The effects of paradoxical sleep deprivation on amphetamine-induced behavioral sensitization in adult and adolescent mice.

Drug-induced behavioral sensitization (BS), paradoxical sleep deprivation (PSD) and adolescence in rodents are associated with changes in the mesolimbic dopaminergic system. We compared the effects of PSD on amphetamine-induced BS in adult and adolescent mice. Adult (90 days old) and adolescent (45 days old) Swiss mice were subjected to PSD for 48h. Immediately after PSD, mice received saline or 2.0mg/kg amphetamine intraperitoneally (i.p.), and their locomotion was quantified in activity chambers. Seven days later, all the animals were challenged with 2.0mg/kg amphetamine i.p., and their locomotion was quantified again. Acute amphetamine enhanced locomotion in both adult and adolescent mice, but BS was observed only in adolescent mice. Immediately after its termination, PSD decreased locomotion of both saline- and amphetamine-treated adolescent mice. Seven days later, previous PSD potentiated both the acute stimulatory effect of amphetamine and its sensitization in adolescent mice. In adult animals, previous PSD revealed BS. Our data suggest that adolescent mice are more vulnerable to both the immediate and long-term effects of PSD on amphetamine-induced locomotion. Because drug-induced BS in rodents shares neuroplastic changes with drug craving in humans, our findings also suggest that both adolescence and PSD could facilitate craving-related mechanisms in amphetamine abuse.

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.

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.

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.

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.

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.

Effects of sleep deprivation on memory in mice: role of state-dependent learning.

STUDY OBJECTIVES: A considerable amount of experimental evidence suggests that sleep plays a critical role in learning/memory processes. In addition to paradoxical sleep, slow wave sleep is also reported to be involved in the consolidation process of memories. Additionally, sleep deprivation can induce other behavioral modifications, such as emotionality and alternations in locomotor activity in rodents. These sleep deprivation-induced alterations in the behavioral state of animals could produce state-dependent learning and contribute, at least in part, to the amnestic effects of sleep deprivation. The aim of the present study was to examine the participation of state-dependent learning during memory impairment induced by either paradoxical sleep deprivation (PSD) or total sleep deprivation (TSD) in mice submitted to the plus-maze discriminative avoidance or to the passive avoidance task. DESIGN: Paradoxical sleep deprivation (by the multiple platform method) and total sleep deprivation (by the gentle handling method) were applied to animals before training and/or testing. CONCLUSIONS: Whereas pre-training or pre-test PSD impaired retrieval in both memory models, pre-training plus pre-test PSD counteracted this impairment. For TSD, pre-training, pre-test, and pre-training plus pre-test TSD impaired retrieval in both models. Our data demonstrate that PSD- (but not TSD-) memory deficits are critically related to state-dependent learning.

Long-term haloperidol treatment (but not risperidone) enhances addiction-related behaviors in mice: role of dopamine D2 receptors.

The high prevalence of psychostimulant abuse observed in schizophrenic patients may be related to the development of mesolimbic dopaminergic supersensitivity (MDS) or nigrostriatal dopaminergic supersensitivity (NDS) in response to the chronic blockade of dopamine receptors produced by typical neuroleptic treatment. We compared the effects of withdrawal from long-term administration of the typical neuroleptic haloperidol (Hal) and/or the atypical agent risperidone (Ris) on MDS and NDS, behaviorally evaluated by amphetamine-induced locomotor stimulation (AILS) and apomorphine-induced stereotypy (AIS) in mice, respectively. We further evaluated the duration of MDS and investigated the specific role of dopamine D2 receptors in this phenomenon by administering the D2 agonist quinpirole (Quin) to mice withdrawn from long-term treatment with these neuroleptics. Withdrawal (48 hours) from long-term (20 days) Hal (0.5 mg/kg i.p.) (but not 0.5 mg/kg Ris i.p.) treatment potentiated both AILS and AIS. Ris co-administration abolished the potentiation of AILS and AIS observed in Hal-withdrawn mice. Ten days after withdrawal from long-term treatment with Hal (but not with Ris or Ris + Hal), a potentiation in AILS was still observed. Only Hal-withdrawn mice presented an attenuation of locomotor inhibition produced by Quin. Our data suggest that the atypical neuroleptic Ris has a pharmacological property that counteracts the compensatory MDS and NDS developed in response to the chronic blockade of dopamine receptors imposed by Ris itself or by typical neuroleptics such as Hal. They also indicate that MDS may be long lasting and suggest that an upregulation of dopamine D2 receptors in response to long-term treatment with the typical neuroleptic is involved in this phenomenon.