Role of state-dependency in memory impairment induced by acute administration of midazolam in mice

Although the memory deficits produced by pre-training benzodiazepines administration have been extensively demonstrated both in humans and in animal studies, there is considerable controversy about the involvement of the state-dependency phenomenon on benzodiazepines-induced anterograde amnesia. The present study aimed to characterize the role of state-dependency on memory deficits induced by the benzodiazepine midazolam (MID) in mice submitted to the plus-maze discriminative avoidance task (PM-DAT). This animal model concomitantly evaluates learning and retention of discriminative avoidance task, exploratory habituation as well as anxiety-like behavior and motor activity. Mice received 2mg/kg MID before training and/or before testing in the PM-DAT. Pre-training (but not pre-test) MID administration impaired the retention of the discriminative avoidance task, which was not counteracted by a subsequent pre-test administration of this drug, thus refuting the role of state-dependency. Conversely, the pre-training administration of MID also led to an impairment of the habituation of exploration in the PM-DAT (an animal model of non-associative memory). This habituation deficit was state-dependent since it was absent in pre-training plus pre-test MID treated mice. Concomitantly, MID pre-training administration induced anxiolytic effects and diminished the aversive effectiveness of the aversive stimuli of the task, leading to an impairment of the acquisition of the discriminative avoidance task. Our findings suggest that pre-training benzodiazepine administration can impair the retention of different types of memory by producing specific deleterious effects on learning or by inducing state-dependent memory deficits.     

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.     

Chronic administration of fluoxetine impairs inhibitory avoidance in male but not female mice

The effects of chronic administration of fluoxetine (20 mg/kg/day i.p.) on a one-trial step-through inhibitory avoidance task were investigated in male and female CD1 mice. In Experiment 1, treatment was administered for 21 days before the training session, whereas in Experiment 2, other subjects were subjected to the same treatment starting 24 h after the training session. The comparison of test versus training latencies showed memory deterioration with pre-training administration of fluoxetine (Experiment 1), which affected males but not females. Sex differences in this task were also observed in Experiment 1, with females showing a better performance. Sex differences were evident in controls as well as in treated animals. The locomotor activity of the animals was also tested in Experiment 1. Due to the absence of sex differences in the drug effects on this measure, the sex differences in the effects of fluoxetine on inhibitory avoidance were hardly attributable to non specific effects on locomotor activity. The lack of effect of post-training administration of fluoxetine (Experiment 2) constitutes additional support of the idea that the observed effect on inhibitory avoidance in Experiment 1 is specifically related to learning and memory.     

Withdrawal from chronic cocaine administration induces deficits in brain reward function in C57BL/6J mice

Anhedonia is a major symptom of cocaine withdrawal, whereas euphoria characterizes the effects of acute administration of this drug in humans. These mood states can be measured quantitatively in animals with brain reward thresholds obtained from the intracranial self-stimulation (ICSS) procedure. Studies have previously reported the reward-enhancing effects of acute cocaine administration using the ICSS procedure in mice, but the effects of chronic cocaine administration and withdrawal on brain reward thresholds have not been widely investigated in this species. Cocaine withdrawal was induced in C57BL/6J mice by removal of intraperitoneal osmotic minipumps that delivered cocaine (90 or 180 mg/kg/day, salt) for 72 h. Mice were tested in the ICSS procedure 3-100 h post-pump removal. Anxiety-like behavior was assessed in the light-dark box 24 h post-pump removal. After an 18-day washout period, tolerance and sensitization to the reward-enhancing effects of cocaine were assessed by injecting bolus cocaine intraperitoneally (0, 2.5, 5, and 10 mg/kg). The results indicated that 72 h administration of 90 and 180 mg/kg/day cocaine significantly lowered brain reward thresholds. Withdrawal from 90 and 180 mg/kg/day of cocaine administration elevated ICSS thresholds to similar extents. No anxiety-like behavior was observed in the light-dark box during withdrawal from chronic cocaine administration, although the number of transitions between compartments and locomotion in the dark compartment markedly decreased. Chronic cocaine administration did not induce tolerance or sensitization to the reward-enhancing effects of acute cocaine. In conclusion, alterations in mood states induced by cocaine administration and withdrawal in mice can be measured using the ICSS procedure.     

