5-HT Receptor Mechanisms in Human Anxiety

Griebel

Neuroscience &Amp; Biobehavioral Reviews

2001

410

251

The natural defensive behaviors of laboratory mice have been evaluated in both seminatural and highly structured situations; and characterized in terms of eliciting stimuli, response to pharmacological agents, behavior patterns, and outcome or effect on the social and physical environment. The defense patterns of laboratory mice and rats are generally similar, but mice show risk assessment on initial exposure to highly threatening stimuli while rats do not, while rats display alarm vocalizations, missing in mice. Quantitative differences in freezing and¯ight for laboratory mice and rats appear to largely re¯ect domestication effects, with wild mice and rats more similar to each other. This nexus of detailed within-species and comparative data on defense patterns makes it possible to reliably elicit speci®c defenses in mice or rats in an experimental context, providing well-validated assays of the natural defensive behaviors themselves, as opposed tò models' of defense.The mouse±rat comparisons indicate considerable cross-species generality for these defense patterns, as does a scattered but considerable literature on other mammalian species, generally involving ®eld studies and typically focusing on those aspects of defensive behavior that are visible at a distance, such as vigilance, or¯ight. Although potential homologies between normal mouse and human defense systems should ideally involve all four pattern components (stimulus, organismic factors, response characteristics, outcome), predictive validity in terms of response to drugs active against speci®c defensive psychopathology is the most extensively investigated of these. Flight, as measured in the Mouse Defense Test Battery shows a consistently appropriate response to panicolytic, panicogenic, and panic-neutral drugs, while some other predictive`panic models' (dPAG-stimulation; DMH-inhibition; possibly conditioned suppression of drinking paradigms) also elicit and (indirectly) measure behaviors potentially related to¯ight. Models unrelated to¯ight (e.g. ultrasonic vocalization to conditioned stimuli); or for which¯ight elements may a relatively minor contributor to the behavior measured (Elevated T-maze) are less predictive of panicolytic or panicogenic action. These ®ndings indicate that natural defensive behaviors provide a well-characterized pattern for analysis of effects of genetic or other physiological manipulations in the mouse, and may also serve as a model for analysis of defenserelated human psychopathology. q 2001 Elsevier Science Ltd. All rights reserved. The recent explosion of genetic techniques and genetically modi®ed animals has greatly exacerbated the need for comprehensive, natural, models or assays of behavior that are relevant to mice, the mammalian species of choice for genetic research [25]; and has additionally focused attention on issues of construction and validation of these tests.Minimally, a behavioral model/assay should enable the reliable elicitation and measurement of a qualitatively consistent behavior pattern for ...

Section: Panic Disorder (Pd)mentioning

confidence: 99%

Mouse defensive behaviors: pharmacological and behavioral assays for anxiety and panic

Griebel

Neuroscience &Amp; Biobehavioral Reviews

2001

410

251

“…Although clinical data are exceedingly sparse, available information suggests that the 5-HTlc/~ antagonist ritanserin is effective in the treatment of anxiety, suggesting that further evaluations of other compounds active at the 5-HT~c/2 site would appear justified (Ceulemans et al 1985;Deakin et al 1991). Although the effects have been small, experimental data suggest that 5-HTm/2 receptors may be involved in the expression of symptoms and conditioned autonomic responses of anxiety (Deakin et al 1991). There also is considerable interest in the potential of 5-HT 3 antagonists for the treatment of anxiety, since these compounds also have shown anxiolytic-like activity in some animal procedures and in preliminary studies with humans (see below, the report by Lecrubier et al in this issue, and Pecknold et al 1991).…”

Section: Anxiolytic Activity Of 5-ht~c/2 and 5-ht 3 Drugs In Animal Pmentioning

confidence: 96%

5-HT receptors as targets for the development of novel anxiolytic drugs: models, mechanisms and future directions

