Adolescent cocaine residually impairs working memory and enhances fear memory in rats

The residual effects of cocaine during adolescence on memory in male young adult rats were studied. Animals were injected with 20 mg/kg cocaine on postnatal Days 28 through 35, whereas lab-chow (LC) and pair-fed (PF) control subjects received saline. Assessment of spatial working and long-term memory in the Morris water maze, and 72-h retention of an inhibitory avoidance task was conducted at about 5 and 9 weeks postcocaine, respectively. Relative to PF control subjects, cocaine-treated subjects showed impairments in the water maze when required to swim to the hidden platform placed in a quadrant diagonal from the location of its original location (i.e., on reversal learning). These same drug-treated animals, however, exhibited enhanced inhibitory avoidance retention relative to both control groups. These seemingly disparate findings are seen as being consistent with previous data showing that cocaine during adolescence residually impairs spatial memory and leads to enhanced fear responses. Moreover, when taken with previous findings from our laboratory, the present water maze data indicate that the deleterious effects of cocaine, when administered during adolescence, is delayed until 5 weeks after initiation of abstinence. It is speculated that alterations to limbic circuitry, especially those associated with the amygdala, account for the behavioral results observed.     

Scopolamine impairs learning performance of rats in a 14-unit T-maze

To assess involvement of muscarinic cholinergic systems in performance of a shock-motivated 14-unit T-maze task, 3-month old Fischer-344 rats were given an IP injection of scopolamine (0.1, 0.3, 1.0 or 3.0 mg/kg), methylscopolamine (1.0 mg/kg), or saline 30 min prior to maze training on 2 consecutive days. Scopolamine, but not methylscopolamine, impaired all components of acquisition performance. Measures of error performance, run time, shock duration, and number of shocks received were significantly increased but only at the 1.0 and 3.0 mg/kg scopolamine doses. The cognitive component of the task, measured by error performance, appeared most affected. Cognitive performance deficits observed following scopolamine administration in the present study resembled age-related impairments in rats and mice previously observed in this task. The cholinergic hypothesis of geriatric memory dysfunction appears to be implicated by these findings; however, the degree to which memory systems are involved remains unclear. Other performance variables such as discriminative control of stimuli or mechanisms of attention are implicated and discussed.     

Estrogen improves working but not reference memory and prevents amnestic effects of scopolamine of a radial-arm maze

This study investigated the effect of estrogen treatment on working memory and reference memory of female rats. In addition, the impact of estrogen on the sensitivity of these two types of memory to the cholinergic antagonist scopolamine was investigated. At 35 days of ages, rats were ovariectomized and implanted chronically with Silastic capsules containing either 25% crystalline estradiol or 100% cholesterol. Thirty days after surgery, animals were trained on an eight-arm radial maze with four arms baited to assess both working and reference memory performance. Following training, females were given scopolamine hydrobromide (0.2 mg/kg i.p.) prior to retesting on the task. Results indicated that estrogen treatment improved working memory performance during maze acquisition but did not affect reference memory performance. Scopolamine treatment impaired performance on the working memory component, but not the reference memory component, while estrogen prevented the impairment of working memory by scopolamine. Results support previous evidence that estrogen selectively enhances performance on tasks that depend on working memory.     

