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 oxotremorine and physostigmine on the inhibitory avoidance impairment produced by amitriptyline in male and female mice

We have previously observed that amitriptyline and other antidepressants produce impairing effects on inhibitory avoidance (also called passive avoidance) in mice of both sexes. In the present study we investigated the involvement of the cholinergic system in the inhibitory avoidance impairment produced by acute amitriptyline in male and female CD1 mice. For this purpose, the effects on said task of acute i.p. administration of several doses of amitriptyline, either alone or in combination with the cholinergic agonists oxotremorine and physostigmine, were evaluated. Pre-training administration of 5, 7.5, 10 or 15 mg/kg of amitriptyline produced a significant impairment of inhibitory avoidance in both males and females. When oxotremorine (0.05 or 0.1 mg/kg) was co-administered with amitriptyline, the antidepressant's impairing effect was partially counteracted, although inhibitory avoidance learning was not significant. Physostigmine (0.15, 0.3 or 0.6 mg/kg) counteracted the impairment produced by amitriptyline, as mice treated with both drugs exhibited inhibitory avoidance learning. These results show that the inhibitory avoidance impairment produced by amitriptyline in male and female mice is mediated, at least partially, by the cholinergic system.     

Amnestic effect of cocaine after the termination of its stimulant action

The effects of cocaine on memory are controversial. Furthermore, the psychostimulant action of cocaine can be a critical issue in the interpretation of its effects on learning/memory models. The effects of a single administration of cocaine on memory were investigated during the presence of its motor stimulating effect or just after its termination. The plus-maze discriminative avoidance task (PM-DAT) was used because it provides simultaneous information about memory, anxiety and motor activity. In Experiment I, mice received saline, 7.5, 10, 15 or 30 mg/kg cocaine 5 min before the training session. In Experiment II, mice were trained 30 min after the injection of saline, 7.5, 10, 15 or 30 mg/kg cocaine. In Experiment III, mice received 30 mg/kg cocaine 30 min pre-training and pre-test. In Experiment IV, mice received 30 mg/kg cocaine immediately post-training. Tests were always conduced 24 h following the training session. Given 5 min before training, cocaine promoted a motor stimulant effect at the highest dose during the training session but did not impair memory. When cocaine was injected 30 min pre-training, the drug did not modify motor activity, but produced marked amnestic effects at all doses tested. This amnesia induced by cocaine given 30 min pre-training was not related to a state-dependent learning because it was not abolished by pre-test administration of the drug. Post-training cocaine administration did not induce memory deficits either. Our results suggest that the post-stimulant phase is the critical moment for cocaine-induced memory deficit in a discriminative task in mice.     

Sildenafil, a selective phosphodiesterase type 5 inhibitor, enhances memory reconsolidation of an inhibitory avoidance task in mice

Intracellular levels of the second messengers cAMP and cGMP are maintained through a balance between production, carried out by adenyl cyclase (AC) and guanylyl cyclase (GC), and degradation, carried out by phosphodiesterases (PDEs). Recently, PDEs have gained increased attention as potential new targets for cognition enhancement, with particular reference to phosphodiesterase type 5 (PDE5A). It is accepted that once consolidation is completed memory becomes permanent, but it has also been suggested that reactivation (memory retrieval) of the original memory makes it sensitive to the same treatments that affect memory consolidation when given after training. This new period of sensitivity coined the term reconsolidation. Sildenafil (1, 3, and 10mg/kg, ip), a cGMP-PDE5 inhibitor, facilitated retention performance of a one-trial step-through inhibitory avoidance task, when administered to CF-1 male mice immediately after retrieval. The effects of sildenafil (1mg/kg, ip) were time-dependent, long-lasting and inversely correlated with memory age. The administration of sildenafil (1mg/kg, ip) 30 min prior to the 2nd retention test did not affect retention of mice given post-retrieval injections of either vehicle or sildenafil (1mg/kg, ip). Finally, an enhancement of retention was also observed in CF-1 female mice receiving sildenafil (1mg/kg, ip) immediately, but not 180 min after retrieval. In the present paper we reported for the first time that systemic administration of sildenafil after memory reactivation enhances retention performance of the original learning. Our results indirectly point out cGMP, a component of the NO/cGMP/PKG pathway, as a necessary factor for memory reconsolidation.     

