Anti-anhedonic actions of the novel serotonergic agent flibanserin, a potential rapidly-acting antidepressant

Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of palatable sweet solutions and to block the formation of conditioned place preferences; these effects are reversed by chronic treatment with tricyclic or atypical antidepressant drugs. The present study was designed to evaluate the antidepressant-like activity in this model of flibaserin (BIMT-17), a novel serotonergic agent with 5-HT1A receptor agonist and 5-HT2 receptor antagonist properties. Two experiments were conducted, using rats (experiment 1) and mice (experiment 2). In experiment 1, decreases in sucrose intake were seen in rats exposed to chronic mild stress, but the effect was unr…

Are the effects of the antidepressants amitriptyline, maprotiline, and fluoxetine on inhibitory avoidance state-dependent?

Abstract State-dependent learning (SDL) is a phenomenon in which the retrieval of newly acquired information is possible if the subject is in the same physiological state as during the encoding phase. SDL makes it possible to separate the effects of drugs per se on learning from the effects due to changes in drug state during the task. The present work was designed to investigate whether the antidepressants amitriptyline (30 mg/kg), maprotiline (25 mg/kg), and fluoxetine (15 mg/kg) produce SDL of the inhibitory avoidance conditioning in male and female CD1 mice. In three separate experiments, independent groups were used for each pharmacological treatment and for each sex using a 2 × 2 expe…

Effects of binge drinking and the anti-inflammatory drug indomethacin on spatial memory and cognitive flexibility in mice.

Abstract In previous research, we found that chronic-intermittent ethanol administration (CIEA), a model of binge drinking, impaired emotional memory in mice, and this impairment was counteracted by the anti-inflammatory drug indomethacin. In the present study, we evaluated the effects of CIEA on spatial memory and cognitive flexibility in adolescent mice of both sexes. Animals were randomly assigned to one of four groups for each sex: SS (saline + saline), SA (saline + alcohol), SI (saline + indomethacin), and AI (alcohol + indomethacin). They were injected with saline, ethanol (3 g/kg) or indomethacin (10 mg/kg) for the first three days of each week, throughout three weeks. 96 h after tre…

Changes in brain oxidative metabolism induced by inhibitory avoidance learning and acute administration of amitriptyline

The effects of antidepressant drugs on memory have been somewhat ignored, having been considered a mere side effect of these compounds. However, the memory impairment caused by several antidepressants could be considered to form part of their therapeutic effects. Amitriptyline is currently one of the most prescribed tricyclic antidepressants, and exerts marked anticholinergic and antihistaminergic effects. In this study, we evaluated the effects of inhibitory avoidance (IA) learning and acute administration of amitriptyline on brain oxidative metabolism. Brain oxidative metabolism was measured in several limbic regions using cytochrome oxidase (CO) quantitative histochemistry. Amitriptyline…

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 cont…

Blood Alcohol Concentration-Related Lower Performance in Immediate Visual Memory and Working Memory in Adolescent Binge Drinkers

The binge drinking (BD) pattern of alcohol consumption is prevalent during adolescence, a period characterized by critical changes to the structural and functional development of brain areas related with memory and cognition. There is considerable evidence of the cognitive dysfunctions caused by the neurotoxic effects of BD in the not-yet-adult brain. Thus, the aim of the present study was to evaluate the effects of different blood alcohol concentrations (BAC) on memory during late adolescence (18–19 years old) in males and females with a history of BD. The sample consisted of 154 adolescents (67 males and 87 females) that were classified as refrainers if they had never previously drunk alc…

Piracetam counteracts the effects of amitriptyline on inhibitory avoidance in CD1 mice.

The purpose of the present work was to study the effects of amitriptyline on animal cognition in relation to some characteristics of its therapeutic effects. The modulation of acute and chronic effects of amitriptyline on inhibitory avoidance in male and female mice by piracetam was investigated. In Experiment 1, mice were subjected to the training phase of inhibitory avoidance conditioning 60 min after acute piracetam (100 mg/kg) or physiological saline administration. Immediately after the behavioural task, they received a single injection of the tricyclic antidepressant amitriptyline (30 mg/kg) or physiological saline. Twenty-four hours later, subjects were tested for avoidance. In Exper…

Indomethacin counteracts the effects of chronic social defeat stress on emotional but not recognition memory in mice

We have previously observed the impairing effects of chronic social defeat stress (CSDS) on emotional memory in mice. Given the relation between stress and inflammatory processes, we sought to study the effectiveness of the anti-inflammatory indomethacin in reversing the detrimental effects of CSDS on emotional memory in mice. The effects of CSDS and indomethacin on recognition memory were also evaluated. Male CD1 mice were randomly divided into four groups: non-stressed + saline (NS+SAL); non-stressed + indomethacin (NS+IND); stressed + saline (S+SAL); and stressed + indomethacin (S+IND). Stressed animals were exposed to a daily 10 min agonistic confrontation (CSDS) for 20 days. All subjec…

Inhibitory avoidance in CD1 mice: sex matters, as does the supplier.