孟鲁司特对东莨菪碱模型小鼠学习记忆及脑内胆碱能神经的影响

目的：研究孟鲁司特（Mon）对东莨菪碱（Scop）致痴呆模型小鼠学习记忆及脑内胆碱能神经的影响。方法：将动物按体重随机分为5组,正常对照组[溶媒（Veh）＋Veh]、阴性对照组（Scop＋Veh）、阳性对照组[Scop＋多奈哌齐（Done）2．0mg／kg]、低剂量孟鲁司特组（Scop＋Mon 1.0mg／kg）、高剂量孟鲁司特组（Scop＋Mon2．0mg／kg）。灌胃给药,除正常对照组腹腔注射生理盐水外,其他各组小鼠给药前30min腹腔注射东莨菪碱（1．0mg·kg^-1·d^-1）,连续给药14d后采用Morris水迷宫和Y迷宫实验测定学习记忆功能,并测定脑海马及皮层乙酰胆碱（ACh）水平及乙酰胆碱酯酶（TChE）的活性。结果：与阴性对照组相比,孟鲁司特（1．0、2．0mg·kg^-1·d^-1）能显著缩短Morris水迷宫隐藏平台训练的潜伏期,增加动物在空间探索实验中对目标象限的搜索时间及原平台所在位置的穿越次数,增加Y迷宫实验中正确反应次数。孟鲁司特还能显著降低小鼠海马及皮层乙酰胆碱酯酶活性,增加乙酰胆碱含量。结论：孟鲁司特通过抑制东莨菪碱所致的痴呆小鼠脑内乙酰胆碱酯酶活性增加乙酰胆碱含量,继而改善小鼠学习记忆损害。     

Effect of wild ginseng on scopolamine‐induced acetylcholine depletion in the rat hippocampus

Objectives The ameliorating effects of wild ginseng on learning and memory deficits were investigated in rats. Methods Rats were treated daily with wild ginseng or cultivated ginseng for 7 days at 30 min before scopolamine injection (2 mg/kg, i.p.). After inducing cognitive impairment by the administration of scopolamine, behavioural assessment using the Morris water maze was performed. Changes in cholinergic system reactivity were also examined by measuring the immunoreactive neurons of choline acetyltransferase and the reactivity of acetylcholinesterase in the hippocampus. Key findings Scopolamine injection induced impaired performance in the water maze test and severe cell losses in hippocampal cholinergic neurons, as indicated by decreased choline acetyltransferase immunoreactivity and increased acetylcholinesterase reactivity. Daily administration of wild ginseng produced a significant improvement in the escape latency for finding the platform in the Morris water maze and reduced the loss of cholinergic immunoreactivity in the hippocampus. The reduced expression of brain‐derived neurotrophic factor mRNA due to the scopolamine injection was recovered to normal levels by the administration of wild ginseng. Conclusions Wild ginseng demonstrates a significant neuroprotective effect against scopolamine‐induced neuronal and cognitive impairment.     

Cocaine produces cholinergically mediated analeptic and EEG arousal effects in rabbits and rats

Cocaine (1-5 mg/kg, IV) shortened the duration of loss of righting reflex produced in pentobarbital-narcotized rabbits. This effect was completely blocked by scopolamine (1 mg/kg, IV), but not by scopolamine methylbromide, suggesting that a central cholinergic mechanism was involved. In urethane-anesthetized rats cocaine (1 mg/kg, IV) consistently generated hippocampal EEG theta rhythm lasting about 40 min. This effect was also abolished by scopolamine. These results suggest that cocaine produced behavioral and EEG arousal responses that involved the septohippocampal cholinergic system.     

Effects of cholinergic and monoaminergic antagonists and tranquilizers upon spatial memory in rats

To explore the pharmacological mechanisms of the spatial memory, performance on the radial arm maze was tested in rats under the following drugs, using a within-subject design; scopolamine (0.25 and 0.5 mg/kg), methylscopolamine (0.5 and 1 mg/kg), phentolamine (5 and 10 mg/kg), propranolol (10 and 20 mg/kg), chlorpromazine (1 and 2 mg/kg), and chlordiazepoxide (5 and 10 mg/kg). The number of correct choices was significantly decreased by scopolamine, while the other drugs, including methylscopolamine, showed no effects on the correct choices. Almost all drugs affected the running time. These findings indicate that the brain cholinergic system is involved in the spatial memory.     

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.     