Beneficial effects of benzodiazepine diazepam on chronic stress-induced impairment of hippocampal structural plasticity and depression-like behavior in mice

Whether benzodiazepines (BZDs) have beneficial effects on the progress of chronic stress-induced impairment of hippocampal structural plasticity and major depression is uncertain. The present study designed four preclinical experiments to determine the effects of BZDs using chronic unpredictable stress model. In Experiment 1, several time course studies on behavior and hippocampus response to stress were conducted using the forced swim and tail suspension tests (FST and TST) as well as hippocampal structural plasticity markers. Chronic stress induced depression-like behavior in the FST and TST as well as decreased hippocampal structural plasticity that returned to normal within 3 wk. In Experiment 2, mice received p.o. administration of three diazepam dosages prior to each variate stress session for 4 wk. This treatment significantly antagonized the elevation of stress-induced corticosterone levels. Only low- (0.5 mg/kg) and medium-dose (1 mg/kg) diazepam blocked the detrimental effects of chronic stress. In Experiment 3, after 7 wk of stress sessions, daily p.o. diazepam administration during 1 wk recovery phase dose-dependently accelerated the recovery of stressed mice. In Experiment 4, 1 wk diazepam administration to control mice enhanced significantly hippocampal structural plasticity and induced an antidepressant-like behavioral effect, whereas 4 wk diazepam administration produced opposite effects. Hence, diazepam can slow the progress of chronic stress-induced detrimental consequences by normalizing glucocorticoid hormones. Considering the adverse effect of long-term diazepam administration on hippocampal plasticity, the preventive effects of diazepam may depend on the proper dose. Short-term diazepam treatment enhances hippocampal structural plasticity and is beneficial to recovery following chronic stress.     

Influence of acute and sub-chronic nicotine pretreatment on morphine state-dependent learning

In the present study, the effects of acute and sub-chronic pretreatment of nicotine on impairment of memory formation and the state-dependent learning by morphine have been investigated in mice. Pre-training administration of morphine (5mg/kg) decreased the learning of a one-trial passive avoidance task, which was reversed by pre-test administration of the same dose of morphine. Amnesia induced by pre-training morphine was also significantly reversed in nicotine (0.001, 0.01 and 0.1 mg/kg)-treated animals on the test day. Morphine induced amnesia was also reversed in animals which had previously received sub-chronic injections of nicotine, once daily for 3 days followed by 14 days of no drug treatment. The restoration of memory by pre-test morphine was also reduced in animals which had previously received once daily injections of atropine (0.25, 0.5 and 1 mg/kg, i.p.) for 3 days after 14 of being days drug free. In the animals, restoration of memory by sub-chronic nicotine administration, was also decreased by once daily administration of atropine (0.25, 0.5 and 1 mg/kg) 10 min prior to injection of nicotine (0.1 microg/kg/day, for 3 days) but not with SCH 23390; R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl (0.01, 0.05 and 0.1 mg/kg) or sulpiride (25, 50 and 100 mg/kg) during 3-days of treatment with nicotine. The results suggest that nicotine may induce sensitization which affects the impairment of memory formation via cholinergic but not dopaminergic systems.     

Neuropeptide Trefoil factor 3 improves learning and retention of novel object recognition memory in mice

Accumulating evidence has implicated neuropeptides in modulating recognition, learning and memory. However, to date, no study has investigated the effects of neuropeptide Trefoil factor 3 (TFF3) on the process of learning and memory. In the present study, we evaluated the acute effects of TFF3 administration (0.1 and 0.5 mg/kg, i.p.) on the acquisition and retention of object recognition memory in mice. We found that TFF3 administration significantly enhanced both short-term and long-term memory during the retention test, conducted 90 min and 24 h after training respectively. Remarkably, acute TFF3 administration transformed a learning event that would not normally result in long-term memory into an event retained for a long-term period and produced no effect on locomotor activity in mice. In conclusion, the present results provide an important role of TFF3 in improving object recognition memory and reserving it for a longer time, which suggests a potential therapeutic application for diseases with recognition and memory impairment.     