The purpose of the present work was to study possible differences in the learning of inhibitory avoidance (also called passive avoidance) in male and female CD1 mice acquired from three different suppliers, for which a one-trial step-through version of the paradigm was employed. Ninety-six mice from Charles River (France), Janvier (France) and Harlan (The Netherlands) laboratories were divided by sex and assigned to group C, J or H, respectively (n=16). The animals were tested in the training phase (foot-shock: 0.3mA, 5s) and again for avoidance (no foot-shock delivered) one week later. Inhibitory avoidance learning (test latencies significantly higher than training latencies) was observed …

Sex differences in the effects of neuroleptics on escape-avoidance behavior in mice: a review.

Abstract The literature of the effects of dopamine antagonists on escape-avoidance, focusing on data obtained in our laboratory with male and female mice, is reviewed. The acute administration of haloperidol, raclopride, clozapine, and SCH 23390 impaired escape-avoidance behavior more in males than in females, and the subchronic administration of haloperidol had a similar effect. This appeared to be a reliable phenomenon, because it was observed in both kinds of administration, in two mouse strains, and with several drugs and doses. The observed results were dose dependent, although the dose–effect relationship was not the same in all drugs. The sex differences in escape avoidance did not s…

Assessing Reliability, Heritability and General Cognitive Ability in a Battery of Cognitive Tasks for Laboratory Mice

This report includes the first sibling study of mouse behavior, and presents evidence for a heritable general cognitive ability (g) factor influencing cognitive batteries. Data from a population of male and female outbred mice (n = 84), and a replication study of male sibling pairs (n = 167) are reported. Arenas employed were the T-maze, the Morris water maze, the puzzle box, the Hebb-Williams maze, object exploration, a water plus-maze, and a second food-puzzle arena. The results show a factor structure consistent with the presence of g in mice. Employing one score per arena, this factor accounts for 41% of the variance in the first study (or 36% after sex regression) and 23% in the second…

Binge Drinking, Alone or With Cannabis, During Adolescence Triggers Different Effects on Immediate Visual Memory in Men and Women

Background: This study examines the interaction between a history of binge drinking (BD), alone or with cannabis consumption, and the effects of acute alcohol exposure on immediate visual memory (IVM) (faces memory task, scenes memory task and IVM-IQ) in adolescents of both sexes.Method: Two hundred and ninety adolescents, grouped into refrainers, binge drinkers and subjects with a history of simultaneous BD/Cannabis co-use, received a risk dose of alcohol or a control drink.Results: Consumption Pattern (refrainers vs. binge drinkers vs. BD/Cannabis consumers) was not significant, while Treatment (acute alcohol vs. control drink) was significant in both sexes. Also, male binge drinkers' per…

Evidence for general cognitive ability (g ) in heterogeneous stock mice and an analysis of potential confounds

The heterogeneous stock (HS) is a genetically outbred line of mice established more than 30 years ago from an 8-way cross of C57BL/6, BALB/c, RIII, AKR, DBA/2, I, A/J and C3H inbred mouse strains. The present study compared the performance of 40 HS mice across a battery of diverse cognitive tasks under a variety of motivations. Indices of emotionality were also included in order to assess their influence on performance. All measures of ability loaded positively on an unrotated first principal component that accounted for 31% of the variance, suggesting the presence of a common factor of general cognitive ability (g) underlying all tasks. A first factor derived from anxiety indices correlate…

Effects of social stress and clomipramine on emotional memory in mice.