Effect of rivastigmine on scopolamine-induced memory impairment in rats

The effect of rivastigmine on memory impairments induced in rats by scopolamine (0.5 mg/kg) was assessed in the Morris water maze and passive avoidance tests and compared with that of tacrine (2.5-17.7 mg/kg). Rivastigmine, (0.5-2.5 mg/kg) inhibited cholinesterase in the cortex and hippocampus by 21-60% and antagonised the deficits in working and reference memory. Tacrine (12.5 and 17.7 mg/kg) produced significantly less inhibition of cholinesterase in the hippocampus but more in the striatum than rivastigmine (0.75 and 1.5 mg/kg) and only antagonised the deficit in reference memory. Rivastigmine (1.5 and 2.5 mg/kg) or tacrine (12.5 mg/kg), injected immediately after completion of the acquisition trial in the passive avoidance test, antagonised the deficit induced by scopolamine (1 mg/kg) in memory retention. The inability of higher doses of the cholinesterase inhibitors to antagonise memory deficits induced by scopolamine may be related to excessive cholinergic stimulation in the central nervous system.     

Effects of scopolamine,pilocarpine, and oxotremorine on the exploratory behavior of two psychogenetically selected lines of rats in a complex maze

Rats of two psychogenetically selected lines received pretest IP injections of scopolamine hydrobromide (0.25, 1.0, or 4.0 mg/kg), pilocarpine hydrochloride (3.0, 6.0, or 12.0 mg/kg) or oxotremorine sesquifumarate (0.2, 0.4, or 0.8 mg/kg) and were subseqently placed in a complex enclosed maze of the Dashiell type that included a small, central, illuminated arena. Animals receiving pilocarpine or oxotremorine injections were pretreated with methscopolamine to counter the peripheral actions of these muscarinic cholinergic agonists. Following vehicle injections, Roman High-Avoidance rats (RHA/Verh) were significantly more active, explored more maze sectors, and required less time to activate the initial 24 different photocell units uniformly distributed throughout the maze than Roman Low-Avoidance rats (RLA/Verh). Scopolamine, pilocarpine, and oxotremorine depressed locomotor activity, reduced the explored area, and increased the time required to activate the initial 24 different photocell units within this complex maze for both RHA/Verh and RLA/Verh rats. Although the doses of scopolamine injected were approximately equally effective in both rat lines (except for total maze activity), the RHA/Verh rats exhibited significant alterations in several measures of maze patrolling after treatment with the lowest dose of pilocarpine, whereas the RLA/Verh rats did not. In contrast, most of the RLA/Verh rats exhibited very pronounced tremors following treatment with the highest dose of oxotremorine, but none of the RHA/Verh rats did. These results demonstrate that manipulation of the central cholinergic system with scopolamine, pilocarpine, or oxotremorine, despite their different pharmacological mechanisms, impair maze patrolling. Furthermore, the results suggest that the two psychogenetically bred lines of rats investigated are differentially sensitive to central cholinergic manipulation with the muscarinic receptor agonists pilocarpine and oxotremorine.     

Prenatal cocaine and/or nicotine exposure in rats: Preliminary findings on long-term cognitive outcome and genital development at birth

