Multiple serotonin mechanisms in animal models of anxiety

Handley, Sheila L.; McBlane, James; Critchley, M. A. E.; Njung'e, K.

doi:10.1016/0166-4328(93)90104-x

Cited by 153 publications

(46 citation statements)

References 48 publications

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“…This kind of differential reactivity to diazepam has also been observed by others in inbred rat strains differing in anxiety-related behavior (Commissaris et al 1990;Ramos et al 1997). Although further experiments are needed to examine the differential reactivity to anxiolytics in the HAB and LAB rats in more detail (for example, by determining the anxiolytic threshold dose in both lines) the present findings support the notion that the efficacy of pharmacological manipulation of anxiety-related behavior depends upon the basal level of anxiety (Fernandez-Teruel et al 1991;Gendron and Brush 1996;Ramos et al 1997;Rodgers et al 1997) and may provide an explanation for the frequent failures of clinically effective anxiolytics when screening tests are performed on normal animals (Handley et al 1993;Rodgers et al 1997;Stephens and Andrews 1991). Differences in central benzodiazepine/ GABA-A receptors, through which diazepam exerts its action, have been demonstrated in anxious and nonanxious rats and mice (Chapouthier et al 1991;Clément et al 1997;Robertson et al 1978).…”

Section: Discussionsupporting

confidence: 70%

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

Liebsch

Linthorst

Neumann

et al. 1998

Neuropsychopharmacology

148

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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...

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Section: Discussionsupporting

confidence: 70%

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

Liebsch

Linthorst

Neumann

et al. 1998

Neuropsychopharmacology

148

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“…Typically, benzodiazepine anxiolytics increase the number of entries into and the time spent on the open arms. Countless drugs have been assayed in this model, and the results obtained summarized in several comprehensive reviews (e.g., Handley et al 1993, Griebel 1995. In order to improve the capacity of the elevated plus-maze for detecting non-benzodiazepine anxiolytics, ethological analysis of behavioral items shown by the animals while exploring the elevated plus-maze (e.g., nose poking out of the enclosed arm and exploration of the open arm end) has been added to the former, spatio temporal measures (Cruz et al 1994, Rodgers andJohnson 1995).…”

Section: Elevated Mazesmentioning

confidence: 99%

“…The British psychologist Sheila Handley, who conceived the idea of the crossed elevated maze, has argued that many of the inconsistencies found with drugs that alter 5-HT neurotransmission in the elevated X and plus mazes may be explained by the fact that these are mixed models, in the sense that the rat displays different strategies of defense while exploring them, which could be influenced in opposite directions by 5-HT (Handley et al 1993). At least two strategies may be easily seen: 1) avoidance of open arms when the rat is in one of the closed arms, and 2) escape from an open arm to enter a safer, closed arm.…”

Section: Elevated Mazesmentioning

confidence: 99%

“…As a consequence, conflict tests have become widely used for assaying anti-anxiety agents, either for screening purposes or for studying their mechanisms of action. How-ever, with the discovery of new anxiolytics, such as buspirone and ritanserin, which act primarily on the neurotransmission mediated by serotonin (5-HT), it became clear that the available conflict tests failed to consistently detect their anxiolytic properties (Handley et al 1993, Griebel 1995. Therefore, conflict tests seem to be fi t only for detecting anxiolytics that act through the neurotransmission mediated by γ -aminobutyric acid (GABA), such as barbiturates or benzodiazepine agonists.…”

Section: Introductionmentioning

confidence: 99%

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Elevated mazes as animal models of anxiety: effects of serotonergic agents

Pinheiro

Zangrossi

Del-Ben

et al. 2007

An. Acad. Bras. Ciênc.

104

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This article reviews reported results about the effects of drugs that act upon the serotonergic neurotransmission measured in three elevated mazes that are animal models of anxiety. A bibliographic search has been performed in MED-LINE using different combinations of the key words X-maze, plus-maze, T-maze, serotonin and 5-HT, present in the title and/or the abstract, with no time limit. From the obtained abstracts, several publications were excluded on the basis of the following criteria: review articles that did not report original results, species other than the rat, intracerebral drug administration alone, genetically manipulated rats, and animals having any kind of experimental pathology. The reported results indicate that the effect of drugs on the inhibitory avoidance task performed in the elevated T-maze and on the spatio temporal indexes of anxiety measured in the X and plus mazes correlate with their effect in patients diagnosed with generalized anxiety disorder. In contrast, the drug effects on the one-way escape task in the elevated T-maze predict the drug response of panic disorder patients. Overall, the drug effects assessed with the avoidance task in the T-maze are more consistent than those measured through the anxiety indexes of the X and plus mazes. Therefore, the elevated T-maze is a promising animal model of generalized anxiety and panic disorder.

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“…However, while there is no doubt that the conventional plus-maze is highly sensitive to the influence of benzodiazepine/GABA A receptor-related manipulations, effects obtained with other anxietymodulating agents (e.g., buspirone) have been very much more variable (5,8,49). Although this profile has led certain authors to doubt the utility/reliability of the model (50,51), alternate interpretations of this pharmacological inconsistency are just as plausible.…”

Section: The Elevated Plus-mazementioning

confidence: 99%

Animal models of anxiety: an ethological perspective

Rodgers¹,

Cao²,

Dalvi³

et al. 1997

Braz J Med Biol Res

523

244

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In the field of anxiety research, animal models are used as screening tools in the search for compounds with therapeutic potential and as simulations for research on mechanisms underlying emotional behaviour. However, a solely pharmacological approach to the validation of such tests has resulted in distinct problems with their applicability to systems other than those involving the benzodiazepine/GABA A receptor complex. In this context, recent developments in our understanding of mammalian defensive behaviour have not only prompted the development of new models but also attempts to refine existing ones. The present review focuses on the application of ethological techniques to one of the most widely used animal models of anxiety, the elevated plus-maze paradigm. This fresh approach to an established test has revealed a hitherto unrecognized multidimensionality to plus-maze behaviour and, as it yields comprehensive behavioural profiles, has many advantages over conventional methodology. This assertion is supported by reference to recent work on the effects of diverse manipulations including psychosocial stress, benzodiazepines, GABA receptor ligands, neurosteroids, 5-HT 1A receptor ligands, and panicolytic/panicogenic agents. On the basis of this review, it is suggested that other models of anxiety may well benefit from greater attention to behavioural detail.

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Multiple serotonin mechanisms in animal models of anxiety

Cited by 153 publications

References 48 publications

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

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

Elevated mazes as animal models of anxiety: effects of serotonergic agents

Animal models of anxiety: an ethological perspective

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