We have previously observed impairing effects of social defeat stress (CSDS) on inhibitory avoidance (IA) in mice. Given the similarity between changes produced by social stress in animals and symptoms of certain human psychopathologies such as depression and anxiety, the effects of the antidepressant clomipramine on IA impairment produced by CSDS were evaluated in the present study. Male CD1 mice were randomly assigned to the groups: non-stressed+saline, non-stressed+clomipramine, stressed+saline and stressed+clomipramine. Stressed animals were subjected to daily agonistic encounters (10 min) in the home cage of the aggressor over a 20-day period. Just before each encounter, non-stressed a…

Effects of acute amitriptyline administration on memory, anxiety and activity in male and female mice

The effects of acute administration of amitriptyline on memory consolidation in male and female CD1 mice were investigated. Three doses of this tricyclic antidepressant (7.5, 15 and 30 mg/kg) were administered immediately after inhibitory avoidance training. Forty-five minutes after injection, subjects explored the elevated plus-maze for five minutes. Subjects were tested for avoidance twenty-four hours later. Amitriptyline impaired inhibitory avoidance consolidation at doses 7.5, 15 and 30 mg/kg in males, and at doses 7.5 and 30 mg/kg in females. In the elevated plus-maze, amitriptyline had no effect on anxiety (percentage of open arm entries) and induced a dose-dependent impairment of act…

Emotional memory impairment produced by binge drinking in mice is counteracted by the anti-inflammatory indomethacin

Abstract The Binge Drinking (BD) pattern of alcohol consumption, prevalent in adolescents and young adults, has been associated with memory impairment. In addition, evidence shows that alcohol abuse causes neuroinflammation, which may contribute to the brain damage produced by alcohol and explain its cognitive consequences. In this study, we evaluated the effectiveness of the anti-inflammatory indomethacin in counteracting the memory impairment produced by alcohol (ethanol) in adolescent mice of both sexes. Animals were randomly assigned to one of four groups for each sex: SS (saline + saline), SA (saline + alcohol), SI (saline + indomethacin) and AI (alcohol + indomethacin). They were inje…

An Animal Model of Alcohol Binge Drinking: Chronic-Intermittent Ethanol Administration in Rodents

Binge drinking (BD), characterized by intermittent consumption of large quantities of alcohol in short periods of time, is the main alcohol consumption pattern in adolescents and young adults. BD has serious biomedical consequences, and it is a prominent risk factor for later development of alcohol use disorders. Rodent models offer exceptional power to study these negative consequences of BD. This chapter focuses on one of these BD models: the chronic-intermittent ethanol administration (CIEA) paradigm. Essentially, CIEA consists of the administration in rats or mice of i.p. injections of ethanol (doses: 3-4 g/kg) for several consecutive days each week, in alternation with several days wit…

Antidepressant drugs and memory: Insights from animal studies

This is a selective review of the literature concerning the effects of antidepressant drugs on animal memory, which was performed with the aid of the PubMed database. Monoamine oxidase inhibitors tend to either have no effect on memory or result in its improvement. Studies with cyclic antidepressants have reported no effect or, more often, memory impairments. Pre-training administration of selective serotonin reuptake inhibitors (SSRIs) has been shown to have either no effect on memory or undermine it (with some isolated exceptions, in which improvements have been recorded), while post-training administration of SSRIs has been demonstrated to improve memory or have no effect. A small group …

Effects of co-administration of amitriptyline and fluoxetine on inhibitory avoidance in mice

We have previously observed that, while the impairing effects of amitriptyline on inhibitory avoidance in mice are consistently observed, those of acute fluoxetine are negligible. Two experiments were designed to investigate whether a regular dose of fluoxetine potentiates the effect of a low dose of amitriptyline that is ineffective when administered alone. Male and female CD1 mice were administered i.p. 30 min before training, as follows. In the first experiment, they were injected with saline, one of three doses of amitriptyline (2.5, 5, 10 mg/kg), one dose of fluoxetine (15 mg/kg), or a combination of amitriptyline (2.5 mg/kg) and fluoxetine (15 mg/kg). In the second experiment, the mic…

Effects of Antidepressants on Inhibitory Avoidance in Mice: A Review

Neither the biological basis of depression (Nemeroff & Vale, 2005; Kasper & McEwen, 2008) nor the precise mechanism of antidepressant efficacy are completely understood (Dudra-Jastrzebska et al., 2007). Indeed, antidepressants are widely prescribed for anxiety and disorders other than depression. For example, they are the drug therapy of choice for severe anxiety disorders such as agoraphobia, generalized anxiety disorder, social phobia, obsessive-compulsive disorder and post-traumatic stress disorder (Baldessarini, 2001). Antidepressants are also employed as a therapeutic tool in disorders such as drug addition (e.g. Schatzberg, 2000), enuresis (e.g. Humphreys & Reinberg, 2005) and chronic…

Dose Dependency of Sex Differences in the Effects of Repeated Haloperidol Administration in Avoidance Conditioning in Mice

Sex differences in the effects of haloperidol in active avoidance conditioning in mice have previously been found in various studies carried out in our laboratory. Males were more affected than females by the disruptive effects of this neuroleptic. The work described here broadens the study of these sex differences to higher doses of haloperidol (0.1 and 0.2 mg/kg) using a repeated administration schedule (5 days). The results did not show sex differences in the deteriorating effects of this dopamine antagonist in the escape-avoidance response, but a tendency in the number of nonresponses was observed in the same direction as former results: male animals were more sensitive than females to …

Differential Effects of Alcohol on Memory Performance in Adolescent Men and Women with a Binge Drinking History.