Prenatal cocaine or nicotine exposure is associated with a variety of teratogenic effects. The current study was conducted to determine their effects alone and in combination on cognitive function and sexual differentiation. Pregnant Long-Evans rats (N = 19) were exposed to either cocaine (15 mg/kg/dose b.i.d. SC on GD 8–20); nicotine (4 mg/kg/day continuous SC infusion on GD 4–20); both nicotine + cocaine; or vehicle only. Birth weight and anogenital distance (AGD) were measured in all pups at birth. Learning and memory were tested in the Morris water maze (MWM) during prepubertal and pubertal ages in five daily consecutive sessions and a sixth session 1 week later and in the radial-arm maze (RAM) during adulthood. In the RAM, a drug challenge of the β-noradrenergic antagonist propranolol (10–20 mg/kg) was given after acquisition training. Maternal weight gain was reduced 13–42% and offspring birth weight was reduced by 7–12% in all three exposure groups compared to controls. Cocaine decreased the AGD of males (2.68 mm) compared to 2.88 mm in noncocaine-exposed male pups (p < 0.025). A sex-selective cocaine effect was also seen after adjustment of AGD measurements for body weight. With this measure cocaine-treated females showed significantly (p < 0.05) greater AGD than those not exposed to cocaine. In the MWM, there were two types of trials: cued reference memory trials and uncued spatial working memory trials. On cued reference memory trials significant cocaine-induced latency deficits were seen on only the first session. On spatial working memory trials cocaine-induced latency deficits were seen throughout daily training on sessions 1–5, but not the retention session 6, 1 week later. During RAM acquisition, there were no significant differences in choice accuracy between exposure groups. Following propranolol challenge, deficits in choice accuracy were demonstrated in rats prenatally exposed to cocaine or nicotine. These rats did not show any response to propranolol, whereas the controls slightly improved their choice accuracy. The results of this study indicated that prenatal cocaine exposure altered long-term cognitive function under basal conditions in the MWM and drug challenge in the RAM, birth weight, and genital development. Cocaine-induced cognitive deficits were predominately in working memory rather than reference memory or long-term retention. Prenatal nicotine exposure was only observed to alter birth weight and cognitive function in response to propranolol challenge in the RAM.     

Scopolamine does not disrupt spatial working memory in rats

The importance of cholinergic systems for spatial working memory was examined by injecting scopolamine at varying times during a 5 hr-long retention interval imposed between the rat's fourth and fifth choices in an 8 arm maze. Regardless of whether or not the testing procedure required the rats to adopt a spatial solution for the task, scopolamine (1.0–5.0 mg/kg) did not impair retention in a manner that was suggestive of an effect on working memory. Modest deficits observed in some conditions appeared to result from drug effects on performance. Previous findings of impaired acquisition of accurate spatial behavior by scopolamine-treated rats evidently reflect an influence of the drug on physiological systems other than those necessary to maintain working memory for spatial information.     

Phellodendron amurense and Its Major Alkaloid Compound, Berberine Ameliorates Scopolamine-Induced Neuronal Impairment and Memory Dysfunction in Rats

We examine whether Phellodendron amurense (PA) and its major alkaloid compound, berberine (BER), improved memory defects caused by administering scopolamine in rats. Effects of PA and BER on the acetylcholinergic system and pro-inflammatory cytokines in the hippocampus were also investigated. Male rats were administered daily doses for 14 days of PA (100 and 200 mg/kg, i.p.) and BER (20 mg/kg, i.p.) 30 min before scopolamine injection (2 mg/kg, i.p.). Daily administration of PA and BER improved memory impairment as measured by the passive avoidance test and reduced the escape latency for finding the platform in the Morris water maze test. Administration of PA and BER significantly alleviated memory-associated decreases in cholinergic immunoreactivity and restored brain-derived neurotrophic factor and cAMP-response element-binding protein mRNA expression in the hippocampus. PA and BER also decreased significantly the expression of proinflammatory cytokines such as interleukin-1β, tumor necrosis factor-α and cyclooxygenase-2 mRNA in the hippocampus. These results demonstrated that PA and BER had significant neuroprotective effects against neuronal impairment and memory dysfunction caused by scopolamine in rats. These results suggest that PA and BER may be useful as therapeutic agents for improving cognitive functioning by stimulating cholinergic enzyme activity and alleviating inflammatory responses.     