Sleep deprivation impairs spatial memory and decreases extracellular signal-regulated kinase phosphorylation in the hippocampus

Loss of sleep may result in memory impairment. However, little is known about the biochemical basis for memory deficits induced by sleep deprivation. Extracellular signal-regulated kinase (ERK) is involved in memory consolidation in different tasks. Phosphorylation of ERK is necessary for its activation and is an important step in mediating neuronal responses to synaptic activities. The aim of the present study was to determine the effects of total sleep deprivation (TSD) on memory and ERK phosphorylation in the brain. Rats were trained in Morris water maze to find a hidden platform (a spatial task) or a visible platform (a nonspatial task) after 6 h TSD or spontaneous sleep. TSD had no effect on spatial learning, but significantly impaired spatial memory tested 24 h after training. Nonspatial learning and memory were not impaired by TSD. Phospho-ERK levels in the hippocampus were significantly reduced after 6 h TSD compared to the controls and returned to the control levels after 2 h recovery sleep. Total ERK1 and ERK2 were slightly increased after 6 h TSD and returned to the control levels after 2 h recovery sleep. These alterations were not observed in the cortex after TSD. Protein phosphotase-1 and mitogen-activated protein kinase phosphatase-2, which dephosphorylates phospho-ERK, were also measured, but they were not altered by TSD. The impairments of both spatial memory and ERK phosphorylation indicate that the hippocampus is vulnerable to sleep loss. These results are consistent with the idea that decreased ERK activation in the hippocampus is involved in sleep deprivation-induced spatial memory impairment.     

Deficits in avoidance responding after paradoxical sleep deprivation are not associated with altered [3H]pirenzepine binding to M1 muscarinic receptors in rat brain

Previous work had indicated that animals that were sleep-deprived and then trained on a passive avoidance task show poor retention of the task 24 h later after being allowed to sleep freely again. Cholinergic involvement is suggested by the fact that this effect is prevented by treatment with the muscarinic agonist pilocarpine during sleep deprivation. The observation that similar deficits are observed in non-deprived rats after treatment with M1-selective antagonist compounds such as dicyclomine or pirenzepine cause similar impairments, and gave rise to the hypothesis that sleep deprivation might induce significant reductions in M1 binding in brain areas involved in learning and memory processes. Rats were deprived of sleep for 96 h and then either immediately killed, or allowed to recover sleep for 24 h before being killed. [3H]pirenzepine binding to M1 sites was examined by quantitative autoradiography in 39 different brain areas in cage controls, sleep-deprived and sleep-recovered animals (N=8 per group). No significant differences among groups were found in any brain region. A separate group of animals was subjected to the sleep deprivation procedure and then trained in a simple avoidance task. Animals were then allowed to sleep and retested 24 h later. This group showed a significant impairment in the avoidance task compared to cage controls, in agreement with previous observations. These data suggest that proactive learning/memory deficits induced by sleep deprivation cannot be attributed to altered M1 binding either immediately after deprivation (when avoidance training occurs) or after sleep has recovered (when acquisition/retention are tested). The possibility remains that alterations in M1 function occur at post-membrane second messenger systems.     

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.     

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.     

Effects of tifluadom on passive avoidance behaviour in DBA/2 mice

The effects of the selective opiate kappa-receptor agonist tifluadom on memory were investigated in a passive avoidance task in 3 sets of experiments carried out with DBA/2 (DBA) mice both familiarized and unfamiliarized with the apparatus. In a first set of experiments, tifluadom (1.0 or 2.5, but not 0.5 mg/kg) administration immediately after training impaired retention performance of non-familiarized mice. This impairment was still evident when the drug was injected 15 or 30, but not 60 min after training. A second set of experiments was carried out with mice familiarized with the apparatus. Tifluadom was less effective in impairing memory in this group of animals, as compared with non-familiarized mice. Finally, in a third set of experiments, carried out with non-familiarized mice, a 15 min immobilization stress, which was ineffective when administered alone, enhanced the effects of tifluadom (1.0 mg/kg). The results are discussed in terms of attenuation of emotionality, resulting in impaired retention, following post-training opiate administration.     

Different effects of scopolamine on the retrieval of spatial memory and fear memory

Retrieval of memory is fundamental for our life as individuals. The participation of cholinergic system in memory consolidation process has been extensively studied, but there are few data concerning the function of this system in memory retrieval process. In the current study, we inject non-selective muscarinic antagonist scopolamine peripherally 20 min before training or testing to see whether cholinergic modulation has effects on the acquisition or retrieval of spatial memory by water maze task and fear memory by inhibitory avoidance task. We find that the cholinergic system is essential for the acquisition of both spatial memory and fear memory. As for the memory retrieval, the cholinergic system has a positive role in the retrieval of spatial memory, because mice injected with scopolamine 20 min before the testing in the water maze show impaired spatial memory retrieval. Whereas injection of scopolamine 20 min before the testing in the inhibitory avoidance task does not cause memory retrieval deficits. That indicates the cholinergic system is not essential for the retrieval of fear memory.     