Long-term, low-level adolescent nicotine exposure produces dose-dependent changes in cocaine sensitivity and reward in adult mice

Cigarette smoking by adolescents is a strong predictor of future drug use, abuse, and dependence. While this "gateway drug effect" is assumed to be related to psychosocial factors, data from our laboratory suggests that adolescent nicotine use may permanently disrupt reward systems through changes in dopamine receptor function. Behavioral pharmacological methods known to be indirectly (motor activity) and directly (conditioned-place-preference) related to drug reinforcement were used to examine changes in cocaine sensitivity. Testing was performed on adult mice that were exposed to nicotine (0.3, 1.0, and 3.0 mg/kg, SC, M-F, b.i.d.) or saline during adolescence (postnatal days 25-57). Prior to testing, subjects had a 28 day drug-free, time-off period. After acclimation to the testing apparatus, the locomotor effects (30 min, 30 cm traveled) of cocaine (5, 10, and 20 mg/kg, IP) were measured daily; cocaine tests were preceded and followed by saline control tests. Following the acute dose-response curve, mice received saline followed by 5 days of 20.0 mg/kg cocaine. Thereafter, mice underwent condition-place-preference testing. A pre-test was performed to determine compartment preference (i.e., no injection, 20 min test). Cocaine (10 mg/kg, IP) was paired with the subjects non-preferred side and saline with the other. Conditioning sessions were conducted for 8 days with the order of drug/saline injections counter-balanced across subjects. A drug-free, post-test occurred on the day following the final conditioning session. A dose-dependent relationship between adolescent nicotine exposure and cocaine reward was noted in the adult mice across both test conditions. Subjects exposed to nicotine showed an increased response to cocaine's motor activating effects and a decreased response to cocaine's rewarding effects. A follow-up study was undertaken to evaluate dopamine D1, D2, and D3 receptor function in adult mice exposed to the highest dose of nicotine from the first study. While both interesting and revealing, the results of motor activity tests with dopamine agonist only approached significance. Further research will be required to more fully examine the mechanism of action for the observed changes in cocaine reward. In summary, this is the first study to demonstrate a dose-response relationship between adolescent nicotine exposure and changes in cocaine reward and sensitivity during adulthood.     

Atypical acquisition and atypical expression of memory consolidation gains in a motor skill in young female adults with ADHD

Individuals with ADHD often show performance deficits in motor tasks. It is not clear, however, whether this reflects less effective acquisition of skill (procedural knowledge), or deficient consolidation into long-term memory, in ADHD. The aim of the study was to compare the acquisition of skilled motor performance, the expression of delayed - consolidation phase - gains and retention, in persons with and without ADHD. Thirty-two participants, 16 with ADHD, were trained on a sequence of finger movements using a well-established training protocol, and tested before training and immediately, 24 h and 2 weeks after training. Both groups showed similar within-session gains in speed; additional, delayed gains were expressed at 24 h, but less robustly in ADHD, and at 2 weeks post-training. However, while controls showed significant delayed gains in accuracy at 24 h and 2 weeks post-training, accuracy deteriorated in ADHD from pre-training to 24 h post-training and was only at pre-training levels by 2-weeks post-training. Our results demonstrate a latent memory consolidation phase in motor sequence learning, expressed as delayed gains in speed and a much delayed recovery of pre-training accuracy, in individuals with ADHD. However, both the acquisition and memory consolidation of motor skills are atypical in ADHD.     

