Enhancing effects of lithium on memory are not by-products of learning or attentional deficits

We recently reported that chronic lithium (LiCl), at therapeutic plasma levels, enhanced spatial working memory and retention of an aversive contingency. Here we examine the possibility that these effects be secondary to LiCl effects on the ability to ignore irrelevant stimuli or on fear conditioning. In Experiment 1, rats subjected to >30 daily intraperitoneal injections of LiCl (2 mmol/kg) or saline underwent conditioned emotional response training (CER: 2 CS pairings with 1-s, 1-mA shock) after 40 pre-exposures either to the CS (latent inhibition-LiCl/latent inhibition-saline, n = 8) or to another stimulus (control-LiCl/control-saline, n = 8). In Experiment 2, eight LiCl and eight saline animals were trained in on-the-baseline (VI-60 s) CER (1-s, 0.15-mA shock in CS-signalled periods) in the Skinner box. In Experiment 1, LiCl animals showed normal latent inhibition. In both experiments, their fear conditioning was unimpaired. Therefore, the previously reported memory improvement under chronic lithium cannot be attributed to changes in the ability to ignore irrelevant stimuli or in fear conditioning.     

Nociceptin system plays a role in the memory retention: involvement of naloxone benzoylhydrazone binding sites.

We investigated the role of nociceptin system in learning and memory in mice. The deficiency of nociceptin receptors and nociceptin itself did not affect the alternation behavior in the Y-maze test. In the passive avoidance test, the step-through latencies of nociceptin receptor knockout mice were longer than those of wild-type mice. Nociceptin shortened the step-through latency in wild-type mice. This impairment on passive avoidance task was reversed by naloxone benzoylhydrazone (NalBzoH), indicating that the amnesic effects of nociceptin may be mediated through the NalBzoH recognition sites. These suggest that nociceptin system plays an important role in the memory retention of passive avoidance task, and NalBzoH-recognized sites are involved in nociceptin-induced impairment of the memory retention.     

Reversible lesion of the rat's orbitofrontal cortex interferes with hippocampus-dependent spatial memory

In this study, tetrodotoxin (TTX) inactivation was employed to evaluate the involvement of the rat's orbitofrontal cortex (OFC) in hippocampus-dependent spatial memory using Morris water maze (MWM) and place avoidance learning (PAL) tasks. In Experiment 1, rats trained in MWM task with two blocks of four trials per day for 3 consecutive days received bilateral injections of either TTX or saline into the OFC 60 min before each daily training session. The acquisition of spatial memory was evaluated 24h after the last training day and it was shown an impairment by the TTX. In Experiment 2, bilateral intra-OFC injections of TTX or saline were made immediately after two blocks of four trials. Testing 24h later, it was revealed that TTX also impairs spatial memory consolidation. In Experiments 3 and 4, rats were trained in a single 30-min session to avoid a 60 degrees segment of the stable circular (80-cm diameter) arena, entering which was punished by a mild shock (PAL task) and retention was tested 24h later in a 30-min extinction session. Bilateral injections of TTX or saline were made into the OFC 60 min before training or immediately after training. Again, TTX impaired the place avoidance retention when it was injected into the OFC either before (acquisition phase) or after (consolidation phase) training. These findings indicate that functional integrity of the OFC is necessary for both the acquisition and the consolidation of hippocampus-dependent spatial memory in rats.     

Cysteamine-induced depletion of somatostatin produces differential cognitive deficits in rats

The effects of a variety of doses of systemically administered cysteamine (a somatostatin depletor) were studied on step-through passive avoidance retention, as well as acquisition and performance of a delayed spatial alternation task and a signaled extinction discrimination task in rats. Retention of single trial passive avoidance was significantly reduced by a pretraining (60-min) dose of cysteamine at 50, 100, 150 and 200 mg/kg s.c. This effect was shown to be sensitive to behavioral manipulation; in a second experiment, a retention deficit was found only at the two highest doses tested (150 and 200 mg/kg s.c.) after a second exposure to the footshock. In the operant conditioning studies, biweekly injections (Monday and Wednesday) of cysteamine administered one hour before testing produced no statistically significant changes in acquisition or performance of either the delayed spatial alternation or the signaled discrimination task. The results of these series of experiments suggest that active somatostatin release or chronic somatostatin depletion may selectively affect performance maintained by different behavioral procedures.     

