Enhanced behavioral depressant effects of reserpine and α-methyltyrosine after 6-hydroxydopamine treatment

The effects of 6-hydroxydopamine treatment on behavioral performance in an operant, shuttle-box and a T-maze task were examined. In spite of marked depletions of brain catecholamines, 6-hydroxydopamine-treated rats showed no significant reductions in performance level in these tasks. However, administration of 1 mg/kg of reserpine which had no effect in control subjects was found to cause severe disruption of bar press responding on a CRF schedule in 6-hydroxydopamine-treated rats. Similarly, low doses of -MPT which also had no observable effect in control rats produced a severe depression of performance of not only CRF responding but also responding in the shuttle-box avoidance and T-maze tasks in centrally-sympathectomized subjects. The relationship of these findings to the proposal that catecholamines are important to the maintenance of behavioral responding and to possible mechanisms involved in the behavioral effects of 6-hydroxydopamine are discussed.     

The septo-hippocampal system and cognitive mapping

Rats were trained on a rewarded alternation task, run as a spatial working memory task on an elevated T-maze. Experiment 1 tested the effects of fornix-fimbria (FOFI) lesions on the acquisition, and of medial septal (MS) lesions on the acquisition and retention of this task, when the rats had to use information provided by being forced to run to a selected goal arm. The FOFI lesion produced an enduring impairment; the MS rats showed a severe impairment initially, but subsequently showed some behavioural recovery, when tested in acquisition or in retention. Experiment 2 similarly tested the effects of lateral septal (LS) lesions on acquisition of the task, and found an impairment which again showed signs of recovery with further testing. Experiment 3 was a transfer test conducted on the rats which had shown recovery in Experiments 1 and 2. The rats were now forced to use information provided by simply being placed on a selected goal arm. Both control animals and lesion animals showed identical choice accuracy, lower than that seen in Experiments 1 and 2. Experiment 4 tested acquisition of the task used in Experiment 3, and acquisition of a task in which the rat had to use information provided by running to the goal arm via a different route. Control rats again performed poorly, and scarcely differed from MS rats. It was concluded that rats have difficulty in using information about ‘places’, and that controls and lesion rats learn the tasks in the same way. The implications for ‘cognitive mapping’ hypotheses are discussed.     

Developmental Toxicity of Aspirin Prenatally Given to Rats: Assessment in Sic: Wistar-KY Rats

Abstract Slc:Wistar-KY rats were administered orally with 62.5, 125, 187.5 or 250 mg/kg aspirin suspended with 0.5 % CMC-Na on days 9–11 of gestation (plug += day 0). Suppression of maternal weight gain and food consumption during treatment was observed at and over 187.5 mg/kg. At term, the fetal mortality increased at and over 187.5 mg/kg and the fetal weight was lowered at and over 125 mg/kg. Among 15 live fetuses at 250 mg/kg, 4 had external malformations. In the skeletal examination (double staining), skeletal anomalies increased at and over 187.5 mg/kg. The skeletal variations such as vertebral anomalies, fused costal cartilages and increased presacral vertebrae were often encountered and delayed ossification was also found at and over 125 mg/kg. The internal anomalies tended to increase at and over 187.5 mg/kg. The live birth rate was significantly lower at 187.5 mg/kg than that in controls, and all pups, except for 3 from a dam, died before weaning. At 125 mg/kg, the pivoting locomotion on day 7 post partum was poorer as compared with controls. The physical and functional development at 62.5 mg/kg was not changed. There were no significant effects on male offspring in the open-field, rotarod, under-water T-maze and avoidance learning tests. However, in the Biel T-maze test (9–10 weeks of age), the aspirin-treated groups showed more errors and the increased elapsed time on the 1st trial day than controls. These results indicate that aspirin may induce a slight learning defect on rat offspring even at the non-teratogenic dose and the Biel T-maze test is more sensitive than any other learning tests given in this study.     