Effects of 3-nitropropionic acid administration on memory and hippocampal lipid peroxidation in sleep-deprived mice

Numerous studies have described memory deficits following sleep deprivation. There is also evidence that the absence of sleep increases brain oxidative stress. The present study investigates the effects of a pro-oxidant agent--3-nitropropionic acid (3-NP)--on hippocampal oxidative stress and passive avoidance performance of sleep-deprived mice. Mice were repeatedly treated i.p. with saline or 5 or 15 mg/kg 3-NP and sleep-deprived for 24 h by the multiple platform method--groups of 4-5 animals placed in water tanks, containing 12 platforms (3 cm in diameter) surrounded by water up to 1 cm beneath the surface or kept in their home cage (control groups). The results showed that: (1) neither a 24 h sleep deprivation period nor 3-NP repeated treatment alone were able to induce memory deficits and increased hippocampal lipid peroxidation; (2) this same protocol of sleep deprivation, combined with 15 mg/kg 3-NP repeated treatment, induced memory deficits and an increase in hippocampal lipid peroxidation. The results support the involvement of hippocampal oxidative stress in the memory deficits induced by sleep deprivation and the hypothesis that normal sleep would prevent oxidative stress.     

Y-maze learning in two strains of mice. Effects of instrumental and pharmacologic sleep deprivation]

Effects of instrumental and pharmacological deprivation of sleep on Y-maze learning have been studied in two inbred strains of mice (C57BR/cd/Orl and C57BL/6/Orl), having identical sleep rhythms, but mainly differing in their ability to learn. Administration of alpha-methyl-DOPA (100 mg/kg) provokes complete suppression of paradoxical sleep (PS) for 9-11 h. Injection immediately after each training session over the first 5 days caused a delay in acquisition of an active avoidance task in C57BR mice. Treated C57BL/6 mice exhibited a significant facilitation of acquisition. Similar results were obtained by instrumental deprivation of sleep for 10 h.     

Effect of reversible inactivation of reuniens nucleus on memory processing in passive avoidance task

The reuniens nucleus (RE) is the largest nucleus of the midline thalamic nuclei (MLN). RE has strongly connections with the amygdala and hippocampus, the structures that are involved in the learning and memory processes. In our previous report we have shown the role of RE in the spatial learning and memory using Morris water maze (MWM) task. Since RE is connected to multiple limbic structures, its involvement in the emotional learning and memory is a possibility. The present study was designed to elucidate the role of RE in acquisition, consolidation, and retrieval on the passive avoidance (PA) task which depends on a distributed network including the thalamus, amygdala, medial prefrontal cortex (mPFC) and hippocampus. For this purpose, rats were chronically implanted with a cannula aimed at the RE through which 0.5 μl tetracaine (2%) or saline were injected. Rats were trained in a PA task and their retention test was performed 24 h later. The injection of saline or tetracaine was applied 5 min before or 5, 90, and 360 min after the acquisition trial and 5 min before the retention tests. Our findings showed that inactivation of RE before training did not affect acquisition, but affected memory retention 24 h later in PA task. Moreover, inactivation of RE only 5 min after training impaired consolidation but not after 90 or 360 min. Also, inactivation of the RE, 5 min before the retrieval test impaired memory retrieval in PA task. In conclusion, it seems that RE is involved in memory processes in rats.     

Estradiol to aged female or male mice improves learning in inhibitory avoidance and water maze tasks

Although 17beta-Estradiol (E2) improves cognitive performance of aged female mice, its mnemonic effects when administered post-training to aged male mice have not been examined. E2 (10 microg, SC) or oil vehicle was administered to intact, 24-month-old female or male congenic (primarily C57BL/6 background) mice immediately after training in the inhibitory avoidance or water maze tasks. Following behavioral testing, effects of 1 or 24 h of E2 exposure on hippocampal levels of E2 and brain-derived neurotrophic factor (BDNF) were examined. Female and male mice administered E2 showed significantly better performance in the inhibitory avoidance task than did vehicle-administered mice. When tested 24 h after training, mice that received E2 had significantly longer latencies to cross-over to the shock-associated side of the chamber than did vehicle-administered mice. Female or male mice administered E2 showed significantly better performance in the reference memory aspect of the spatial water maze task. When tested 30 min after training, mice administered E2 had shorter latencies to, and spent longer swimming in, the quadrant that the hidden platform had previously been located in. E2 administration produced physiological levels of E2 in the hippocampus 1 and 24 h after E2. BDNF levels in the hippocampus were decreased following 1 h of E2 exposure compared to vehicle. These findings suggest that E2 to female and male mice may overcome age-related deficits in reference memory in an emotional or spatial learning task.     