Blockade of adenosine A(1) receptors prevents methylphenidate-induced impairment of object recognition task in adult mice

Methylphenidate (MPH) is the preferred treatment used for attention-deficit/hyperactivity disorder (ADHD). Recently, misuse for MPH due to its apparent cognitive enhancer properties has been reported. Adenosine is a neuromodulator known to exert influence on the dopaminergic neurotransmission, which is the main pharmacological target of MPH. We have reported that an overdosage of MPH up-regulates adenosine A₁ receptors in the frontal cortex, but this receptor was not involved in its anxiolytic effects. In this study, the role of adenosine A₁ receptor was investigated on MPH-induced effects on aversive and recognition memory in adult mice. Adult mice received acute and chronic (15 days) administration of methylphenidate (5 mg/kg, i.p.), or an acute overdosage (50 mg/kg, i.p) in order to model misuse. Memory was assessed in the inhibitory avoidance and object recognition task. Acute administration 5 mg/kg improved whereas 50 mg/kg disrupted recognition memory and decreased performance in the inhibitory avoidance task. Chronic administration did not cause any effect on memory, but decreased adenosine A₁ receptors immunocontent in the frontal cortex. The selective adenosine A₁ receptor antagonist, (DPCPX 1 mg/kg, i.p.), prevented methylphenidate-triggered recognition memory impairment. Our findings showed that recognition memory rather than aversive memory was differently affected by acute administration at both doses. Memory recognition was fully impaired by the overdosage, suggesting that misuse can be harmful for cognitive functions. The adenosinergic system via A₁ receptors may play a role in the methylphenidate actions probably by interfering with dopamine-enhancing properties of this drug.     

Interactive effects of a protein kinase AII inhibitor and testosterone on spatial learning in the Morris water maze

Neurohormones such as testosterone (TE) are important in modulation of learning and memory. In the present study, we investigated the interactive effects of pre-training bilateral intra-hippocampal infusions of testosterone and H-89, a selective PKAII inhibitor, on spatial acquisition in the Morris water maze (MWM). Different doses of TE (20, 40 and 80 μg/side) and H-89 (5 and 10 μM/side) were administered 30 min before start of the training each day. Control animals received bilateral intra-hippocampal infusions of DMSO as vehicle for TE and H-89. Animals were trained for 4 days and each day included one block of four trials. The results of this study showed that bilateral infusion of TE (40 and 80 μg/side) or H-89 (10 μM/side) impaired spatial learning as indicated by significant increases in escape latency and traveled distance compared to the control group. Although pre-training bilateral infusions of a low concentration of either TE (20 μg/side) or H-89 (5 μM/side) into the CA1 region of the hippocampus did not affect learning capabilities, but the combination of the low doses of the drugs led to significant deficits in spatial acquisition. Overall, our data suggest that spatial acquisition was affected by PKAII inhibition or TE administration. Moreover, when co-administered, these drugs had a negative synergistic impact on acquisition.     

Oxiracetam prevented the scopolamine but not the diazepam induced memory deficits in mice

In mice, the elevated plus-maze paradigm was used to investigate the effect of scopolamine hydrobromide and diazepam and their interaction with oxiracetam on the retrieval of spatial memory trace. This paradigm measures (using the transfer latency) an animal's capacity to escape from the open arm to the enclosed one. The retention session followed 24 h after the acquisition one. Experiment 1: Scopolamine (0.25 and 0.5 mg/kg) and diazepam (0.5 and 1.0 mg/kg) given 30 min before the retention session significantly prolonged the transfer latency as compared with the saline treated mice and those given the lowest dose of scopolamine (0.125 mg/kg) and diazepam (0.25 mg/kg). Experiment 2: Oxiracetam administered at doses of 3, 10 and 30 mg/kg immediately after the acquisition session prevented the scopolamine induced prolongation of the transfer latency. Thus, oxiracetam forestalled the impairment of retrieval of memory trace: the animals were able to remember the spatial configuration of the plus-maze. On the contrary, oxiracetam was not effective in the diazepam treated mice. We suggest that beneficial effect of oxiracetam might be confounded or blocked by the anxiolytic effect of diazepam.     