Aims Binge drinking (BD) is characterized by intermittent consumption of large quantities of alcohol in short periods. This pattern of drinking is prevalent among adolescents, and has been associated with undermined learning and memory ability. This study investigates the relationships between a history of BD and the effects of acute exposure to alcohol on learning and memory performance in adolescent men and women. Methods A high, acute dose of alcohol or control refreshment was administered to a sample of 172 adolescent undergraduate students, some of which had a history of BD and others of which had refrained from alcohol consumption. Subsequently, immediate visual memory (IVM) and worki…

Sex differences in escape-avoidance response in mice after acute administration of raclopride, clozapine, and SCH 23390.

Sex differences in the effects of haloperidol in the escape-avoidance response in mice have previously been found in various studies carried out in our laboratory. Males were more affected than females by the disruptive effects of this neuroleptic. The work described herein extended the study of these sex differences to raclopride, clozapine, and SCH 23390, using several doses of each drug in acute administration. The results showed dose-dependent sex differences in the deteriorating effects of these dopamine antagonists in the escape-avoidance response. Male mice were more affected by the inhibitory effects of these drugs, showing fewer escape responses and more nonresponses than females. …

Methods for Evaluating the Interaction Between Social Stress and Environmental Enrichment in Animal Models of Nicotine Addiction

The environmental enrichment (EE) paradigm has been evaluated as a means of counteracting some of the consequences of chronic stress in rodents as well as a model of protective environment against drug abuse development. In the present chapter, our main aim is to describe the models of EE and chronic social stress and how they can be applied jointly in order to evaluate the effects of early psychosocial stress in animals exposed of different environments (enriched environment or standard environment). Furthermore, both paradigms could be applied in animal models of nicotine addiction, so the guidelines for the application of a chronic oral nicotine treatment in mice will be described. The h…

Coffee and Anxiety

Abstract This chapter discusses the effects of coffee consumption on anxiety response, taking into account vulnerability factors such as sex and genetics. In light of research concerning the effects of coffee on normal anxiety, and particularly research carried out in our laboratory, current knowledge can be summarized as follows: (1) men appear to be more sensitive to the effects of coffee than women; and (2) coffee can increase alertness in habitual consumers after acute deprivation, but not above the level of that observed in nonconsumers. In addition, we discuss clinical evidence of the varying sensitivity of anxiety disorder patients to the effects of coffee. The caffeine challenge tes…

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 avoidan…

Attenuation of sucrose consumption in mice by chronic mild stress and its restoration by imipramine

Chronic exposure to mild unpredictable stressors (CMS) has previously been found to reduce the consumption of palatable, sweet solutions in rats. In the present study, the utility of this procedure was assessed in mice. Male AP mice subjected to CMS showed reduced consumption of a 2% or 4% sucrose solution. This effect was reversed by chronic (3 weeks) treatment with the tricyclic antidepressant imipramine (20 mg/kg per day). These results extend previous reports of a generalized decrease in sensitivity to reward (anhedonia) in rats caused by CMS and the efficacy of antidepressant treatment in this paradigm. Chronic unpredictable mild stress in mice appears to provide a realistic animal mod…

Effects of several degrees of chronic social defeat stress on emotional and spatial memory in CD1 mice

In the present study, the effects of several degrees of CSDS (Chronic Social Defeat Stress) on emotional and spatial memory in mice were evaluated in separate experiments. Male CD1 mice were randomly assigned to four experimental groups (n=10-12) for each experiment: NS (non-stressed), S5, S10 and S20 (5, 10 and 20 sessions of CSDS, respectively). The S groups underwent the corresponding number of agonistic encounters (10min each) over a 20-day period. 24h after the last session of CSDS, mice performed the inhibitory avoidance (Experiment 1) or the Morris water maze test (Experiment 2). In both experiments, animals were also evaluated in the elevated plus maze for 5min to obtain complementa…