Short-term memory deficits correlate with hippocampal-thalamic functional connectivity alterations following acute sleep restriction

Acute sleep restriction heavily influences cognitive function, affecting executive processes such as attention, response inhibition, and memory. Previous neuroimaging studies have suggested a link between hippocampal activity and short-term memory function. However, the specific contribution of the hippocampus to the decline of short-term memory following sleep restriction has yet to be established. In the current study, we utilized resting-state functional magnetic resonance imaging (fMRI) to examine the association between hippocampal functional connectivity (FC) and the decline of short-term memory following total sleep deprivation (TSD). Twenty healthy adult males aged 20.9 ± 2.3 years (age range, 18–24 years) were enrolled in a within-subject crossover study. Short-term memory and FC were assessed using a Delay-matching short-term memory test and a resting-state fMRI scan before and after TSD. Seed-based correlation analysis was performed using fMRI data for the left and right hippocampus to identify differences in hippocampal FC following TSD. Subjects demonstrated reduced alertness and a decline in short-term memory performance following TSD. Moreover, fMRI analysis identified reduced hippocampal FC with the superior frontal gyrus (SFG), temporal regions, and supplementary motor area. In addition, an increase in FC between the hippocampus and bilateral thalamus was observed, the extent of which correlated with short-term memory performance following TSD. Our findings indicate that the disruption of hippocampal–cortical connectivity is linked to the decline in short-term memory observed after acute sleep restriction. Such results provide further evidence that support the cognitive impairment model of sleep deprivation.     

A Critical Time-Window for the Selective Induction of Hippocampal Memory Consolidation by a Brief Episode of Slow-Wave Sleep

Although extensively studied, the exact role of sleep in learning and memory is still not very clear. Sleep deprivation has been most frequently used to explore the effects of sleep on learning and memory, but the results from such studies are inevitably complicated by concurrent stress and distress. Furthermore, it is not clear whether there is a strict time-window between sleep and memory consolidation. In the present study we were able to induce time-locked slow-wave sleep (SWS) in mice by optogenetically stimulating GABAergic neurons in the parafacial zone (PZ), providing a direct approach to analyze the influences of SWS on learning and memory with precise time-windows. We found that SWS induced by light for 30 min immediately or 15 min after the training phase of the object-in-place task significantly prolonged the memory from 30 min to 6 h. However, induction of SWS 30 min after the training phase did not improve memory, suggesting a critical time-window between the induction of a brief episode of SWS and learning for memory consolidation. Application of a gentle touch to the mice during light stimulation to prevent SWS induction also failed to improve memory, indicating the specific role of SWS, but not the activation of PZ GABAergic neurons itself, in memory consolidation. Similar influences of light-induced SWS on memory consolidation also occurred for Y-maze spatial memory and contextual fear memory, but not for cued fear memory. SWS induction immediately before the test phase had no effect on memory performance, indicating that SWS does not affect memory retrieval. Thus, by induction of a brief-episode SWS we have revealed a critical time window for the consolidation of hippocampus-dependent memory.     

The effects of acute restraint stress and dexamethasone on retrieval of long-term memory in rats: an interaction with opiate system

This study investigated whether application of acute restraint stress or dexamethasone, as a glucocorticoid receptor agonist, impaired retrieval of long-term memory and if pretreatment with opiate antagonist naloxone blocked their effects on memory retrieval. Young adult male rats were trained in one trial inhibitory avoidance task (1 mA, 1.5 s footshock). On retention test given 48 h after training, the latency to re-enter dark compartment of the apparatus was recorded. Thirty minutes before retention test, the rats were exposed to a 10 min of restraint stress in a Plexiglass tube or were injected with dexamethasone (1 mg/kg) with or without prior treatment of naloxone (1 or 2 mg/kg). The results showed that both acute restraint stress and dexamethasone impaired retention performance. Both doses of naloxone were effective in blocking the impairing effect of stress, but only higher dose of naloxone blocked dexamethasone-induced impairment. The applied stress increased circulating corticosterone levels as assessed immediately after the retention test, indicating that stress-induced impairment of memory retrieval is mediated, in part, by increased plasma levels of glucocorticoids. These findings further indicate that acute restraint stress and glucocorticoids impair retrieval of long-term memory, and provide evidence for the existence of an interaction between glucocortioids and opiate system on this process.     