Dose- and time-dependent scopolamine-induced recovery of an inhibitory avoidance response after its extinction in rats

The present investigation was aimed at elucidating the dose and time dependency of scopolamine-induced recovery of inhibitory avoidance after its extinction. Two experiments were conducted: in the first, we analyzed the effects of four doses (1, 2, 4, and 8 mg/kg) of the musacrinic receptor antagonist scopolamine, on the expression of this conditioned response once it had been extinguished. Independent groups of rats were trained in a one-trial, step-through inhibitory avoidance task and submitted to daily retention (extinction) tests. After extinction had occurred, animals were injected intraperitoneally 10 min before retention testing, either with saline or scopolamine. Results show that scopolamine produced a dose-dependent recovery of the avoidance response. The second experiment was carried out in the same animals, which were now tested for retention of inhibitory avoidance at 1, 2, 3, 6, and 9 months after completion of the first experiment. All rats received counterbalanced injections of saline or scopolamine 10 min before testing at each time interval. Reliable recovery of the avoidance response was observed at the 1-month interval with a clear dose dependency while, after the second month, only the groups treated with the two higher doses continued responding. The results indicate that recovery of the extinguished response produced by muscarinic blockade follows dose- and time-dependent curves, and can be achieved long after a single training session. These data suggest that the inhibitory avoidance memory trace is retained in the brain after behavioural extinction of this response, thus supporting the view of extinction as new learning that affects the retrieval of the original memory, but does not modify its storage.     

NBQX does not affect learning and memory tasks in mice: a comparison with D-CPPene and ifenprodil

The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)-quinoxaline (NBQX) did not impair working memory measured as alternation behavior in the Y-maze in mice. No depressant effect on alternation was detected even when NBQX impaired locomotion measured as the total number of arm entries. Similar profile of action in the Y-shaped maze was observed after administration of an anti-ischemic drug ifenprodil. In contrast, the N-methyl-D-aspartate (NMDA) antagonist (D-(E)-4-(3-phosphonoprop-2-enyl)piperazine-2-carboxylate (D-CPPene) impaired spontaneous alternation. In the step-through passive avoidance task, mice were trained to avoid dark compartment entry. NBQX and ifenprodil did not impair learning in this task when administered before or immediately after training. In contrast, D-CPPene disturbed acquisition when administered before but not immediately after training or before retention test. These observations suggest that AMPA receptors are not critically involved in the formation of spatial working memory and acquisition (storage) in the passive avoidance, and have no effect on recall (retrieval) from long-term memory.     

Stress-induced increases in avoidance responding: an animal model of post-traumatic stress disorder behavior?

One prominent symptom of post-traumatic stress disorder (PTSD) is avoidance of stimuli reminiscent of the traumatic event. We attempted to study this aspect of PTSD in two experiments. Groups of rats received forty 3-s tailshocks, or served as home cage controls (HCC). Twenty-four hours later, all subjects received a 4-h session of leverpress escape/avoidance conditioning. In Experiment 1, shock periods in the absence of a response were 1 s; in Experiment 2 they were 30 s. No group differences were observed in Experiment 1. In Experiment 2, previously shocked animals made more avoidance responses and had a higher percent avoidance during the fourth hour of the session than controls. Further, previously shocked animals had a higher efficiency ratio (the percent of responses that were avoidances). No group differences were observed in leverpresses during the safety period (an index of anxiety) in either study. Results are discussed in terms of the effects of stress on avoidance behavior as a potential model for this important feature of PTSD.     

Postnatal administration of two peptide solutions affects passive avoidance behaviour of young rats.

The effects of two subcutaneously injected peptide solutions CERE (100 mg/kg b. wt.) and E021 (1 mg/kg b. wt.) and of 0.9% saline on passive avoidance reaction (PAR) of young rats were examined. Animals were trained and tested in a step-through avoidance task using a footshock of 0.5 mA or 1 mA. Step-through latencies were observed up to 200 s and from these data the percentage of good learners (latency = 200 s) and bad learners (latency < 200 s) was calculated. Two experimental schedules were performed (n > 6). In Expt. 1 rat pups were chronically treated with the substances within the first 7 days after birth. In Expt. 2 the 7 days of treatment started in the 4th postnatal week. In both experiments PAR acquisition was trained on the 28th day after birth (learning trial), PAR extinction testing started on the 29th day (retention trials). After applying a 0.5-mA footshock, rat pups treated with E021 within the first 7 days of life (Expt. 1) displayed significantly slower PAR extinction when compared to saline- and CERE-treated rats. In the 1 mA groups, significant differences in step-through latencies were measured between 0.9% saline- and E021-pretreated animals on retention day 11 and between saline and CERE on retention days 9 and 13. E021-treated rats of Expt. 2, receiving a footshock intensity of 0.5 mA, showed significant lower step-through latencies when compared to E021-treated rats of Expt. 1. In Expt. 2 no significant differences between treatment groups were observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

