The elevated gradient of aversion: a new apparatus to study the rat behavior dimensions of anxiety, fear, and impulsivity

Few behavioral tests allow measuring several characteristics and most require training, complex analyses, and/or are time-consuming. We present an apparatus based on rat exploratory behavior. Composed of three different environments, it allows the assessment of more than one behavioral characteristic in a short 3-min session. Factorial analyses have defined three behavioral dimensions, which we named Exploration, Impulsivity, and Self-protection. Behaviors composing the Exploration factor were increased by chlordiazepoxide and apomorphine and decreased by pentylenetetrazole. Behaviors composing the Impulsivity factor were increased by chlordiazepoxide, apomorphine, and both acute and chronic imipramine treatments. Behaviors composing the Self-protection factor were decreased by apomorphine. We submitted Wistar rats to the open-field test, the elevated-plus maze, and to the apparatus we are proposing. Measures related to exploratory behavior in all three tests were correlated. Measures composing the factors Impulsivity and Self-protection did not correlate with any measures from the two standard tests. Also, compared with existing impulsivity tests, the one we proposed did not require previous learning, training, or sophisticated analysis. Exploration measures from our test are as easy to obtain as the ones from other standard tests. Thus, we have proposed an apparatus that measured three different behavioral characteristics, was simple and fast, did not require subjects to be submitted to previous learning or training, was sensitive to drug treatments, and did not require sophisticated data analyses.

Differential response to gepirone but not to chlordiazepoxide in malnourished rats subjected to learned helplessness

The learned helplessness (LH) paradigm is characterized by learning deficits resulting from inescapable events. The aims of the present study were to determine if protein-calorie malnutrition (PCM) alters learning deficits induced by LH and if the neurochemical changes induced by malnutrition alter the reactivity to treatment with GABA-ergic and serotonergic drugs during LH. Well-nourished (W) and PCM Wistar rats (61 days old) were exposed or not to inescapable shocks (IS) and treated with gepirone (GEP, 0.0-7.5 mg/kg, intraperitoneally, N = 128) or chlordiazepoxide (0.0-7.5 mg/kg, intraperitoneally, N = 128) 72 h later, 30 min before the test session (30 trials of escape learning). The results showed that rats exposed to IS had higher escape latency than non-exposed rats (12.6 ± 2.2 vs 4.4 ± 0.8 s) and that malnutrition increased learning impairment produced by LH. GEP increased the escape latency of W animals exposed or non-exposed to IS, but did not affect the response of PCM animals, while chlordiazepoxide reduced the escape deficit of both W and PCM rats. The data suggest that PCM animals were more sensitive to the impairment produced by LH and that PCM led to neurochemical changes in the serotonergic system, resulting in hyporeactivity to the anxiogenic effects of GEP in the LH paradigm.

Development of differential tolerance to the sedative and anti-stress effects of benzodiazepines.

Differential degree of tolerance has been reported to develop for anticonvulsant, sedative and skeletal muscle relaxant effects of benzodiazepines (BZDs). Acute treatment with BZDs reportedly reduces the formation of gastric stress ulcers and attenuates stress-induced immunosuppression. The present study investigates whether tolerance develops to these antistress effects of BZDs by using diazepam and chlordiazepoxide as representative drugs. A single dose of diazepam (5 mg/kg, i.p.) or chlordiazepoxide (20 mg/kg, i.p.) produced a significant reduction in locomotor activity, a measure of sedative effect and antagonized the effect of restraint stress (RS) on gastric mucosal lesions and anti-sheep red blood cell (SRBC) antibody titre. With chronic treatment (X 7 d), there was a marked tolerance to the sedative effect of both the studied BZD drugs, while much less tolerance developed to their ulcer protective action. However, no tolerance was observed to the attenuating effect of diazepam and chlordiazepoxide on RS-induced immunosuppression. Thus, the results of the present study indicate that different mechanisms may be involved in the development of tolerance to the sedative, antiulcer and immunomodulatory effects of BZDs.

Effects of stress on gamma glutamyl transpeptidase (GGT) activity in lymphoid system of rats: modulation by drugs.

Effects of stress and its modulation by adaptogens were evaluated on gamma glutamyl transpeptidase (GGT) activity in different tissues of the lymphoid system in rats. Restrain stress (RSx5) suppressed the GGT activity in different tissues of lymphoid system viz. the lymphocyte, the spleen, the thymus and the macrophage, and the maximum effect was seen in the spleen. Chlordiazepoxide, a prototype anti-stress agent, which did not alter GGT activity per se, reversed the effect of RS on this enzyme activity in tissues of lymphoid system studied. Azardirachta indica (Al, Neem), an indigenous adaptogen stimulated the GGT activity per se and nearly normalised RS induced suppression of GGT in lymphoid system. The observed suppression of GGT activity in lymphoid system by stress and its modulation by natural and synthetic adaptogens indicates that GGT could be a consistent cellular/biochemical marker of stress responsiveness and stress-induced immunomodulation.

Early malnutrition alters the effect of chlordiazepoxide on inhibitory avoidance

In order to study the functional consequences of brain changes caused by early malnutrition, rats were fed a protein-deficient diet from birth until 49 days of age and a balanced diet from day 50 to day 70. The animals were submitted to a step-down inhibitory avoidance task and to the flinch-jump nociceptive test at 49 and 70 days of age. Malnourished rats showed longer step-down latencies and lower flinch and junp theresholds than eutrophic animals. Chlordiazepoxide (5 mg/Kg, ip) shortened step-down latency of well-nourished rats, whereas it failed to do so in malnourished rats. Since well-nourished animals also became resistant to chlordiazepoxide when tested with a higher shock intensity, generating avoidance latencies comparable to those of malnourished animals, we conclude that the drug resistance induced by malnutrition may be secondary to enhanced pain sensitivity and/or reactivity

El efecto inhibidor de tres drogas tranquilizantes en la formación de "úlcera de stress" en ratas en condiciones experimentales / The inhibitory effect of 3 tranquilizing drugs on the formation of stress ulcer in rats, under experimental conditions

Utilizando ratas en jaulas de inmovilización y dosis apropiadas (p/v) se trató de determinar el efecto inhibidor de tres drogas tranquilizantes, diazepam (Valium**R), clorodiazepóxido (LibriumR) y cloropromazina (Largactil**R) en la formación de "úlcera de stress", en condiciones experimentales. En la comparación de los promedios numéricos de úlceras observadas en los estómagos de los grupos de ratas tratadas con la droga y su respectivo control, solamente el grupo tratado con diazepam ofrece una diferencia significativa (p<0.05). Se infiere que hay algún efecto inhibidor debido a la aplicación de la droga. Sin embargo, debido a que los grupos experimentales utilizados aquí fueron relativamente pequeños, se sugiere aumentar la muestra, a fin de consolidar los resultados con varios métodos estadísticos