Andrés Parra

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 model of depression.

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 formed by the remaining antidepressants has been shown to improve memory, with the exception of trazodone, which impairs memory. These findings are discussed in the light of knowledge regarding the actions of antidepressants on several neurotransmission systems. The possibility that the effects of antidepressants on memory are the core of the therapeutic effects of these drugs is also considered.

Predicting how equipotent doses of chlorpromazine, haloperidol, sulpiride, raclopride and clozapine reduce locomotor activity in mice

Distinguishing the specific effects of neuroleptics on one particular behaviour from its non-specific effects on motility is not easy. In this study, the effects of five neuroleptics on spontaneous motor activity were compared and the ED(50) values of these drugs to impair activity were calculated. Male and female mice were evaluated in an actimeter or in a shuttle-box used as an open field after the administration of chlorpromazine (0.4, 1.2, 3.6 mg/kg), haloperidol (0.1, 0.3, 0.9 mg/kg), raclopride (0.1, 0.3, 0.9 mg/kg), sulpiride (10, 30, 90 mg/kg) and clozapine (0.4, 1.2, 3.6 mg/kg), and two automatic and two observational activity measures were obtained. A very high correlation between automatic and observational measures, absence of sex differences, and a dose-dependent decrease of activity were observed with every compound. The results allow us to make accurate comparisons between these drugs in their potency in reducing spontaneous motor activity.

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 controls as well as in treated animals. The locomotor activity of the animals was also tested in Experiment 1. Due to the absence of sex differences in the drug effects on this measure, the sex differences in the effects of fluoxetine on inhibitory avoidance were hardly attributable to non specific effects on locomotor activity. The lack of effect of post-training administration of fluoxetine (Experiment 2) constitutes additional support of the idea that the observed effect on inhibitory avoidance in Experiment 1 is specifically related to learning and memory.

Sex Differences in the Effects of Neuroleptics on Escape-Avoidance Behavior in Mice: A Review

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 seem related to sex differences in the well-known deteriorating effects of these drugs on motor activity. In addition, an analysis of all our studies showed that there were no sex differences in the variability of responses, reinforcing the idea that female subjects should be included in these types of studies.

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

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 x 2 experimental design. The results do not show SDL in any of the drugs. In the case of amitriptilyline, the data can be attributed to a memorization deficit, while the maprotiline results are interpreted as simultaneously influenced by memorization deficit and performance facilitation due to motor impairment. Fluoxetine treatment did not produce any deteriorating effect on the conditioning. Drugs had some different effects on the performance of males and females, males showing a slightly higher deterioration than females with administration of amitriptyline and maprotiline. This study shows that these antidepressants affect the acquisition/consolidation but not the retrieval process in the inhibitory avoidance learning.

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 Experiment 2, the same doses of amitriptyline and piracetam were chronically administered. Mice were subjected to the training phase of inhibitory avoidance on the 22nd day, and to the test phase 24 h later. Forty-five minutes after test, subjects explored the elevated plus-maze for 5 min in order to assess whether the effects of amitriptyline on avoidance performance may reflect general behavioural changes. Results obtained were that: (a) acute and chronic amitriptyline impaired inhibitory avoidance of male and female mice, (b) piracetam counteracted the effect of acutely administered amitriptyline on inhibitory avoidance, and (c) piracetam counteracted the effects of chronically administered amitriptyline in males but not females in the same learning task. These effects do not seem to be mediated by non-specific drug effects on spontaneous motor activity or anxiety.

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 foot shock levels), at the doses stated, was carried out on naive animals. No analgesic effect of the drug was found. Taken together, the results indicate that acute maprotiline produces anterograde amnesia, and tolerance does not appear after 21 days of treatment.

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 produced a clear impairment in the IA task. In animals exposed only to the apparatus, amitriptyline decreased CO activity in nine brain regions, without affecting the remaining regions. In animals that underwent the IA training phase, amitriptyline reduced CO activity in only three of these nine regions. In animals treated with saline, IA acquisition increased CO activity in the medial prefrontal cortex, the prelimbic cortex, and the medial mammillary body, and diminished it in the medial septum and the nucleus basalis of Meynert with respect to animals exposed only to the IA apparatus. In animals treated with amitriptyline, IA acquisition did not modify CO activity in any of these regions, but increased it in the anteromedial nucleus of the thalamus, the diagonal band of Broca, and the dentate gyrus. The results reveal a pattern of changes in brain oxidative metabolism induced by IA training in saline-treated animals that was clearly absent in animals submitted to the same behavioural training but treated with amitriptyline.

Gender differences in escape-avoidance behavior of mice after haloperidol administration

Gender differences in the disruptive effects of haloperidol on some reinforced behaviors have been observed in different species. However, the inhibitory action of haloperidol on the acquisition and performance of escape-avoidance behavior has only been investigated in male subjects. The present experiment was designed to investigate possible gender differences in the effects of haloperidol on the initial phase of an escape-avoidance learning task. Male and female mice of the OF1 strain were given a single training session in a shuttle-box. Thirty minutes prior to the behavioral test, mice were injected IP with haloperidol (0.25 mg/kg) or physiological saline (10 ml/kg). Latencies of escape and avoidance responses and the number of nonresponses, escapes, avoidances, pseudoavoidances, crossings during the adaptation period, and crossings during intertrial intervals (ITIs) were evaluated. The disruptive action of haloperidol on the escape-avoidance behavior of the mice was greater in males than in females. The number of nonresponses were higher and the number of escapes lower in treated males than in their female counterparts. These gender differences were not found in control subjects. Activity measures of spontaneous motor behavior (crossings in the adaptation period and during ITIs) did not present gender differences either. Several possible mechanisms responsible for this greater susceptibility of males to the inhibitory effects of haloperidol on escape-avoidance learning are discussed, especially the modulating role of female hormones on dopaminergic activity.