GSK3抑制剂氯化锂对脆性X综合征模型小鼠避暗行为的干预作用

目的探讨糖原合成酶激酶3(glycogen synthase kinase3,GSK3)抑制剂氯化锂对脆性X综合症小鼠模型的避暗行为的干预作用及机制。方法通过对30日龄脆性X综合症小鼠连续腹腔注射不同剂量氯化锂5 d,用药第4天和第5天进行避暗实验;同时用免疫印迹技术检测Fmr1 knockout(KO)及wild type(WT)小鼠的海马和皮层总GSK 3β和磷酸化GSK 3β(P-GSK3β)的变化。结果在避暗实验中,KO鼠与WT鼠,两者潜伏期及错误次数分别为(56±32)s,(83±24)s;(7±3)次,(3±2)次;免疫印迹实验结果:KO鼠皮层及海马P-GSK3β表达平均灰度值分别为69,63;WT鼠皮层和海马均为100。注射氯化锂后,KO鼠和WT鼠总GSK3β无明显改变,而KO鼠60 mg/kg,120 mg/kg,200 mg/kg组皮层P-GSK3β表达平均灰度值分别为:147,151,234;海马P-GSK3β分别为108,111,146,较空白组增多;P<0.05。WT鼠用氯化锂后,潜伏期和错误次数以及P-GSK3β表达变化无统计学意义。结论氯化锂能改善KO鼠的学习记忆能力,可能与氯化锂导致的P-GSK3β的表达增加有关,对脆性X综合征基因敲除小鼠有治疗作用。     

Reinforced spatial alternation as an animal model of obsessive-compulsive disorder (OCD): investigation of 5-HT2C and 5-HT1D receptor involvement in OCD pathophysiology.

BACKGROUND: This study introduces a laboratory model of compulsive behavior based on persistence in the context of rewarded spatial alternation. METHODS: Rats were screened for spontaneous persistence during T-maze reinforced alternation. Experiment 1: One high and one low spontaneous persistence group (n = 8) received 20 injections of fluoxetine, a matched pair saline, both followed by 4 days of meta-chlorophenylpiperazine (mCPP) challenge. Experiment 2: Five matched groups of rats (n = 9) received pretreatment (20 injections) with fluoxetine, mCPP, desipramine, diazepam or saline, followed by 4 days of mCPP challenge (fluoxetine in mCPP group). After washout, animals received 2 days of naratriptan, followed by another 2-day mCPP challenge. RESULTS: In both experiments mCPP significantly increased persistence in saline controls. Fluoxetine also acutely increased persistence scores: after a gradual return to baseline, these scores showed tolerance to mCPP. Experiment 1: This pattern was significant in high but not low initial persistence groups. Experiment 2: Fluoxetine and mCPP showed cross-tolerance. Neither desipramine nor diazepam protected against mCPP challenge. Persistence scores returned to baseline during washout and naratriptan and were thereafter increased by another mCPP challenge in all but the fluoxetine and mCPP groups, suggesting 5-HT2C receptor mediation. CONCLUSIONS: This model is based on spontaneous persistence behavior showing pharmacological responses concordant with those of compulsive symptomatology.     

Sex differences in learning deficits induced by prenatal stress in juvenile rats

Stress during pregnancy results in neurochemical and behavioral alterations observed throughout adulthood and aging. We here examined the impact of prenatal stress (PS) on cognitive functions in juvenile—4-week-old—rats, focusing on putative sex differences. Dams received an unpredictable 90-min duration contention stress between gestational day E17 and E20. Locomotion and learning ability were examined in offsprings between day P24 and P29 using actimetry, spontaneous alternation in the Y-maze, delayed alternation in the T-maze, and passive avoidance. Both male and female PS rats showed increased activity. In the Y-maze, diminished spontaneous alternation (males: −20%; females: −29%) were seen for PS rats compared to non-PS rats. The number of arm entries was unchanged among groups. In the T-maze, PS rats failed to perform delayed alternation, as shown by equal time spent and number of entries in both the novel and previously explored arms. In the passive avoidance test, PS resulted in significant impairments for female offspring only of both step-through latency and percentage of animals to criterion. PS thus induced severe learning impairments affecting both short-term and long-term memories that could be observed early in lifetime, in 4-week-old, juvenile rats. In addition, marked sex differences were evidenced, particularly in the passive avoidance response that may reflect differential developmental neuroadaptations in precise brain structures.     