Basolateral Amygdala Lesions Block the Memory-enhancing Effect of Glucocorticoid Administration in the Dorsal Hippocampus of Rats

These experiments examined the effects of bilateral amygdala nuclei lesions on modulation of memory storage induced by bilateral intrahippocampal microinfusions of glucocorticoids in male Sprague-Dawley rats. Post-training infusions of the glucocorticoid receptor (type II) agonist RU 28362 (3.0 or 10.0 ng) enhanced inhibitory avoidance retention, and infusions of the glucocorticoid receptor antagonist RU 38486 (3.0 or 10.0 ng) administered shortly before training in a water maze spatial task did not affect acquisition, but impaired retention. In both tasks, neurochemically induced lesions of the basolateral but not of the central amygdala blocked the memory-modulatory effects of the intrahippocampal infusions of the drugs affecting glucocorticoid receptors. Lesions of the central amygdala alone impaired inhibitory avoidance retention, but basolateral amygdala lesions alone did not affect acquisition or retention in either task. These findings are consistent with previous evidence indicating that lesions of the basolateral amygdala block the memory-modulatory effects of systemically administered glucocorticoids, and provide further evidence that the basolateral amygdala is a critical area involved in regulating glucocorticoid effects in other brain regions involved in memory storage.     

The acute inhibition of rapid eye movement sleep by citalopram may impair spatial learning and passive avoidance in mice

Rapid eye movement (REM) sleep is known to be essential for memory. Hence, REM sleep deprivation impairs memory processes. The frequently prescribed selective serotonin reuptake inhibitors (SSRIs) are known to cause REM sleep deprivation and to impair cognitive performance in humans and rodents. We suggested that impaired memory processes by citalopram in C57/BL6 mice could be explained by the acute inhibition of REM sleep. We hypothesized that those acute citalopram 5 and 10 mg/kg injections induced REM sleep deprivation, altered cognitive performance in passive avoidance, impaired spatial memory compared to controls. Three experiments have been realized: (1) mice received successively physiological saline, injection of citalopram 5 and 10 mg/kg and were recorded by polysomnographic recording after each injection. (2) Cognitive performance was evaluated in the passive avoidance with two groups of mice. One group received citalopram before training and one, after training. (3) Spatial learning was evaluated with another group of animals in the Y-maze test. At 5 and 10 mg/kg, citalopram delayed REM sleep onset and decreased REM sleep amounts (vs. controls). The same doses were administrated in the passive avoidance test and have significantly shortened latency to enter the dark compartment. In the Y-maze, citalopram-treated mice showed a decreased percentage of time spent in the novel arm in contrast to the two other arms compared with controls. We showed that citalopram impaired cognitive performance in behavioral tasks. Those impairments could be linked to REM sleep deprivation induced by citalopram although causal relationship needs to be investigated in further studies.     

Antidepressants differentially modify the extinction of an aversive memory task in female rats

Treatment of major depression, posttraumatic stress disorder and other psychopathologies with antidepressants can be associated with improvement of the cognitive deficits related to these disorders. Although the mechanisms of these effects are not completely elucidated, alterations in the extinction of aversive memories are believed to play a role in these psychopathologies. We have recently verified that female rats present low levels of extinction when submitted to the plus-maze discriminative avoidance task. In the present study, female rats were treated long term with clinically used antidepressants (fluoxetine, nortriptyline or mirtazapine) and subjected to the plus-maze discriminative avoidance task to evaluate learning, memory, extinction and anxiety-related behaviors as well as behavioral despair in the forced swimming test. All groups learned the task and exhibited retrieval. Chronic treatment with fluoxetine (but not with the other antidepressants tested) increased extinction of the discriminative task. In the forced swimming test, the animals treated with fluoxetine and mirtazapine showed decreased immobility duration. In conclusion, fluoxetine potentiated extinction, while both fluoxetine and mirtazapine were effective in ameliorating depressive-like behavior in the forced swimming test, suggesting a possible dissociation between the effects on mood and the extinction of aversive memories in female rats.