Animal Models of Adolescent Binge Drinking

Effects of Alcohol, Coffee, and Tobacco, Alone or in Combination, on Physiological Parameters and Anxiety in a Young Population

The objective was to evaluate the effects of a single dose of alcohol, caffeine, and nicotine, alone or in combination, on physiological parameters (systolic and diastolic blood pressure [SBP and DBP] and heart rate [HR]) and state-trait anxiety in healthy young volunteers.The procedure reproduces the conditions under which the subjects (Intake of alcohol or alcohol-nicotine reduced DBP. Comparisons between control and combined treatment (coffee-alcohol-nicotine) groups revealed a decrease in HR in the former group but not in the latter. The coffee consumers alone exhibited a tendency toward an increase in SA, while the control group showed a tendency toward a decrease in this measure. When…

Acute effects of fluoxetine on inhibitory avoidance consolidation in male and female OF1 mice

The effects of acute administration of fluoxetine on memory consolidation using an inhibitory avoidance task were investigated in male and female OF1 mice. Several doses of this antidepressant (5, 10, and 20 mg/kg) were intraperitoneally administered immediately after the training session. The test session was carried out four days later and response latencies were measured in both sessions. The results showed that the highest dose of fluoxetine significantly increased response latencies of inhibitory avoidance compared with the lowest dose and the control group. Sex differences in this task were observed, females showing a better performance. But the drug's effects were not sexually dimorp…

The Higher the Dose, the Greater the Sex Differences in Escape–Avoidance Response in Mice After Acute Administration of Haloperidol

Abstract MONLEON, S. AND A. PARRA. The higher the dose, the greater the sex differences in escape–avoidance response in mice after acute administration of haloperidol . PHARMACOL BIOCHEM BEHAV 60 (1) 279–284, 1998.—Sex differences in the effects of haloperidol in the escape–avoidance response have previously been found in various studies carried out in our laboratory in which mice were used as experimental subjects. Males were more affected than females by the disruptive effects of this neuroleptic of frequent clinical use. In the present work these sex differences were evaluated in a unique training session using several doses of the drug (0.075, 0.25, and 0.75 mg/kg IP). The number of avo…

PO2-10BLOOD ALCOHOL CONCENTRATION AND MEMORIES OF FACES AND SCENES IN ADOLESCENT BINGE DRINKERS

Efectos fisiológicos y psicológicos de una alta dosis de alcohol en hombres y mujeres jóvenes

El objetivo de este estudio fue evaluar los efectos de una dosis alta de alcohol sobre parametros fisiologicos y psicologicos en hombres y mujeres jovenes con historia previa de consumo de alcohol. La presion sanguinea sistolica y diastolica, la frecuencia cardiaca, la ansiedad estado, el procesamiento atencional, la estimacion temporal y la destreza manual fueron registradas antes (fase 1) y despues (fase 2) de la ingesta de alcohol (38,4 g) o de una bebida no alcoholica. La ansiedad rasgo fue registrada solamente en la fase 2. Los resultados mostraron que el consumo agudo de una dosis alta de alcohol: i) en hombres, mejora el procesamiento atencional (aunque la ejecucion de los consumidor…

Inhibitory avoidance learning in CD1 mice: Effects of chronic social defeat stress

Chronic social defeat stress (CSDS) is an animal model widely used to determine the neurobiological mechanisms of stress and its associated pathologies. In this study, the effects of CSDS on inhibitory avoidance (IA) were evaluated in post-pubertal and adult male CD1 mice, instead of the C57BL/6J strain used in the CSDS standard protocol. CSDS consisted of daily 5-min (experiments 1 and 2) or 10-min (experiment 3) agonistic encounters on 21 consecutive days. Twenty four hours after the last session of CSDS, all the mice were tested for IA. They were also evaluated in an elevated plus-maze, obtaining complementary measures of locomotor activity and emotionality. In experiments 1 and 2, IA le…

Effects of acute and chronic maprotiline administration on inhibitory avoidance in male mice

The effects of acute and chronic administration of maprotiline (5, 10 or 20 mg/kg, intraperitoneally) were assessed on inhibitory avoidance in male mice. Acute administration of maprotiline before training did not effect training phase latencies, but impaired performance (i.e. produced shorter latencies) in the test at doses of 5 and 20 mg/kg. When given after training, the drug did not modify test latencies at any of the doses used. Chronic administration for 21 days (interrupted 24 h before training) also shortened latencies in the test but not in training. An experiment on the acute effects of maprotiline on analgesia (determination of flinch and jump thresholds for increasing electric f…