The influence of early exposure to methylphenidate on addiction-related behaviors in mice.

Methylphenidate (MET) has a putative cognitive enhancer effect that has led adolescents and young adults to increase and indiscriminate its use aiming to ameliorate their productivity. However, the impacts of MET on addiction-related behaviors, emotional levels, and cognition are still not fully understood. To investigate the influence of chronic treatment with MET during adolescence on addiction-like behaviors, memory, and anxiety in adult mice. Thirty-day-old female mice received i.p. 10 mg/kg MET or Veh injections for 10 consecutive days. Forty days after the treatment (mice were 70-days-old), animals were submitted to the behavioral evaluation under the effects of MET, which included: MET-induced conditioned place preference (CPP), behavioral sensitization, and plus-maze discriminative avoidance task. Pre-exposure to MET during adolescence promoted an early expression of CPP and also facilitated the development of MET-induced behavioral sensitization during adulthood. These addictive-like behaviors were accompanied by anxiogenic effects of MET but not by any memory-enhancing effect. We demonstrated that exposure to MET during adolescence can increase the vulnerability to addiction-like behaviors and anxiety during adulthood. Our results reinforce the necessity of a more efficient system to control MET indiscriminate use, thus avoiding its potential tardive addictive effects.

Effects of prenatal immune activation on amphetamine-induced addictive behaviors: Contributions from animal models.

BACKGROUND: Prenatal environmental adversities may affect brain development and are associated with increased risk for schizophrenia, an illness with 50% comorbidity with addiction. Maternal immune activation by poly-inosinic-citidilic acid (Poly(I:C)) exposure can promote behavioral alterations consistent with schizophrenia symptoms in rodents. OBJECTIVES: Considering the vulnerability to addiction in patients with schizophrenia, we evaluated the interactions between prenatal Poly(I:C) administration and addiction in two animal models (behavioral sensitization and conditioned place preference - CPP) in mice repeatedly treated with amphetamine (AMP). Additionally, stereotyped behavior and cross-sensitization with cocaine (COC) were also investigated. METHODS: Swiss male mice offspring were submitted to prenatal administration of 5mg/kg Poly(I:C) in the 9(th) day of pregnancy. At the age of 90days, mice were treated with 2.5mg/kg AMP for 9days to evaluate behavioral sensitization or stereotyped behavior. Cross-sensitization with 10mg/kg COC was evaluated 24h after the last treatment day. For AMP-induced CPP evaluation, mice were treated during 8 consecutive days. RESULTS: Prenatal Poly(I:C) administration potentiated both AMP-induced behavioral sensitization and CPP. Furthermore, Poly(I:C) increased cross-sensitization with COC. CONCLUSIONS: Prenatal administration of Poly(I:C) is able to potentiate vulnerability to addiction in two animal models, without however modulating stereotyped behavior.

Effects of rimonabant on the development of single dose-induced behavioral sensitization to ethanol, morphine and cocaine in mice.

RATIONALE: The endocannabinoid system has been implicated in the neurobiological mechanism underlying drug addiction, especially the primary rewarding dopamine-dependent processes. Therefore, endocannabinoid receptor antagonists, such as the CB1 cannabinoid antagonist rimonabant, have been proposed as candidates for preventive addiction therapies. OBJECTIVES: Investigate the possible involvement of CB1 receptors in the development of behavioral sensitization to ethanol, morphine and cocaine in mice. METHODS: We compared the effects of different doses of rimonabant (0.3, 1, 3 and 10mg/kg) on spontaneous locomotor activity in the open-field, hyperlocomotion induced by acute administration of ethanol (1.8g/kg), morphine (20mg/kg) or cocaine (10mg/kg) and on subsequent drug-induced locomotor sensitization using a two-injection protocol in mice. We also investigated a possible depressive-like effect of an acute rimonabant challenge at the highest dose and its potential anxiogenic property. RESULTS: At the highest dose, rimonabant abolished ethanol- and cocaine-induced hyperlocomotion and behavioral sensitization without modifying spontaneous and central locomotor activity or inducing depressive-like behavior on the forced swim test in mice. The other doses of rimonabant also selectively blocked acute ethanol-induced central hyperlocomotion. Although rimonabant at 0.3 and 1mg/kg potentiated the central hyperlocomotion induced by acute morphine injection, it was effective in attenuating morphine-induced behavioral sensitization at all doses. CONCLUSIONS: Because the neural basis of behavioral sensitization has been proposed to correspond to some components of addiction, our findings indicate that the endocannabinoid system might be involved in ethanol, cocaine and morphine abuse.