Pyroglutamic acid improves learning and memory capacities in old rats

The effects of the arginine salt of pyroglutamic acid (2-oxo-pyrrolidone carboxylic acid, PCA) on learning and memory capacities of old rats were studied in a subchronic treatment schedule (i.p. injection of 0.1 and 1 g/kg/day for 15 days). The acquisition and extinction of active avoidance behaviour were studied in a pole-jumping test situation. The retention of passive avoidance response was examined in a step-through passive avoidance task. PCA facilitated the rate of acquisition of pole-jumping response, and inhibited the extinction of the response. The dose of 1 g/kg was more potent than 0.1 g/kg in this respect. Also in the passive avoidance task, the treatment with PCA was followed by an improvement of avoidance retention. These results indicate that PCA is a behaviourally active compound in that it improves learning and memory capacities in old rat.     

Neonatal administration of vasopressin antiserum induces long-term deficits on active and passive avoidance behaviour in rats

Two-day-old male rats received a subcutaneous injection of arginine-vasopressin (AVP) antiserum and avoidance behaviour was studied 3 months later. Rats treated with the antiserum showed a clear retention deficit in a one-trial learning, step-through passive avoidance situation. Anti-AVP treatment also induced an impairment on the acquisition of a two-way active avoidance task. Systolic blood pressure was lower than normal in these animals. The results obtained appear to be indicative of the high vulnerability of the developing nervous system, and are discussed in the context of the different hypothesis on the role of central or peripheral mechanisms in the behavioural effects of AVP. Although no definite conclusions may be drawn in this regard, the present data strongly suggest that neonatal administration of AVP antiserum exerts long-lasting effects upon the functionality of several physiological mechanisms related to the behavioural adaptation of the organism.     

Activation of dopamine D1 receptors in the medial septum improves scopolamine-induced amnesia in the dorsal hippocampus

In the present study, we investigated the influence of intra-medial septum (intra-MS) injections of dopamine D1 receptor agents on amnesia induced by intra-CA1 injections of a muscarinic acetylcholine receptor antagonist, scopolamine. This study used a step-through inhibitory (passive) avoidance task to assess memory in adult male Wistar rats. The results showed that in the animals that received post-training intra-MS injections of saline, intra-CA1 administrations of scopolamine (0.75, 1, and 2 μg/rat) decreased inhibitory avoidance (IA) memory consolidation as evidenced by a decrease in step-through latency on the test day, which was suggestive of drug-induced amnesia. Post-training intra-MS injections of a dopamine D1 receptor agonist, SKF38393 at doses of 0.1, 0.15, and 0.3 μg/rat had no effect, but at dose of 0.5 μg/rat impaired IA memory consolidation. Interestingly, intra-MS injections of SKF38393 (0.15, 0.3 and 0.5 μg/rat) significantly prevented amnesia induced by intra-CA1 injections of scopolamine (1 μg/rat). Intra-MS injections of a dopamine D1 receptor antagonist, SCH23390 (0.5 and 0.75 μg/rat) by itself impaired IA memory consolidation, and also at dose of 0.75 μg/rat increased amnesia induced by intra-CA1 administrations of an ineffective dose of scopolamine (0.5 μg/rat). Post-training intra-MS injections of ineffective doses of SCH23390 (0.1, 0.3 and 0.5 μg/rat) prevented an effective dose of SKF38393 response to the impaired effect of scopolamine. These results suggest that dopamine D1 receptors in the MS via projection neurons to the hippocampus affect impairment of memory consolidation induced by intra-CA injections of scopolamine.     

Behavioral actions of vasoactive intestinal peptide (VIP)

The effect of vasoactive intestinal peptide (VIP) was studied on fear-motivated behaviours, exploration of a novel environment and on novelty and ACTH-induced grooming. VIP was administered via a plastic cannula into the lateral ventricle. Retention of a step-through passive avoidance task was inhibited by 10 and 30 ng VIP injected 1 hour before the retention test. Extinction of pole-jumping active avoidance behaviour was facilitated by 10 and 100 ng VIP. Mild effects were observed in an open field test on exploration and grooming activity. In conclusion, VIP produces inhibitory effects on fear-motivated behaviours.     