阿扑吗啡注射对大鼠视觉线索辨别学习和逆反学习的影响

目的 利用阿扑吗啡和旋转T迷宫装置,观察阿扑吗啡对大鼠视觉线索辨别学习和逆反学习的影响.方法 首先通过食物奖励与灯光线索的结合,训练所有动物的视觉线索辨别学习任务.在此期间,分别在每次学习前30 min或学习后立即腹腔注射阿扑吗啡(0.5 mg/kg).当动物达到所规定的学习标准后,开始逆反学习的训练.结果 与生理盐水注射组相比[学习次数分别为(168.00±16.97)次和(163.20±20.08)次],视觉线索辨别学习前、后的阿扑吗啡注射都能干扰视觉线索辨别学习任务的获得[学习次数分别为(259.20±26.29)次和(264.00±16.97)次];而只有在视觉线索辨别学习后立即注射阿扑吗啡,才能干扰逆反学习任务的获得[学习次数为(451.20±39.44)次,而相应的生理盐水组为(360.00±29.39)次].结论 对于视觉线索辨别学习,阿扑吗啡注射干扰了学习的获得和保持;对于随后的逆反学习,视觉线索辨别学习后的阿扑吗啡注射通过抑制原有学习策略的消退过程,从而干扰逆反学习任务的获得.     

The novel selective PDE9 inhibitor BAY 73-6691 improves learning and memory in rodents

The present study investigated the putative pro-cognitive effects of the novel selective PDE9 inhibitor BAY 73-6691. The effects on basal synaptic transmission and long-term potentiation (LTP) were investigated in rat hippocampal slices. Pro-cognitive effects were assessed in a series of learning and memory tasks using rodents as subjects. BAY 73-6691 had no effect on basal synaptic transmission in hippocampal slices prepared from young adult (7- to 8-week-old) Wistar rats. A dose of 10muM, but not 30 muM, BAY 73-6691 enhanced early LTP after weak tetanic stimulation. The dose effective in young adult Wistar rats did not affect LTP in hippocampal slices prepared from young (7- to 8-week-old) Fischer 344 X Brown Norway (FBNF1) rats, probably reflecting strain differences. However, it increased basal synaptic transmission and enhanced early LTP after weak tetanic stimulation in hippocampal slices prepared from very old (31- to 35-month-old) FBNF1 rats. BAY 73-6691 enhanced acquisition, consolidation, and retention of long-term memory (LTM) in a social recognition task and tended to enhance LTM in an object recognition task. Bay 73-6691 attenuated the scoplamine-induced retention deficit in a passive avoidance task, and the MK-801-induced short-term memory deficits in a T-maze alternation task. The mechanism of action, possibly through modulation of the NO/cGMP-PKG/CREB pathway, is discussed. Our findings support the notion that PDE9 inhibition may be a novel target for treating memory deficits that are associated with aging and neurodegenerative disorders such as Alzheimer's disease.     

Effects of P2, a peptide derived from a homophilic binding site in the neural cell adhesion molecule on learning and memory in rats

The neural cell adhesion molecule (NCAM) plays a pivotal role in neural development, regeneration, synaptic plasticity, and memory processes. P2 is a 12-amino-acid peptide derived from the second immunoglobulin-like (Ig) module of NCAM mediating cis-homophilic interactions between NCAM molecules present on the same cell. P2 is a potent NCAM agonist, capable of promoting neuronal differentiation and survival in vitro. The aim of this study was to assess the effect of P2 on learning and memory. Rats treated with P2 intracerebroventricularly (1 h prior to test) performed significantly better than controls in the reinforced T-maze, a test of spatial working memory. Further, rats treated with P2 exhibited decreased anxiety-like behavior while learning the T-maze task. In the social recognition test, both intracerebroventricular (1 h prior to test) and systemic (1 and 24 h prior to test) P2 treatment enhanced short-term social memory and counteracted (administration 24 h prior test) scopolamine-induced social memory impairment. In contrast, P2 (1 h prior to test) did not significantly improve long-term (24 h) retention of social memory, nor did it have any significant effects on long-term memory evaluated by the Morris water maze (administration between 2 days before training and 5.5 h posttraining). In the open field test, P2 (1 h prior to test) decreased general locomotion and rearing, but did not influence any other anxiety-related behaviors, indicating only a minimal influence on baseline anxiety levels. Taken together, these data indicate that in vivo P2 enhances short-term memory and protects against the amnestic effects of scopolamine, while modulating emotional behavior in a learning or novelty-related task.     