Functional capacity after pediatric liver transplantation: a pilot study.

The prospective cross-sectional study investigated the 6MWT performance in pediatric group of liver transplant recipients (6-17 yr, median post-transplantation time of 22 months) and compared to the normal values obtained in healthy children as well as evaluated the reproducibility of the 6MWT. We analyzed the relationship between walked distance and the 6MWw, distance walked × body weight) with the anthropometric, clinical, and pulmonary functions. In post-transplanted group, the average walked distance was significantly shorter compared with control (687 ± 80 m vs. 511 ± 72 m, p < 0.001). The calculated ICC coefficient confirmed the reproducibility among tests. The Pearson correlation revealed that only walked distance in the 6MWT was moderately correlated with tidal volume. Conversely, the 6MWw was significantly correlated with age, weight, height, BMI, FVC, PEF rate, and volume expiratory. According to multiple regression analysis, age, VE and FVC factors explained 80% of the variance in the 6MWw. In conclusion, the pediatric liver transplant recipients' performance in the 6MWT is significantly lower than the values for healthy children of the same age. Notably, the 6MWw may provide relevant information, constituting an additional parameter in the determination of functional capacity.

Prevalence of obstructive sleep apnea in patients with mucopolysaccharidosis types I, II, and VI in a reference center.

PURPOSE: Mucopolysaccharidosis (MPS) encompasses a group of rare lysosomal storage disorders that are associated with the accumulation of glycosaminoglycans in organs and tissues. Respiratory disorders occur in all MPS types. In these patients, the prevalence of obstructive sleep apnea syndrome (OSAS), which may confer additional morbidity, remains overlooked, and the results of the few existing studies are controversial. The present study aimed to characterize the prevalence of OSAS in patients with MPS types I, II, and VI in a reference center. METHODS: Forty-five patients with MPS (I, n=17; II, n=16; and VI; n=12) in the Centro de Referência em Erros Inatos do Metabolismo, who underwent full-night polysomnography, were enrolled in a retrospective study. Demographic data and clinical history were collected from medical records of the first medical consultation. RESULTS: The prevalence of OSAS in patients with MPS was 69.8%. MPS type I patients seemed to be more susceptible to OSA-induced hypoxemia, as indicated by reduced mean SpO2 levels during both NREM and rapid eye movement sleep as well as during SpO2 nadir. CONCLUSIONS: Patients with MPS displayed a high prevalence of OSAS, often with moderate to high severity. Together, our results reinforce the need for OSAS screening in all patients with MPS.

Therapeutic effects of the transplantation of VEGF overexpressing bone marrow mesenchymal stem cells in the hippocampus of murine model of Alzheimer's disease.

Alzheimer's disease (AD) is clinically characterized by progressive memory loss, behavioral and learning dysfunction and cognitive deficits, such as alterations in social interactions. The major pathological features of AD are the formation of senile plaques and neurofibrillary tangles together with neuronal and vascular damage. The double transgenic mouse model of AD (2xTg-AD) with the APPswe/PS1dE9 mutations shows characteristics that are similar to those observed in AD patients, including social memory impairment, senile plaque formation and vascular deficits. Mesenchymal stem cells (MSCs), when transplanted into the brain, produce positive effects by reducing amyloid-beta (Aß) deposition in transgenic amyloid precursor protein (APP)/presenilins1 (PS1) mice. Vascular endothelial growth factor (VEGF), exhibits neuroprotective effects against the excitotoxicity implicated in the AD neurodegeneration. The present study investigates the effects of MSCs overexpressing VEGF in hippocampal neovascularization, cognitive dysfunction and senile plaques present in 2xTg-AD transgenic mice. MSC were transfected with vascular endothelial growth factor cloned in uP vector under control of modified CMV promoter (uP-VEGF) vector, by electroporation and expanded at the 14th passage. 2xTg-AD animals at 6, 9 and 12 months old were transplanted with MSC-VEGF or MSC. The animals were tested for behavioral tasks to access locomotion, novelty exploration, learning and memory, and their brains were analyzed by immunohistochemistry (IHC) for vascularization and Aß plaques. MSC-VEGF treatment favored the neovascularization and diminished senile plaques in hippocampal specific layers. Consequently, the treatment was able to provide behavioral benefits and reduce cognitive deficits by recovering the innate interest to novelty and counteracting memory deficits present in these AD transgenic animals. Therefore, this study has important therapeutic implications for the vascular damage in the neurodegeneration promoted by AD.