Skill-memory consolidation in the striatum: critical for late but not early long-term memory and stabilized by cocaine

The sensorimotor striatum is important for procedural learning, including skill learning. Our previous findings indicate that this part of the striatum mediates the acquisition of a motor skill in a running-wheel task and that this skill learning is dependent on striatal D1 dopamine receptors. Here, we investigated whether the sensorimotor striatum is also involved in the consolidation of this skill memory and whether this consolidation is modified by the indirect dopamine receptor agonist cocaine. Rats were trained on a running wheel for 2 days (40 min/day) to learn a new motor skill, that is, the ability to control the movement of the wheel. Before each training session, the animals received an injection of vehicle or cocaine (25mg/kg, i.p.). Immediately following the training session, an intrastriatal infusion of 2% lidocaine (1 microl) or a sham infusion were administered. Wheel-skill performance was tested before and repeatedly after the training. Our results show that post-trial intrastriatal infusion of lidocaine disrupted late-stage long-term skill memory (post-training days 6-26), but spared early long-term memory (1 day after the training). Skill consolidation was more susceptible to such disruption in animals that practiced less during the training. Cocaine given pre-trial prevented this post-trial disruption of skill consolidation. These findings indicate that the sensorimotor striatum is critical for the consolidation of late but not early long-term skill memory. Furthermore, cocaine appeared to stabilize motor-memory formation by protecting consolidation processes after the training.     

Cocaine increases EEG beta: a replication and extension of Hans Berger's historic experiments

The effects of cocaine by two routes of administration were studied on the resting, awake human EEG during a 2 min sequential subtraction task. Fifty subjects were given 1 of 3 intravenous cocaine doses (0.2, 0.4 and 0.6 mg/kg). Thirty-three subjects received 1 of 3 oral doses of cocaine (2, 3 and 4 mg/kg). The EEG was analyzed as spectral power for delta, theta, alpha and beta bands. At each dose for both routes of administration, cocaine increased beta power. The increase was observed at the 5 min post-drug test session for the subjects given intravenous cocaine and at both 45 and 75 min test sessions for subjects given oral doses. In addition, a decrease in delta power was found at the 5 min test for the intravenous group and theta power was decreased at the 45 min test session. The increase in beta power was correlated with the area under the cocaine plasma versus time curve, but not with the cardiovascular effects of cocaine. The increased beta activity observed with cocaine may be a consequence of the direct stimulation of a central noradrenergic arousal system.     

Dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory memory tasks in mice

Pre-clinical and clinical studies on dimebon (dimebolin or latrepirdine) have demonstrated its use as a cognitive enhancer. Here, we show that dimebon administered to 3-month-old C57BL6N mice 15 min prior to training in both appetitive and inhibitory learning tasks via repeated (0.1 mg/kg) and acute (0.5 mg/kg) i.p. injections, respectively, increases memory scores. Acute treatment with dimebon was found to enhance inhibitory learning, as also shown in the step-down avoidance paradigm in 7-month-old mice. Bolus administration of dimebon did not affect the animals' locomotion, exploration or anxiety-like behaviour, with the exception of exploratory behaviour in older mice in the novel cage test. In a model of appetitive learning, a spatial version of the Y-maze, dimebon increased the rate of correct choices and decreased the latency of accessing a water reward after water deprivation, and increased the duration of drinking behaviour during training/testing procedures. Repeated treatment with dimebon did not alter the behaviours in other tests or water consumption. Acute treatment of water-deprived and non-water-deprived mice with dimebon also did not affect their water intake. Our data suggest that dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory tasks in mice.     