Barrett¹,

Vanover²

1993

Psychopharmacology

150

The introduction of buspirone for the treatment of anxiety, together with the eventual suggestion of a mode of action involving the serotonin (5-HT)1A receptor subtype, has generated considerable research activity and renewed interest in the potential role of 5-HT in anxiety. The further identification of multiple 5-HT1 receptors, coupled with the possibility that these subtypes potentially are involved in discrete biobehavioral regulation and pathophysiological conditions, has greatly expanded the search for tools capable of probing these receptors and has raised hopes for a new generation of more specific compounds to treat other disorders associated with the 5-HT system such as depression, aggression, and sleep and eating disturbances. The involvement of 5-HT in anxiety has prompted a careful reevaluation of several traditional areas of research. This has included those methods used in the in vivo evaluation of drugs in preclinical animal test procedures used to assess potential anxiolytic activity, as well as the mechanisms associated with adaptive changes occurring during long-term drug administration. The proliferation of various procedures for studying the anxiolytic effects of 5-HT drugs has not always been accompanied by systematic behavioral and pharmacological validation. At the present time, this area of research is characterized by numerous inconsistent findings. Procedures that are objective and impartial to the behavioral effects of drugs provide distinct advantages for addressing some of these issues, as will the results from carefully controlled clinical studies. The main objective of this article is to provide an overview of the recent developments in research involving the 5-HT system and anxiety. The emphasis will be on the 5-HT1 receptor system and a review of the results in the predominant animal models used to evaluate these drugs, as well as an overview of the mechanisms currently believed to be responsible for the therapeutic activity of this class of compounds. Studies with the pigeon are reviewed, since this species appears distinctly sensitive to the anxiolytic-like effects of 5-HT1A drugs in conflict procedures. Although chronic administration of 5-HT1A drugs appears necessary for clinical anxiolytic and antidepressant activity, the most noteworthy neuropharmacological effects in animals seem to occur in 5-HT2 and, perhaps, 5-HT3 receptors which are downregulated. Studies summarizing the activity of drugs interacting with 5-HT1C/2 and 5-HT3 receptor sites are also discussed as they too may be involved in anxiety or the actions of anxiolytic drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

Animal Models of Human Emotion and Cognition.

“…Flight. The observation that PD patients usually report an urgent desire to flee from where the attack is occurring (American Psychiatric Association, 1994) has led several authors to suggest that panic symptoms are due to pathological, spontaneous activation of neuronal mechanisms underlying flight reactions (Deakin & Graeff, 1991;Deakin, Guimaraes, Wang, Hellewell, & Hensman, 1991;Graeff, 1990). In accordance with this suggestion, data from the MDTB clearly demonstrated that panicmodulating agents specifically decrease animals' flight responses.…”

Section: Clinical Relevance Of the Defensive Behaviors Of The Micementioning

confidence: 99%

The Mouse Defense Test Battery: An experimental model of different emotional states.

Sanger¹

There are few well-accepted animal models of psychiatric disorders. However, a number of animal models of anxiety have been proposed, most of which involve exposure of animals to external (e.g., cues previously paired with footshock) or internal (e.g., drugs) stimuli that are assumed to be capable of inducing anxiety in humans. The actual measures taken include suppression of previously punished activities, conditioned emotional responses, a range of sonic and ultrasonic vocalizations, and social and exploratory behaviors (for reviews, see Sanger, Perrault, Morel, Joly, & Zivkovic, 1991;Treit, 1985).The suggestion has been made many times that defensive behaviors of lower mammals constitute a significant model for understanding human emotional disorders (e.g., R. J. Blanchard & Blanchard, 1984; see also Brain & Marrow, this volume). Defensive behaviors occur in response to a number of threatening stimuli, including predators, attacking conspecifics, and dangerous objects or situations. Such behaviors can readily be studied in wild rats, which show a complete defensive repertoire in response t o danger. In contrast, in laboratory rats, defensive threat and attack behaviors in response to predators have been much reduced through systematic selection for docility by breeders (R. J. Blanchard, Flannelly, & Blanchard, 1986). However, the disadvantages of using wild rats as subjects in laboratory research are obvious. For example, it is clear that the difficulty and cost in obtaining and maintaining these animals are greater than for laboratory rats.There are reasons to believe that the laboratory mouse has not been so severely selected on the basis of its defensive behaviors. The smaller size of the mouse and its reduced potential to inflict serious wounds, plus the ease of handling mice with a tail pickup, have enabled greater tolerance of defensive attack behavior in this species, and indeed, domesticatedWe acknowledge the contribution of Professors D. Caroline and Robert J. Blanchard (University of Hawaii) in offering suggestions and stimulating discussion during the course of this work.