Effects of acute and long-term typical or atypical neuroleptics on morphine-induced behavioural effects in mice.

1. It has been suggested that the high prevalence of drug abuse in schizophrenics is related to chronic treatment with typical neuroleptics and dopaminergic supersensitivity that develops as a consequence. Within this context, atypical neuroleptics do not seem to induce this phenomenon. In the present study, we investigated the effects of acute administration or withdrawal from long-term administration of haloperidol and/or ziprasidone on morphine-induced open-field behaviour in mice. 2. In the first experiment, mice were given a single injection of haloperidol (1 mg/kg, i.p.) or several doses of ziprasidone (2, 4 or 6 mg/kg, i.p.) and motor activity was quantified by the open-field test. The aim of the second experiment was to verify the effects of an acute injection of haloperidol (1 mg/kg) or ziprasidone (6 mg/kg) on 20 mg/kg morphine-induced behaviours in the open-field test. In the third experiment, mice were treated with 1 mg/kg haloperidol and/or 2, 4 or 6 mg/kg ziprasidone for 20 days. Seventy-two hours after the last injection, mice were injected with 20 mg/kg, i.p., morphine and then subjected to the open-field test. Acute haloperidol or ziprasidone decreased spontaneous general activity and abolished morphine-induced locomotor stimulation. 3. Withdrawal from haloperidol or ziprasidone did not modify morphine-elicited behaviours in the open-field test. The results suggest that withdrawal from neuroleptic treatments does not contribute to the acute effect of morphine in schizophrenic patients.

Opposite effects of neonatal hypoxia on acute amphetamine-induced hyperlocomotion in adult and adolescent mice.

We investigated whether the effect of neonatal hypoxia on amphetamine-induced hyperlocomotion can reproduce the ontogenic (age of onset) properties of schizophrenia. Neonatal hypoxia enhanced amphetamine-induced hyperlocomotion in adult mice and decreased it in adolescent mice. These findings provide ontogenic validity for this very simple animal model of schizophrenia.

Short-term sleep deprivation reinstates memory retrieval in mice: the role of corticosterone secretion.

While the effects of sleep deprivation (SD) on the acquisition and consolidation phases of memory have been extensively characterized, its effects on memory retrieval remain overlooked. SD alone is a stressor, and stress-activated glucocorticoids promote bimodal effects on memory. Because we have recently demonstrated that 72h SD impairs memory retrieval in the plus-maze discriminative avoidance task (PM-DAT) in mice, this study investigated whether shorter SD periods would facilitate retrieval. In Experiment I, the temporal forgetting curve of the PM-DAT was determined and an interval between training/testing in which retrieval was no longer present was used in all subsequent experiments. In Experiments II and III, retrieval performance and corticosterone concentration, respectively, were quantified in mice that were sleep deprived for 12 or 24h before testing. In Experiments IV and V, the effects of the corticosterone synthesis inhibitor metyrapone were evaluated on 12h SD-induced retrieval reinstatement and corticosterone concentration enhancement, respectively. Experiment VI determined whether pre-test acute administration of exogenous corticosterone would mimic the facilitatory effects of 12h SD on retrieval. Thirty days after training, mice presented poor performance of the task; however, SD for 12h (but not for 24) before testing reinstated memory retrieval. This facilitatory effect was accompanied by increased corticosterone concentration, abolished by metyrapone, and mimicked by pre-test acute corticosterone administration. Collectively, short-term SD can facilitate memory retrieval by enhancing corticosterone secretion. This facilitatory effect is abolished by longer periods of SD.

Sleep deprivation increases mortality in female mice bearing Ehrlich ascitic tumor.