Inflammatory markers are associated with inhibitory avoidance memory deficit induced by sleep deprivation in rats

Sleep deprivation (SD) causes detrimental effects to the body, such as memory impairment and weight loss. SD also changes the concentration of inflammatory mediators such as cytokines, which, in turn, can affect cognitive functioning. Thus, the objective of this study was to investigate the involvement of these inflammatory mediators in inhibitory avoidance memory deficit in sleep-deprived rats. Male Wistar rats were deprived of sleep by the modified multiple platform method for 96 h, while their respective controls remained in their housing cages. To assess memory after SD, all animals underwent training, followed by the inhibitory avoidance task test 24 h later. Also, the weight of each animal was recorded daily. In the first experiment, animals received an acute administration of lipopolysaccharide (LPS, 50 or 75 μg/kg i.p.) 3 h before the inhibitory avoidance training. In the experiment 2, the animals received acute or chronic administration of anti-IL-6 antibody (Ab, 2 μg/kg i.p.). The acute administration was performed 3 h before the inhibitory avoidance training, while the chronic treatment administrations were performed daily during the SD period. The 75 μg/kg dose of LPS, but not the 50 μg/kg dose, caused a significant attenuation of memory impairment in the sleep-deprived animals. Although the treatments with the anti-IL-6 Ab did not produce any significant changes in cognitive performance, the Ab attenuated weight loss in sleep-deprived animals. Taken together, these results suggest the involvement of inflammatory mediators in the modulation of memory deficit and weight loss that are observed in sleep-deprived rats.     

MPTP-induced deficits in motor activity: Neuroprotective effects of the spintrapping agent, α-phenyl-tert-butyl-nitrone (PBN)

Summary In Experiment 1, groups of mice were administered either saline or MPTP (2 × 30mg/kg, s.c., separated by a 24-hr interval) 30min after being injected either PBN (15, 50 or 150mg/kg, s.c., low, medium and high doses, respectively) or L-Deprenyl (0.25 or 10.0mg/kg, s.c., low and high doses, respectively), the reference compound used, or saline. Tests of spontaneous motor activity 14 days later indicated that the MPTP-induced hypokinesia for locomotion and rearing was alleviated by prior administration with PBN (50 or 150mg/kg) or L-Deprenyl (10.0mg/kg); lower doses of PBN (15mg/kg) and L-Deprenyl (0.25mg/kg) did not affect the MPTP-induced deficits. Dopamine (DA) concentrations in the striatum confirmed a more severe loss of DA in the MPTP, PBN(15) + MPTP and Deprenyl(0.25) + MPTP groups than in the control group. Significant protection of DA was observed in the PBN(50) + MPTP, PBN(150) + MPTP and Deprenyl(10) + MPTP groups that did not exhibit an hypokinetic behaviour. In Experiment 2, the effects of repeated treatment with PBN (50mg/kg, s.c. over 12 days), post-MPTP, were studied in aged (15-month-old) and young (3-month-old) mice. Subchronic administration of PBN increased substantially the motor activity of old and young mice that had received MPTP. Aged control (saline) mice showed an activity deficit compared to young control mice; this deficit was abolished by repeated PBN treatment. The results suggest that moderate-to-high doses of PBN whether injected in a single dose prior to MPTP or subchronically following MPTP injections may afford protective effects against both the functional changes and DA-loss caused by MPTP treatment, possibly through an antioxidant mechanism.     

Butyrylcholinesterase inhibitors ameliorate cognitive dysfunction induced by amyloid-β peptide in mice

The cholinesterase inhibitor, rivastigmine, ameliorates cognitive dysfunction and is approved for the treatment of Alzheimer's disease (AD). Rivastigmine is a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE); however, the impact of BuChE inhibition on cognitive dysfunction remains to be determined. We compared the effects of a selective BuChE inhibitor, N1-phenethyl-norcymserine (PEC), rivastigmine and donepezil (an AChE-selective inhibitor) on cognitive dysfunction induced by amyloid-β peptide (Aβ_1-40) in mice. Five-week-old imprinting control region (ICR) mice were injected intracerebroventricularly (i.c.v.) with either Aβ_1-40 or the control peptide Aβ_40-1 on Day 0, and their recognition memory was analyzed by a novel object recognition test. Treatment with donepezil (1.0 mg/kg), rivastigmine (0.03, 0.1, 0.3 mg/kg) or PEC (1.0, 3.0 mg/kg) 20 min prior to, or immediately after the acquisition session (Day 4) ameliorated the Aβ_1-40 induced memory impairment, indicating a beneficial effect on memory acquisition and consolidation. In contrast, none of the investigated drugs proved effective when administrated before the retention session (Day 5). Repeated daily administration of donepezil, rivastigmine or PEC, on Days 0-3 inclusively, ameliorated the cognitive dysfunction in Aβ_1-40 challenged mice. Consistent with the reversal of memory impairments, donepezil, rivastigmine or PEC treatment significantly reduced Aβ_1-40 induced tyrosine nitration of hippocampal proteins, a marker of oxidative damage. These results indicate that BuChE inhibition, as well as AChE inhibition, is a viable therapeutic strategy for cognitive dysfunction in AD.     