Prenatal chlorpyrifos exposure in rats causes persistent behavioral alterations

Use of chlorpyrifos (CPF) has been curtailed due to its developmental neurotoxicity. In rats, postnatal CPF administration produces lasting changes in cognitive performance, but less information is available about the effects of prenatal exposure. We administered CPF to pregnant rats on gestational days (GD) 17–20, a peak period of neurogenesis, using doses (1 or 5 mg/kg/day) below the threshold for fetal growth impairment. We then evaluated performance in the T-maze, Figure-8 apparatus and 16-arm radial maze, beginning in adolescence and continuing into adulthood. CPF elicited initial locomotor hyperactivity in the T-maze. Females showed slower habituation in the Fig. 8 maze; no effects were seen in males. In the radial-arm maze, females showed impaired choice accuracy for both working and reference memory and again, males were unaffected. Despite the deficits, all animals eventually learned the maze with continued training. At that point, we challenged them with the muscarinic antagonist, scopolamine, to determine the dependence of behavioral performance on cholinergic function. Whereas control females showed impairment with scopolamine, CPF-exposed females did not, implying that the delayed acquisition of the task had been accomplished through alternative mechanisms. The differences were specific to muscarinic circuits, as control and CPF groups responded similarly to the nicotinic antagonist, mecamylamine. Surprisingly, adverse effects of CPF were greater in the group receiving 1 mg/kg as compared to 5 mg/kg. Promotional effects of acetylcholine (ACh) on cell differentiation may thus help to offset CPF-induced developmental damage that occurs through other noncholinergic mechanisms. Our results indicate that late prenatal exposure to CPF induces long-term changes in cognitive performance that are distinctly gender-selective. Additional defects may be revealed by similar strategies that subject the animals to acute challenges, thus, uncovering the adaptive mechanisms that maintain basal performance.     

Behavioural and neurotoxic long-lasting effects of MDMA plus cocaine in adolescent mice

The poly-drug pattern is the most common among MDMA users, with cocaine being a frequently associated drug. The aim of the present work was to evaluate the behavioural and neurotoxic long-term effects of exposure during adolescence to MDMA alone or plus cocaine. Mice of 28 to 30 days of age received a treatment of two daily injections of an identical dose of MDMA (5, 10 or 20 mg/kg), alone or plus cocaine (25 mg/kg), for 3 days (6 administrations). Three weeks after receiving MDMA, an increase in the time dedicated by the animals to social contacts with their conspecifics was observed, whilst their behaviour in the elevated plus maze showed no differences from that of non-treated mice. After being exposed to MDMA plus cocaine, mice spent more time in social contacts during the interaction test, as well as exhibiting an anxiolytic profile in the elevated plus maze, with an increase in the time and number of entries in the open arms. The activity of mice treated with cocaine alone or plus MDMA remained constant; the decrease observed among the rest of the animals after the second hour was absent in their case. The level of dopamine in the striatum was diminished in mice treated with 20 mg/kg of MDMA, but this neurotransmitter was not affected in animals exposed to the same dose plus cocaine. The present results highlight pronounced alterations in the behaviour of adult mice after exposure to MDMA and cocaine during adolescence, and demonstrate that these long-term effects can occur without the dopaminergic system becoming affected.     

Oxiracetam antagonizes the disruptive effects of scopolamine on memory in the radial maze

The effects exerted by oxiracetam on the disruption of performance induced by scopolamine in the radial arm maze were investigated in overtrained rats. Scopolamine induced a dose-related decrease in the efficiency of responding and an increase of running time. The effect of the SC injection of 0.2 mg/kg scopolamine on the efficiency of responding was antagonized by the IP administration of 30 mg/kg oxiracetam, while the effect on running time induced by the same dose of scopolamine was not. Physostigmine (0.3 mg/kg SC) antagonized both effects of 0.2 mg/kg scopolamine. Methylscopolamine, at the dose of 0.2 mg/kg SC, was devoid of any effect on both parameters. Increasing the dose of methylscopolamine to 0.63 mg/kg did cause serious peripheral effects which eventually prevented some animals from completing the task. Similar peripheral effects were observed after administration of 0.63 mg/kg scopolamine. The effects of this dose of scopolamine on efficiency and running time were not antagonized by pretreatment with 100 mg/kg oxiracetam. Oxiracetam alone (30 or 100 mg/kg IP) did not modify the performance of previously trained rats. The present results suggest that oxiracetam selectively restores cholinergic mechanisms which are involved in learning and memory.     