OBJECTIVES: Sleep deprivation is a growing public health hazard, yet it is still under-recognized. Sleep disorders and disruption of sleep patterns may compromise the immune function and adversely affect host resistance to infectious diseases. This is a particular risk in cancer patients, who report a high frequency of sleep disturbances. The present study investigated the effects of sleep deprivation on the development of Ehrlich ascitic tumors (EAT) in female BALB/c mice. Our study also evaluated whether EAT would induce alterations in sleep pattern. Spleen lymphocyte cell populations and mortality were also quantified. METHODS: Female BALB/c mice were intraperitoneally inoculated with EAT cells. Immediately after the inoculation procedure, animals were sleep deprived for 72 h. Ten or 15 days after inoculation, the number of tumoral cells was quantified and the lymphocytic cell population in the spleen was characterized by flow cytometry. In addition, the effect of sleep deprivation on EAT-induced mortality was quantified and the influence of EAT on sleep patterns was determined. RESULTS: Sleep deprivation did not potentiate EAT growth, but it significantly increased mortality. Additionally, both EAT and sleep deprivation decreased frequencies of splenic CD4+, CD8+ and CD19+ cells. With respect to sleep patterns, EAT significantly enhanced paradoxical sleep time. CONCLUSIONS: Although sleep deprivation did not potentiate EAT growth, it decreased the survival of female tumor-bearing mice.

Role of state-dependent learning in the cognitive effects of caffeine in mice.

Caffeine is the most widely used psychoactive substance in the world and it is generally believed that it promotes beneficial effects on cognitive performance. However, there is also evidence suggesting that caffeine has inhibitory effects on learning and memory. Considering that caffeine may have anxiogenic effects, thus changing the emotional state of the subjects, state-dependent learning may play a role in caffeine-induced cognitive alterations. Mice were administered 20 mg/kg caffeine before training and/or before testing both in the plus-maze discriminative avoidance task (an animal model that concomitantly evaluates learning, memory, anxiety-like behaviour and general activity) and in the inhibitory avoidance task, a classic paradigm for evaluating memory in rodents. Pre-training caffeine administration did not modify learning, but produced an anxiogenic effect and impaired memory retention. While pre-test administration of caffeine did not modify retrieval on its own, the pre-test administration counteracted the memory deficit induced by the pre-training caffeine injection in both the plus-maze discriminative and inhibitory avoidance tasks. Our data demonstrate that caffeine-induced memory deficits are critically related to state-dependent learning, reinforcing the importance of considering the participation of state-dependency on the interpretation of the cognitive effects of caffeine. The possible participation of caffeine-induced anxiety alterations in state-dependent memory deficits is discussed.

Amphetamine-induced memory impairment in a discriminative avoidance task is state-dependent in mice.

In both humans and laboratory animals, the reports of cognitive effects following acute amphetamine (Amph) administration are mixed and depend, for example, on the timing of administration (e.g. before or after task acquisition) and/or on the memory model used. Besides its cognitive effects, Amph produces other important behavioural effects, including alterations in anxiety and general activity, which could modify the subject's internal state, thereby facilitating state-dependent learning. Importantly, state-dependency has been linked to drug dependence in humans. This study evaluates the role of state-dependent learning in Amph-induced memory deficits in mice submitted to a discriminative avoidance task. Mice were given Amph (3 mg/kg) before training and/or before testing in the plus-maze discriminative avoidance task, an animal model that concomitantly evaluates learning, memory, anxiety-like behaviour and general activity. Pre-training Amph administration did not affect the ability to learn the discriminative task, but rather induced anxiogenic-like effects and a marked retention deficit in the test session. This memory impairment was completely absent when animals received Amph before both the training and the test sessions. Amph-induced memory impairment of a discriminative avoidance task is state-dependent, such that a response acquired in the 'Amph state' cannot be recalled in the normal state. The involvement of anxiety alterations in this 'Amph state' is discussed.

Ethanol-induced memory impairment in a discriminative avoidance task is state-dependent.

BACKGROUND: A considerable amount of experimental evidence has demonstrated ethanol (EtOH) induced amnestic effects following EtOH administration during pretraining in a variety of tasks both in humans and in laboratory animals. Although the phenomenon of state-dependency is known to play a critical role in memory deficits induced by both pharmacological and nonpharmacological pretraining perturbations, the involvement of this phenomenon in EtOH-induced anterograde amnesia has been overlooked. This study aimed to investigate the role of state-dependency in EtOH-induced amnestic effects and its interactions with the well-known anxiolysis and locomotor alterations. METHODS: Mice were treated with 1.2 or 2.4 g/kg EtOH before training and/or before testing in the plus-maze discriminative avoidance task, an animal model that concomitantly evaluates learning, memory, anxiety-like behavior, and general activity. RESULTS: Whereas both doses of EtOH induced anxiolysis, the 1.2 g/kg dose enhanced locomotion while the 2.4 g/kg dose decreased it. In addition, the administration of 1.2 g/kg of this drug during pretraining caused memory impairment, which was counteracted by the pretest administration of the same dose, revealing the participation of the state-dependency. Conversely, the administration of 2.4 g/kg EtOH led to amnestic effects irrespective of the time of the administration (pretraining and/or pretest), eliminating the influence of state-dependency. CONCLUSIONS: Our data demonstrate that EtOH-induced memory deficits are critically related to state-dependency, which can also be affected by the dose range. These results indicate the possible participation of EtOH-induced modifications in anxiety and motor activity levels in relation to state-dependent memory deficits.