Protective effects of idebenone and α-tocopherol on β-amyloid-(1–42)-induced learning and memory deficits in rats: implication of oxidative stress in β-amyloid-induced neurotoxicity in vivo

Amyloid β-peptide (Aβ), the major constituent of the senile plaques in the brains of patients with Alzheimer's disease, is cytotoxic to neurons and has a central role in the pathogenesis of the disease. Previous studies have suggested that oxidative stress is involved in the mechanisms of Aβ-induced neurotoxicity in vitro. In the present study, we examined whether oxidative stress contributes to learning and memory deficits caused by continuous intracerebroventricular infusion of Aβ-(1–42). In the Aβ-(1–42)-infused rats, spontaneous alternation behaviour in a Y-maze and spatial memory in a water maze task were significantly impaired, as compared with Aβ-(40–1)-infused control rats. The retention of passive avoidance learning was also significantly impaired by treatment with Aβ-(1–42). Potent antioxidants idebenone and α-tocopherol prevented the behavioural deficits in Y-maze and water maze, but not passive avoidance, tasks in Aβ-(1–42)-infused rats when they were repeatedly administered by mouth once a day from 3 days before the start of Aβ infusion to the end of behavioural experiments. Lipid peroxide levels in the hippocampus and cerebral cortex of Aβ-(1–42)-infused rats did not differ from those in control animals, and neither idebenone nor α-tocopherol affected the lipid peroxide levels. These results suggest that treatment with antioxidants such as idebenone and α-tocopherol prevents learning and memory deficits caused by Aβ.     

Nicotine improves learning and memory in rats: morphological evidence for acetylcholine involvement

It has been suggested that nicotine improves rapid information processing (learning and memory) tasks. However, it is not clear which aspects of cognition actually underlie these improvements because relatively less attention has been given to nicotinic cholinergic systems compared to muscarinic systems. The authors therefore studied the effects of nicotine on the learning and memory performance by a step-through passive avoidance task. Nicotine (0.4 mg/kg) was administered s.c. single dose (acute group), once a day for 3 days (subchronic group) or 21 days (chronic group). Nicotine treated and control rats were trained in one trial learning step-through passive avoidance task, where retention latencies were carried out 1 h, 24 h, and 3 days after learning trial. Treatment with nicotine before training session prolonged the latencies significantly (p < .01). Control group, acute, subacute and chronic nicotine treatment groups showed latencies 4.75 +/- 0.6, 69.4 +/- 14, 116.2 +/- 30, and 118.5 +/- 23 s, respectively. In addition, to prove the actual contribution of nicotinic cholinergic system in improvement of learning and memory processing, histological methods that permit the visualization and quantification of ACh levels were used. Electron microscopic evaluation revealed increased numbers of Ach-containing vesicles especially in hippocampus in chronic nicotine-treated rats; although frontal and temporal cortex in addition to hippocampus showed increment in Ach vesicles in a lesser extent in all nicotine treatment groups. These results indicate that long-term nicotine treatment can be important for improving cognitive function in regard to increased cholinergic activity.     

Cycloheximide impairs and enhances memory depending on dose and footshock intensity

This experiment examined the effects on memory of interactions of cycloheximide dose and training foot shock intensity. Mice received injections of cycloheximide (120 mg/kg, s.c.) or saline 30 min prior to inhibitory avoidance training with shock intensities of 100, 150, 250 or 300 μA (1 s duration). Memory was tested 48 h later. The saline control mice showed increasing memory latencies as a function of shock intensity. The ability of cycloheximide to impair memory increased as the training shock intensity increased. In a second experiment, mice were trained with a 200 μA (1 s duration) shock and received injections of saline or cycloheximide at one of several doses (30, 60 or 120 mg/kg). Under these training conditions, cycloheximide enhanced memory in an inverted-U dose-response manner. These findings are consistent with prior findings suggesting that protein synthesis inhibitors act on memory by altering modulators of memory formation as a secondary consequence of the inhibition of protein synthesis rather than by interfering with training-initiated synthesis of proteins required for memory formation.     

Genomic and nongenomic effects of intrahippocampal microinjection of testosterone on long-term memory in male adult rats

In addition to their well-known genomic effects via intracellular receptors, androgens rapidly alter neuronal excitability through a nongenomic pathway. The nongenomic effect of testosterone, as the main androgen, apart from its traditional effects, was assessed in one of the fundamental centers of learning and memory, the hippocampus, on long-term memory (LTM) in passive avoidance conditioning. Different doses of testosterone enanthate (T) or testosterone-BSA (T-BSA) bilaterally were injected into the CA1 region of the hippocampus 15 min before shock delivery (1 mA during 5 s) in a two-compartment passive avoidance apparatus. After 24 h, animals were tested for passive avoidance retrieval. Bilateral injection of 20 microg T or 55 microg T-BSA into the CA1 significantly decreases step-through latency. Therefore, it seems that testosterone can impair LTM in passive avoidance conditioning both via intracellular receptors and through nongenomic pathway.