Chronic lithium treatment magnifies learning in rats

Recent electrophysiological work shows that chronic lithium treatment increases long-term potentiation (LTP) in neurons of the hippocampus, and LTP is thought to be the major neurophysiological basis for the development of learning and memory. This suggests that lithium might enhance learning and memory. Available studies have mainly assessed memory using aversive conditioning paradigms, but very little is available on the effect of lithium on learning. Since lithium may diminish anxiety or negative affect in adult rats, which would hinder aversive learning, the present study used three different positive reinforcement spatial cognitive tasks to determine whether chronic lithium affects learning. Each task differed in complexity, in the type of learning required, and in the reward received. For 4 weeks prior to, and throughout all learning assessments, rats had continual access to lithium chow or to a control chow diet. After 4 weeks’ access to their designated chow diet, rats began conditioning in the hole-board spatial discrimination or T-maze delayed alternation tasks in a counterbalanced fashion. They immediately began conditioning in the opposite task once completing the first. This was then followed with social place-preference conditioning, after 24-h isolation from their home-cage social partner. Chronic lithium increased learning in all three paradigms, regardless of the reward received. Indeed, both food and social interaction supported enhanced learning. Thus the learning effect was not merely due to an effect of lithium on food palatability. Importantly, clinically relevant serum lithium levels were evidenced at the time of testing. Lithium also marginally enhanced memory as well. Thus chronic lithium treatment may improve learning and memory in Alzheimer’s disease, and do so not only by blocking the formation of beta-amyloid and neurofibrillary tangles as suggested by previous research, but also by enhancing mechanisms involved in basal learning and memory formation, such as hippocampal synaptic plasticity.     

The elevated T-maze task as an animal model to simultaneously investigate the effects of drugs on long-term memory and anxiety in mice

The elevated T-maze (ETM) is an apparatus derived from the elevated plus-maze test, which is used to evaluate anxiety. Because anxiety is a biasing factor in models of memory, this study proposed the ETM as a task for the simultaneous assessment of memory and anxiety in mice. The ETM consists of one enclosed and two open arms. The procedure is based on the avoidance of open spaces learned during training session, in which mice were exposed to the enclosed arm as many times as needed to stay 300s. In the test session, memory is assessed by re-exposing the mouse to the enclosed arm and the latency to enter an open arm was recorded. The anxiolytic diazepam (DZP; 1 or 2mg/kg) and the amnestic biperiden (BPR; 0.5, 1 or 3mg/kg) were injected at three distinct times: pre-training, post-training, and pre-test. Pre-training administration of BPR 1 and DZP 2 increased the number of trials needed to reach the avoidance criterion, suggesting a passive avoidance learning impairment. However, BPR induced hyperlocomotion, which could bias the interpretation of any BPR-induced effects during the training session. Pre-training injection of BPR did not affect the spontaneous increase in the latency to enter an open arm between trials, while DZP reduced latencies in the first three trials suggesting anxiolysis. In the test session, pre-training injection of BPR 1 and DZP 2 reduced latencies to enter an open arm, indicating memory impairment. Post-training and pre-test injection of DZP or BPR did not affect memory. In conclusion, the proposed ETM task is practical for the detection of the anxiolytic and amnesic effects of drugs.     

Ketamine affects memory consolidation: differential effects in T-maze and passive avoidance paradigms in mice

The effects of ketamine, an N-methyl-D-aspartate (NMDA) antagonist, on memory in animals have been limited to the sub-anesthetic dose given prior to training in previous studies. We evaluated the effects of post-training anesthetic doses of ketamine to selectively manipulate memory consolidation, and the effect of pre-retention sub-anesthetic doses of ketamine on memory retrieval in passive avoidance and T-maze tasks in mice. Repeated post-training anesthetic doses of ketamine impaired the consolidation of memory in the T-maze but not in passive avoidance paradigms. This impairment was not permanent but diminished 1-2 days after ketamine withdrawal. Sub-anesthetic post-training doses of ketamine (5 mg/kg) had no effect on memory consolidation, and larger doses (10, 20 and 50 mg/kg) did not influence the retrieval of memory in the T-maze. The data suggest that repeated anesthetic doses of ketamine block NMDA receptors and affect memory consolidation. Moreover, NMDA mechanisms antagonized by ketamine appear to be selectively involved in spatial (T-maze) memory mechanisms but may not be necessary for non-spatial (passive avoidance) memory consolidation.