Inhibitory effects of modafinil on emotional memory in mice.

Modafinil (MOD), a psychostimulant used to treat narcolepsy, excessive daytime sleepiness, and sleepiness due to obstructive sleep apnea, appears to promote a possible facilitatory effect on cognitive function. In the present study, we investigated the effects of the acute administration of MOD on the different steps of emotional memory formation and usage (acquisition, consolidation and retrieval) as well as the possible participation of the state-dependency phenomenon on the cognitive effects of this compound. Mice were acutely treated with 32, 64 or 128 mg/kg MOD before training or testing or immediately after training and were subjected to the plus-maze discriminative avoidance task. The results showed that although pre-training MOD administration did not exert any effects on learning, the doses of 32 or 64 mg/kg induced emotional memory deficits during testing. Still, the post-training acute administration of the higher doses of MOD (64 and 128 mg/kg) impaired associative memory consolidation. When the drug was administered pre-test, only the 32 mg/kg dose impaired the task retrieval. Importantly, the cognitive impairing effects induced by 32 mg/kg MOD were not related to the phenomenon of state-dependency. In all, our findings provide pre-clinical evidence of potential emotional memory amnesia induced by MOD. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Mild acute stress reactivates memory of a discriminative avoidance task in mice.

Previous studies have demonstrated that stress or glucocorticoids impair the retrieval of spatial memory in rodents and declarative memory in humans. However, the effects on memory retrieval of stress introduced a long time after learning have not been well studied. We investigated whether a mild, extrinsic stressor (1-s 0.1 or 0.3 mA foot shock) would reactivate low baseline retrieval of an aversive memory [the plus-maze discriminative avoidance task (PM-DAT)] and if it would be modulated by glucocorticoids. In Experiment 1, male Swiss mice received pre-test foot shock (n = 10 mice/group) 7 days after training and just before testing. A time-retrieval curve for low baseline retrieval for the subsequent experiments was also determined (Experiment 2, n = 10 mice/group). We investigated if pre-test foot shock could modify corticosterone release (Experiment 3, n = 8-9 mice/group) and reinstate retrieval in the PM-DAT (Experiment 4, n = 15 mice/group). The effects of metyrapone (100 mg/kg) on retrieval reinstatement (Experiment 5, n = 15 mice/group) and serum corticosterone enhancement (Experiments 6, n = 7-9 mice/group) induced by foot shock were analyzed. Finally, the effects of foot shock itself on PM-DAT exploration were verified (Experiment 7, n = 10 mice/group). We demonstrated here that foot shock reinstated the retrieval of a low baseline, discriminative avoidance task 30 (but not 7) days after training. This facilitative effect was not dependent on corticosterone secretion because metyrapone abolished the enhancement of corticosterone concentration but did not reverse the stress-induced reinstatement of retrieval.

Short-term social isolation induces depressive-like behaviour and reinstates the retrieval of an aversive task: mood-congruent memory in male mice?

BACKGROUND: Although mood-congruent memory (MCM), or the tendency to recall information consistent with one's mood, is a robust phenomenon in human depression, to our knowledge, it has never been demonstrated in animals. METHODS: Mice were subjected to social isolation (SI) or crowding for 12 hours and had their depressive-like behaviour (evaluated by the forced swim, tail suspension, sucrose preference and splash tests) or their serum corticosterone concentrations evaluated. In addition, we determined the temporal forgetting curve of the plus-maze discriminative avoidance task (PM-DAT) and examined the effects of SI or crowding on memory retrieval in the PM-DAT. Finally, we verified the effects of metyrapone pretreatment on reinstatement of memory retrieval or on the increase of corticosterone levels induced by SI. RESULTS: Twelve hours of SI produced depressive-like behaviour, enhanced corticosterone concentration and reinstated retrieval of a forgotten discriminative aversive (i.e., negatively valenced) task. Depressive-like behaviour was critical for this facilitative effect of SI because 12 hours of crowding neither induced depressive-like behaviour nor enhanced retrieval, although it increased corticosterone levels at the same magnitude as SI. However, corticosterone increase was a necessary condition for MCM in mice, in that the corticosterone synthesis inhibitor metyrapone abolished SI-induced retrieval reinstatement. LIMITATIONS: Our study did not investigate the effects of the social manipulations proposed here in a positively valenced task. CONCLUSION: To our knowledge, the present paper provides the first evidence of MCM in animal models.