Scopolamine during the paradoxical sleep window impairs radial arm maze learning in rats

It has been proposed that there are paradoxical sleep windows (PSW) during which REM sleep is required for effective learning. Thus, rats deprived of REM sleep during 0-4 (but not 5-8) h after training show impaired learning of a radial maze task. As cholinergic (ACh) systems are active during REM sleep and may be involved in learning, this experiment investigated the effects on learning of pharmacological manipulation of the cholinergic system during the period identified as the PSW. Sprague-Dawley rats were randomly assigned to groups that were physically deprived of REM for 4 h either immediately after training or beginning 4 h after training or treated with the ACh receptor antagonist scopolamine (0-0.4 mg/kg at 0 and 2 h after training or 0.006 mg/kg at 4 and 6 h after training) on each of 9 days of radial maze training. Post-training REM deprivation (0-4 h but not 5-8 h after training) and scopolamine dose-dependently impaired learning. Results suggest that REM sleep and intact ACh neurotransmission are required during the PSW for rats to learn the radial maze task.     

Detection of cholinergic mediation of behavior in 7-, 9-, and 12-day old rat pups

A training procedure that permitted infant rats (7, 9, and 12 days old) to acquire a T maze discrimination to escape footshock (Experiment 1) was used to study the effects of the cholinergic antagonist, scopolamine hydrobromide (0, 0.2 mg/kg and 0.8 mg/kg) (Experiment 2). These results indicated that (1) Scopolamine had no effect on T maze choice behavior, unlike previous results for 15- and 23-day old rats, but (2) scopolamine did increase latency to choice in the discrimination task at all ages, an effect previously seen in 15-day old animals, but opposite that seen after scopolamine administration to 23-day old animals or adults. This “paradoxical” effect of scopolamine on response latency is present approximately two weeks prior to earlier estimates of the time course of maturation of the cholinergic system.     

Anticholinergic sensitivity following chronic nicotine administration as measured by radial-arm maze performance in rats

Chronic nicotine administration in rats has been previously found to improve choice accuracy performance of rats in the radial-arm maze. A nicotine-induced choice accuracy improvement was also seen in the current study. Rats were trained to asymptotic levels of choice accuracy performance on a working memory paradigm in an 8-arm radial maze. During and after 3 weeks of chronic nicotine treatment, rats were tested for sensitivity to acute doses of the nicotinic and muscarinic receptor antagonists, mecamylamine and scopolamine. During the first week of administration, nicotine-treated rats were supersensitive to the sedation caused by mecamylamine. This suggests that nicotine may not have been acting as a simple nicotinic agonist, since in this case, the opposite effect, an attenuated effect of mecamylamine in the nicotine-treated group, would have been expected. Three to 4 weeks after withdrawal from chronic nicotine administration, the treated rats were more sensitive to the choice accuracy deficits caused by the muscarinic blocker scopolamine (0.16 mg/kg) and the nicotinic blocker mecamylamine (10 mg/kg). This supersensitivity may have been due to a lasting change caused by chronic nicotine in the cholinergic bases of memory function.     

Effect of scopolamine on the hippocampal theta rhythm during an eight-arm radial maze task in rats

The changes in the hippocampal theta rhythm during an impairment of reference and working memory of radial maze task induced by scopolamine administration were studied. Intraperitoneal injection of scopolamine at doses of 0.5 and 1.0 mg/kg caused a significant increase in the number of total, reference memory and working memory errors. On the other hand, scopolamine significantly increased the hippocampal theta power (5-12 Hz) at doses (0.5 and 1.0 mg/kg) that caused an impairment of reference and working memory. A significant increase in the peak frequency of the hippocampal theta rhythm was also observed with scopolamine, even at a dose of 0.2 mg/kg. At doses of 0.2, 0.5 and 1.0 mg/kg, scopolamine caused a decrease in the locomotor activity during the radial maze task. From these results, it may be concluded that an increase in amplitude of the hippocampal theta rhythm induced by scopolamine is closely associated with memory/learning function of the eight-arm radial maze.