Behavioral, Physiological, and Neuroendocrine Stress Responses and Differential Sensitivity to Diazepam in Two Wistar Rat Lines Selectively Bred for High- and Low-Anxiety–Related Behavior

Abstract

Two Wistar rat lines, selectively bred for high-anxietyrelated behavior (HAB) and low-anxiety-related behavior (LAB) in the elevated plus-maze test, were tested for the susceptibility of their behavioral characteristics to anxiolytic treatment and for their endocrine and physiological reactivity to different stressors. Injection of 1mg/kg diazepam failed to affect line differences in coping strategy but resulted in a marked (20-fold) Genetic factors contribute to the high interindividual variability in type and/or intensity of the behavioral, neuroendocrine, and physiological stress responses observed in various species, including humans and laboratory rats (Boissy 1995;Clément et al. 1997;Cools et al. 1990;Curé and Rolinat 1992;Prasad et al. 1996;Spanagel et al. 1995;Tesser 1993;Zuckerman 1993). This fact has been used as the basis for selective bidirectional breeding programs from which strains and lines differing in their behavioral and/or neuroendocrine reFrom the Max Planck Institute of Psychiatry, Munich, Germany. Address correspondence to: Dr. R. Landgraf, Max Planck Institute of Psychiatry, Kraepelinstr. 2, 80804 Munich, Germany.Received January 15, 1997; revised March 25, 1998; accepted April 16, 1998. 382 G. Liebsch et al. N EUROPSYCHOPHARMACOLOGY 1998 -VOL . 19 , NO . 5 sponses to environmental challenges have emerged (Brush 1991;Castanon and Mormède 1994;Cools et al. 1993;Gentsch et al. 1988;Walker et al. 1992). Recently, we reported the establishment of two Wistar rat lines selectively bred for differing behavioral performances in the elevated plus-maze test, now termed high-anxiety-related behavior (HAB) and low-anxiety-related behavior (LAB) lines, respectively ). This animal model of inborn anxiety provides the advantage of avoiding conditioned stimuli that by themselves are likely to trigger behavioral, neuroendocrine, and physiological alterations. Interestingly, the HAB and LAB animals also prefer different coping strategies in a forced swim test ), pointing toward a link between anxiety and coping with stressful situations.The elevated plus-maze test is based on the creation of a conflict between the exploratory drive of a rat and its innate fear of open, exposed areas. It is one of the most widely used nonconditioned animal models of anxiety and has been extensively validated pharmacologically and ethologically (Dawson and Tricklebank 1995;Pellow 1986;Pich et al. 1993). However, various clinically effective anxiolytic substances often yield contradictory results when administered to "normal" unstressed rats in this test (Griebel 1995;Rodgers et al. 1997), indicating that-in parallel to the situation in humans (Green and Hodges 1991; Lader 1991)-the efficacy of an anxiolytic may depend upon the animal's basal level of anxiety. To test this prediction and to characterize further our breeding lines, in the first experiment, male rats from the HAB and LAB lines were injected with a classical anxiolytic, diazepam, and submitted to a plus-maze test and a forced swim test to assess the e...

Neuroendocrine and Behavioral Effects of Repetitive Transcranial Magnetic Stimulation in a Psychopathological Animal Model Are Suggestive of Antidepressant-like Effects

“…The virtually identical outcome of the CRH challenge test in the rTMS-treated and control HAB rats makes it unlikely that changes at the pituitary CRH-CRH 1 receptor-signaling pathway account for differences in neuroendocrine stress response. This observation, confirming previous results showing a similar response of pituitary corticotropes to a CRH challenge in HAB and LAB rats (Liebsch et al 1998a), suggests that rTMSinduced line-specific differences in neuroendocrine regulation are likely to occur at the hypothalamic/hippocampal level. Indeed, the recent finding of a specific activation in terms of immediate-early gene expression in the paraventricular nucleus of the hypothalamus in response to rTMS supports this notion (Ji et al 1998).…”

“…Experiments were carried out on adult ( n ϭ 65; 358 Ϯ 19 g body weight) male HAB and LAB rats. At the age of 10 weeks, prior to the experiments performed, HAB and LAB rats were tested on the elevated plus-maze (EPM) according to the breeding protocol to confirm the emotional trait (Landgraf et al 1999;Liebsch et al 1998aLiebsch et al , 1998b. Rats were housed in groups of six in the breeding unit of the Max Planck Institute of Psychiatry under standard laboratory conditions (12:12 hr light:dark cycle with lights on at 0700, 22 Ϯ 1 Њ C, 60% humidity, pelleted food and water ad libitum).…”

“…All four arms were connected at the center by a 10 ϫ 10 cm square platform. This test has been validated for the detection of emotional responses to anxiogenic and anxiolytic substances (Pellow et al 1985) as well as for the determination of inborn emotionality (Liebsch et al 1998a(Liebsch et al , 1998b. Briefly, it is based on the creation of a conflict between the exploratory drive of the rat and its innate aversion to open, exposed and elevated areas.…”

“…The HAB and LAB lines, differing markedly in their inborn anxiety-related and acute stress coping behaviors (Liebsch et al 1998a(Liebsch et al , 1998b, provide a promising tool for investigating the relationship between inborn emotionality, acute stress coping, physiological and neuroendocrine stress responses and their underlying mechanisms (Liebsch et al 1998a). Moreover, animals genetically predisposed to certain behavioral strategies offer a unique opportunity to test therapeutic agents that are a potential treatment for abnormal behaviors, e.g., in human psychiatric disorders (Gentsch et al 1988).…”

“…We therefore characterized the effects of rTMS on the regulation of HPA system activity, stress coping and anxiety-related behavior in two Wistar rat lines selectively bred for high (HAB) and low (LAB) anxiety-related behavior under a regimen adapted from clinical conditions. These two rat lines differ not only in their inborn anxiety, but also in their stress coping strategies, their HPA system susceptibility to external stressors and their reactivity to benzodiazepine treatment (Landgraf et al 1999;Liebsch et al 1998a). As a key part of the study, a series of computer-assisted, magnetic resonance imaging (MRI)-based reconstructions of the current density distributions induced by rTMS in the rat and human brain were performed.…”