Effects of zolpidem on sedation, anxiety, and memory in the plus-maze discriminative avoidance task.

RATIONALE: Zolpidem (Zolp), a hypnotic drug prescribed to treat insomnia, may have negative effects on memory, but reports are inconsistent. OBJECTIVES: We examined the effects of acute doses of Zolp (2, 5, or 10 mg/kg, i.p.) on memory formation (learning, consolidation, and retrieval) using the plus-maze discriminative avoidance task. METHODS: Mice were acutely treated with Zolp 30 min before training or testing. In addition, the effects of Zolp and midazolam (Mid; a classic benzodiazepine) on consolidation at different time points were examined. The possible role of state dependency was investigated using combined pre-training and pre-test treatments. RESULTS: Zolp produced a dose-dependent sedative effect, without modifying anxiety-like behavior. The pre-training administration of 5 or 10 mg/kg resulted in retention deficits. When administered immediately after training or before testing, memory was preserved. Zolp post-training administration (2 or 3 h) impaired subsequent memory. There was no participation of state dependency phenomenon in the amnestic effects of Zolp. Similar to Zolp, Mid impaired memory consolidation when administered 1 h after training. CONCLUSIONS: Amnestic effects occurred when Zolp was administered either before or 2-3 h after training. These memory deficits are not related to state dependency. Moreover, Zolp did not impair memory retrieval. Notably, the memory-impairing effects of Zolp are similar to those of Mid, with the exception of the time point at which the drug can modify consolidation. Finally, the memory effects were unrelated to sedation or anxiolysis.

Sleep deprivation impairs emotional memory retrieval in mice: influence of sex.

The deleterious effects of paradoxical sleep deprivation on memory processes are well documented. However, non-selective sleep deprivation occurs more commonly in modern society and thus represents a better translational model. We have recently reported that acute total sleep deprivation (TSD) for 6 h immediately before testing impaired performance of male mice in the plus-maze discriminative avoidance task (PM-DAT) and in the passive avoidance task (PAT). In order to extend these findings to females, we examined the effect of (pre-test) TSD on the retrieval of different memory tasks in both male and female mice. Animals were tested using 3 distinct memory models: 1) conditioning fear context (CFC), 2) PAT and 3) PM-DAT. In all experiments, animals were totally sleep-deprived by the gentle interference method for 6h immediately before being tested. In the CFC task and the PAT, TSD induced memory impairment regardless of sex. In PM-DAT, the memory impairing effects of TSD were greater in females. Collectively, our results confirm the impairing effect of TSD on emotional memory retrieval and demonstrate that it can be higher in female mice depending on the memory task evaluated.

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.

Adolescent mice are more vulnerable than adults to single injection-induced behavioral sensitization to amphetamine.

Drug-induced behavioral sensitization in rodents has enhanced our understanding of why drugs acquire increasing motivational and incentive value. Compared to adults, human adolescents have accelerated dependence courses with shorter times from first exposure to dependence. We compared adolescent and adult mice in their ability to develop behavioral sensitization to amphetamine following a single injection. Adult (90-day-old) and adolescent (45-day-old) male Swiss mice received an acute intraperitoneal injection of saline or amphetamine (1.0, 2.0 or 4.0 mg/kg). Seven days later, half of the mice from the saline group received a second injection of saline. The remaining animals were challenged with 2.0 mg/kg amphetamine. Following all of the injections, mice were placed in activity chambers and locomotion was quantified for 45 min. The magnitude of both the acute and sensitized locomotor stimulatory effect of amphetamine was higher in the adolescent mice. Previous experience with the test environment inhibited the acute amphetamine stimulation in both adolescent and adult mice, but facilitated the detection of elevated spontaneous locomotion in adolescent animals. These results support the notion that the adolescent period is associated with an increased risk for development of drug abuse. Additionally, they indicate a complex interaction between the environmental novelty, adolescence and amphetamine.