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      Animal models of anxiety: an ethological perspective

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          Abstract

          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/GABAA 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-HT1A 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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          Anxiolytic-like effect of (S)-WAY 100135, a 5-HT1A receptor antagonist, in the murine elevated plus-maze test.

          The effects of (S)-WAY 100135 ((S)-N-tert-butyl-3-(4-(2-methoxyphenyl)- piperazin-1-yl)-2-phenyl-propanamide dihydrochloride; 2.5-20.0 mg/kg), a 5-HT1A receptor antagonist, on the behaviour of male mice were examined in the elevated plus-maze test of anxiety. An ethological scoring technique was used to provide a comprehensive profile of drug action. Only minor changes in behaviour were observed at 2.5 and 5.0 mg/kg, and consisted of reductions in some (though not all) risk assessment measures. At 10 mg/kg, the compound increased percent open arm entries and percent open arm time, without altering general activity levels. This classic anxiolytic-like profile was confirmed by major reductions in risk assessment measures including protected head-dips and protected stretched attend postures. Although many of the same changes were also observed at 20 mg/kg, the absence of an effect on percent open arm time and a tendency towards increased non-exploratory behaviour suggested (1) some loss of anxiolytic activity and (2) a possible contribution of non-specific factors at higher doses. Present findings indicate that (S)-WAY 100135 produces clear anxiolytic-like effects in the murine elevated plus-maze, a profile that can be distinguished from that produced by 5-HT1A receptor partial agonists in the same test.
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            Multiple serotonin mechanisms in animal models of anxiety: environmental, emotional and cognitive factors.

            Responses to serotonergic drugs in animal models of 'anxiety' are reviewed with emphasis on the elevated X-maze. Evidence for the 'classic' hypothesis, that decreasing serotonergic function is anxiolytic and increasing it anxiogenic, is most consistent in models of behavioural inhibition where the stimulus inhibits an approach response (conflict models). However, paradoxical drug effects are also frequent, especially where the aversive stimulus evokes an active response. Both types of drug effect are equally frequent in the elevated X-maze. 'Anxiety' models may detect multiple sites and mechanisms of action of the same drug; this may indicate multiple anxiety-related neurological mechanisms in the brain. However, not all drug effects in 'anxiety' models are necessarily related to anxiety itself. It is possible that cognitive factors may affect stimulus evaluation, and response inhibition by an aversive stimulus may be a special case of a wider role for serotonin in behavioural control. Clinical implications of these observations are considered.
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              Ethological analysis of cholecystokinin (CCKA and CCKB) receptor ligands in the elevated plus-maze test of anxiety in mice.

              The literature on the effects of CCK receptor manipulations in animal models of anxiety is rife with inconsistency, and the data subject to a variety of methodological and interpretative difficulties. In the present paper, the effects of a range of CCK receptor ligands on anxiety in male mice have been assessed using an ethological version of the elevated plus-maze test. Compounds selected for study were the agonists, CCK-4 and CCK-8s (12.5-100 micrograms/kg), and the antagonists, devazepide, L-365, 260 and PD 135158 (1.0 microgram/kg-1.0 mg/kg). CCK-4 failed to produce any significant behavioural effects over the dose range tested, while treatment with the sulphated octapeptide, CCK-8s, induced signs of behavioural inhibition at 100 microgram/kg without altering anxiety-related indices. Furthermore, in contrast to the clear anxiolytic profile of diazepam (1 mg/kg), and despite the comprehensive behavioural profiles yielded by ethological analysis, all three CCK receptor antagonists studied (devazepide, L-365, 260 and PD 135158) were found to be without significant effect under present test conditions. Together, present findings provide little support for the involvement of CCK receptor mechanisms in anxiety and, in particular, the form of anxiety evoked in mice by exposure to a plus-maze.
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                Author and article information

                Contributors
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Journal
                bjmbr
                Brazilian Journal of Medical and Biological Research
                Braz J Med Biol Res
                Associação Brasileira de Divulgação Científica (Ribeirão Preto )
                1414-431X
                March 1997
                : 30
                : 3
                : 289-304
                Article
                S0100-879X1997000300002
                10.1590/S0100-879X1997000300002
                9246227
                b9319962-c626-464c-9cc0-b42c0404bbc2

                http://creativecommons.org/licenses/by/4.0/

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                SciELO Brazil

                Self URI (journal page): http://www.scielo.br/scielo.php?script=sci_serial&pid=0100-879X&lng=en
                Categories
                BIOLOGY
                MEDICINE, RESEARCH & EXPERIMENTAL

                Medicine,General life sciences
                plus-maze,behavioural profiling,animal models of anxiety,ethology,defence,risk assessment,pharmacology

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