ABSTRACT
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'.
Subject(s)
Amnesia/chemically induced , Benzhydryl Compounds/adverse effects , Central Nervous System Stimulants/adverse effects , Disease Models, Animal , Memory/drug effects , Nootropic Agents/adverse effects , Performance-Enhancing Substances/adverse effects , Animals , Avoidance Learning/drug effects , Behavior, Animal/drug effects , Benzhydryl Compounds/administration & dosage , Benzhydryl Compounds/pharmacology , Central Nervous System Stimulants/administration & dosage , Central Nervous System Stimulants/pharmacology , Cognition Disorders/chemically induced , Discrimination Learning/drug effects , Dose-Response Relationship, Drug , Male , Maze Learning/drug effects , Memory, Episodic , Mice , Modafinil , Nootropic Agents/administration & dosage , Nootropic Agents/pharmacology , Performance-Enhancing Substances/administration & dosage , Performance-Enhancing Substances/pharmacology , Random Allocation , Retention, Psychology/drug effectsABSTRACT
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.
Subject(s)
Avoidance Learning/physiology , Emotions/physiology , Mental Recall/physiology , Sleep Deprivation/psychology , Animals , Conditioning, Psychological/physiology , Discrimination Learning/physiology , Fear/physiology , Female , Male , Mice , Sex FactorsABSTRACT
Repeated or even a single exposure to drugs of abuse can lead to persistent locomotor sensitization, which is the result of an abundance of neuroplastic changes occurring within the circuitry involved in motivational behavior and is thought to play a key role in certain aspects of drug addiction. There is substantial controversy about the addictive potential of modafinil, a wake-promoting drug used to treat narcolepsy that is increasingly being used as a cognitive enhancer and has been proposed as a pharmacotherapy for cocaine dependence. Male mice were used to investigate the ability of modafinil to induce locomotor sensitization after repeated or single administration in mice. Bidirectional cross-sensitization with cocaine and modafinil-induced conditioned place preference were also evaluated. Both repeated and single exposure to moderate and high doses of modafinil produced a pronounced locomotor sensitization that cross-sensitized in a bidirectional way with cocaine. Remarkably, when cocaine and modafinil were repeatedly administered sequentially, their behavioral sensitization was additive. Supporting these behavioral sensitization data, modafinil produced a pronounced conditioned place preference in the mouse. Taken together, the present findings provide pre-clinical evidence for the addictive potential of modafinil. Our data also strongly suggest that similar neural substrates are involved in the psychomotor/rewarding effects of modafinil and cocaine.
Subject(s)
Benzhydryl Compounds/pharmacology , Central Nervous System Sensitization/drug effects , Central Nervous System Sensitization/physiology , Central Nervous System Stimulants/pharmacology , Cocaine-Related Disorders/physiopathology , Cocaine/pharmacology , Motor Activity/drug effects , Motor Activity/physiology , Neuronal Plasticity/drug effects , Neuronal Plasticity/physiology , Substance-Related Disorders/physiopathology , Animals , Brain/drug effects , Brain/physiopathology , Choice Behavior/drug effects , Choice Behavior/physiology , Conditioning, Classical/drug effects , Conditioning, Classical/physiology , Dose-Response Relationship, Drug , Drug Synergism , Injections, Intraperitoneal , Male , Mice , Modafinil , Motivation/drug effects , Motivation/physiology , Reward , Social EnvironmentABSTRACT
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.
