 15 mg/kg, and chlorpromazine hydrochloride, 10 mg/kg, caused elevations in the homovanillic acid (HVA) concentrations in the caudate nucleus of mice, and amantadine pretreatment blocked this response to d-amphetamine but not that to chlorpromazine. Due to the many similarities in the pharmacological, behavioral, biochemical and clinical effects of amantadine and d-amphetamine, they may act at the same receptor and the observed antagonism may be due to a competitive blockade so that d-amphetamine fails to reach its site of action.     

东莨菪碱和毒扁豆碱对吗啡处理大鼠Morris水迷宫空间学习能力的影响

目的:研究吗啡及胆碱能系统的药物对大鼠空间学习能力的影响 方法:应用Morris水迷宫学习程序研究吗啡处理大鼠的空间学习能力及其在东莨菪碱和毒扁豆碱作用下的变化.结果:高剂量吗啡(10mg/kg)和低剂量吗啡(3mg/kg)对大鼠学习能力的影响差异有显著性;东莨菪碱(3mg/kg)和吗啡(10mg/kg)联合给药,可以使吗啡时学习能力的损害进一步加重;毒扁豆碱(0.1mg/kg)可以改善吗啡所致的学习能力损害,但不能完全逆转.结论:吗啡损害大鼠空间学习能力,已存在量-效关系;胆碱能系统与吗啡处理大鼠空间学习能力关系密切,有可能影响成瘾的发生及治疗.     

A comparison of the effects of scopolamine and diazepam on acquisition and retention of inhibitory avoidance in mice

Administration of either the muscarinic antagonist scopolamine or the benzodiazepine diazepam prior to training produced a dose-dependent impairment in the retention of one-trial inhibitory avoidance training in mice. To investigate the nature of this drug effect, the effects of scopolamine and diazepam were subsequently assessed on both acquisition and retention of inhibitory avoidance using a multiple-trial, training-to-criterion procedure. The training was conducted using either continuous trials in which the mouse was free to shuttle back and forth between shock and safe compartments or discrete trials in which the mouse was moved from the shock compartment of the safe compartment at the start of each trial. In either case, training continued until the mouse refrained from crossing into the shock compartment for a specified length of time on a single trial. Scopolamine (1.0 mg/kg) administered before training significantly increased the number of trials required to attain criterion, but did not affect retention when these mice were tested 2, 16, or 28 days later. In contrast, diazepam (1.0 mg/kg) did not significantly alter the number of trials necessary to reach criterion, but impaired retention of the inhibitory response in mice trained using discrete trials. The differences in the amnestic effects of scopolamine and diazepam revealed by this detailed analysis suggest that diazepam does not impair inhibitory avoidance performance through an effect on cholinergic function.     

Fluoxetine enhances memory processing in mice

Fluoxetine (FLU) increases brain concentrations of serotonin by blocking its uptake, without appreciably affecting the dopamine or norepinephrine systems. The present experiments provide evidence that a subcutaneous injection of FLU enhanced post-memory processing (“consolidation”) and retrieval, but not acquisition in young adult mice. FLU (15 mg/kg) enhanced 1-week memory retention when injected 2 min post-training. Similar enhancement was obtained with intracerebroventricular injection (20 μg per mouse). FLU enhanced retention when administered prior to training (1–5 mg/kg). FLU (2.5 mg/kg) enhanced recall scores when injected 1 h before the 1-week retention test, indicating an enhancing effect on memory retrieval. Neither the pre-training nor pre-testing effects depended on improved acquisition, since FLU did not improve acquisition of T-maze foot-shock avoidance over the dose range 0.5–35 mg/kg. The sensitive period for post-training enhancement by FLU (15 mg/kg) was less than 90 min, as shown by the temporal gradient typical of memory-enhancing drugs. The amnesia induced by a protein synthesis inhibitor anisomycin, or by an anticholinergic drug scopolamine, was blocked by FLU (15 mg/kg) injected post-training. Finally, FLU (15 mg/kg) injected after one-trial passive avoidance training enhanced 1-week retention, demonstrating effectiveness in this task as well as in the active avoidance task.     

The effects of dexmedetomidine, an alpha 2 agonist, on learning and memory, assessed using passive avoidance and water maze tasks in rats.

The effects of dexmedetomidine, a specific and potent alpha 2 agonist, on the performance of rats in passive avoidance and water maze tasks were studied. Pre-training administration of subanaesthetic dose (9.0 micrograms/kg) of dexmedetomidine impaired the retention of the passive avoidance task (assessed 24 hr after training) but it did not affect the training of this task. Smaller doses (0.3, 0.9 and 3.0 micrograms/kg) did not affect the training or retention of this aversively motivated task. On the other hand, pre-training administration of 0.3 and 0.9 microgram/kg dexmedetomidine impaired the acquisition of the water maze task, whereas larger doses (3.0 and 9.0 micrograms/kg) had no significant effect on spatial learning. Pre-training administration of dexmedetomidine (0.3-9.0 micrograms/kg) increased swimming speed in rats. Only a large dose (300 micrograms/kg) of dexmedetomidine, administered immediately after training, impaired the retention of the passive avoidance task and the acquisition of the water maze task. These data agree with previous findings that pharmacological manipulation of the noradrenergic system affects the retention of aversively-motivated (passive avoidance) tasks. The present results suggest that the dose-response curve of dexmedetomidine for impairment of learning/memory differs between the passive avoidance and water maze tasks.     

The α<Subscript>2</Subscript>-adrenoceptor antagonist atipamezole reduces the development and expression of <Emphasis Type="SmallCaps">d</Emphasis>-amphetamine-induced behavioural sensitization

The possible effect of atipamezole, a potent and specific alpha(2)-adrenoceptor antagonist, on the development and expression of d-amphetamine-induced behavioural sensitization was evaluated in mice. Male (C57Bl/6J) mice were given daily doses of d-amphetamine (2 mg/kg). In addition, groups of mice received injections of atipamezole (0.3 or 1 mg/kg) 20 min before d-amphetamine or vehicle administration. Idazoxan (1 mg/kg) was used in some experiments to extend the results to other alpha(2)-adrenoceptor antagonists. Challenge doses of d-amphetamine were administered to the mice on days 7-9 to evaluate the effects of alpha(2)-adrenoceptor antagonists on the d-amphetamine sensitization, evidenced by increased locomotor activation.Mice treated repeatedly with d-amphetamine developed strong locomotor sensitization that was reduced by pretreatment with alpha(2)-adrenoceptor antagonists. Acute atipamezole at both doses attenuated the expression of d-amphetamine-induced sensitization. Atipamezole at 1 mg/kg alone had no effect on locomotor activity, but the lower dose (0.3 mg/kg) increased locomotor activity after repeated administration.These results indicate that alpha(2)-adrenoceptor antagonists modulate the actions of d-amphetamine in a manner not explicable by their enhancing actions on noradrenaline and dopamine release, and may thus provide a novel approach to the treatment of motor complications caused by dopaminergic agents, such as dyskinesias, and perhaps also drug dependence.