The relation between dopamine oxidation currents in the nucleus accumbens and conditioned increases in motor activity in rats following repeated administration of d‐amphetamine or cocaine

Chronoamperometric recording techniques were used to monitor extracellular dopamine efflux in the nucleus accumbens associated with unconditioned and conditioned increases in motor activity in rats, following the intravenous administration of either d-amphetamine (0.63 mg/kg) or cocaine (3 mg/kg), or the presentation of a conditioned stimulus paired repeatedly with one of these psychostimulants. Each drug was administered daily for 7 days, either in the home cage or an environment in which a compound stimulus (light offset, odour) was presented. Rats in control groups received saline instead of drug in the distinctive test environment. On day 7 of training, significant increases in unconditioned motor activity were observed in the 30 min session following infusions of either d-amphetamine or cocaine. Associated dopamine oxidation currents in the nucleus accumbens increased immediately following administration of either drug and remained significantly elevated above baseline during the entire 30 min recording period. On the test day, presentation of the conditioned stimulus with vehicle infusions, in the distinct environment, was accompanied by an increase in dopamine oxidation currents and a conditioned increase in motor activity, only in the groups in which these stimuli had been paired with d-amphetamine or cocaine. Neither the magnitude or duration of the conditioned motor activity matched the corresponding change in extracellular dopamine efflux in the nucleus accumbens. Accordingly, it is argued that the increase in dopamine concentration serves as a neurochemical correlate of the unconditioned and conditioned stimuli. The change in motor activity constitutes the unconditioned and conditioned responses that are subserved by the neural systems activated by the initial rise in extracellullar dopamine.     

Influence of morphine- or apomorphine-induced sensitization on histamine state-dependent learning in the step-down passive avoidance test

Effects of morphine- or apomorphine-induced sensitization on histamine state-dependent memory of passive avoidance task were examined in mice. Pre-training intracerebroventricular (i.c.v.) administration of histamine (20 microg/mouse) decreased the learning of a one-trial passive avoidance task. Pre-test administration of histamine (10 and 20 microg/mouse) reversed amnesia induced by pre-training of histamine, with maximum response at 20 microg/mouse. Pre-training histamine-induced amnesia was also reversed in morphine- or apomorphine-sensitized mice that had previously received once daily injections of morphine (20 and 30 mg/kg) or apomorphine (0.5 and 1 mg/kg) for 3 days. The reversion of histamine-induced amnesia in morphine-sensitized mice was decreased by once daily administration of naloxone (0.5 and 1 mg/kg), SCH 23390 (0.05 and 0.1 mg/kg) or sulpiride (25, 50 and 100 mg/kg) prior to injection of morphine (30 mg/kg/day, 3 days). Furthermore, once daily administration of sulpiride (50 and 100 mg/kg) but not SCH 23390 (0.01, 0.05 and 0.1 mg/kg) prior to apomorphine (1 mg/kg, for 3 days) decreased the reversion of pre-training histamine-induced amnesia by apomorphine. The results suggest that apomorphine or morphine sensitization affects the impairment of memory induced by histamine and thus it is postulated that opioid and dopamine receptors may play an important role in this effect.