Animal Models Of Anxiety Research Articles

Anxiolytic effects of ethanol and phenobarbital are abolished in test-experienced rats submitted to the elevated plus maze

Prior test experience compromises the anxiolytic efficacy of benzodiazepines (BZs) either in rats or mice, a phenomenon not exclusive to the elevated plus-maze (EPM) animal model of anxiety, which is referred to as “one-trial tolerance.” However, it remains to be determined whether a similar event occurs when testing other drugs that also possess binding-sites on the GABA A receptor, such as ethanol and barbiturates. In the present study, we have addressed this issue using maze-naive and maze-experienced (free exploration of the EPM 48 h earlier for 5 min) rats pretreated with ethanol (1.0–1.4 g/kg) or phenobarbital (20–60 mg/kg) and submitted to the EPM. The results confirmed the anxiolytic profile of both drugs, represented by increased open arm exploration and decreased risk assessment behavior, in maze-naive rats. However, in maze-experienced rats, neither ethanol nor phenobarbital anxiolytic effects were observed, suggesting that prior maze experience compromised the drugs' anxiolytic activity. Thus, the “one-trial tolerance” phenomenon might also be extended to other drugs that bind to the GABA A receptor complex.

Acute and subchronic effects of MDMA (“ecstasy”) on anxiety in male mice tested in the elevated plus-maze

3,4-Methylenedioxymethamphetamine (MDMA) is a compound structurally similar to methamphetamine, which has become one of the most widely used illicit substances. Animal studies investigating acute effects of MDMA on anxiety are unclear since, although an anxiogenic-like action of MDMA in different animal models of anxiety has been mainly described, there is also evidence supporting an anxiolytic-like effect for this drug. An attempt was made to clarify the possible anxiogenic-like profile of MDMA (1, 8 and 15 mg/kg ip) by analyzing its effect on behavior of male mice in the elevated plus-maze test. Moreover, the possible development of tolerance to the effects of MDMA on anxiety after its subchronic administration for 5 consecutive days was examined. The parameters evaluated included: (1) total time in open arms, (2) total time in closed arms, (3) total time in central area, (4) number of open arm entries, (5) number of closed arm entries and (6) number of central area entries. Acute treatment with MDMA (8 mg/kg) significantly reduced the time spent in the open arms, as well as markedly increasing the number of entries in the closed arms and in the central area, as compared with the control group, suggesting that MDMA, at this dose, has an anxiogenic-like activity. Mice subchronically treated with the drug (1 and 8 mg/kg) displayed a notable reduction in the time spent in the open arms, accompanied by an increase in the time spent in the closed arms and in the central platform. These results indicate that the anxiogenic-like effect found after acute treatment is not only maintained but also more marked after subchronic treatment. In contrast, mice treated subchronically with the highest dose of MDMA (15 mg/kg) exhibited a significant increase in the time spent in the open arms as well as a marked reduction in the time spent in the closed arms, supporting an anxiolytic-like activity of the drug. A possible dual pharmacological property of MDMA on anxiety is suggested.

Genetic effects on an animal model of anxiety

Genetic effects on behavioural measures thought to model anxiety have been reported on 15 mouse chromosomes. In general the individual effect from each locus is small, contributing to 10% or less of the total variation, but through use of crosses between inbred rodents the power to detect such effects is high: 39 loci have been reported at stringent levels of significance. Novel multivariate analyses of these data go some way to characterizing the genetic architecture of anxiety and also to validating the tests that are used for its measurement. However, we are still some way from finding the molecular variants that explain the heritability of the trait.

Do animal models of anxiety predict anxiolytic-like effects of antidepressants?

Chronically administered antidepressant drugs, particularly selective serotonin (5-HT) reuptake inhibitors (SSRIs), are clinically effective in the treatment of all anxiety disorders, while the clinical effectiveness of "traditional" anxiolytics, such as benzodiazepines (BDZs), is limited to generalised anxiety disorder or acute panic attacks. This implies that animal models of anxiety should be sensitive to SSRIs and other antidepressants in order to have predictive validity. We reviewed the literature on the effects of antidepressants in the so-called animal models of anxiety and found that only the isolation-induced calls in guinea-pig pups may reveal anxiolytic-like action of all antidepressant classes after acute administration. Some other models, such as marble-burying or conditioned-freezing behaviours, and isolation- or shock-induced ultrasonic vocalisation models, may detect anxiolytic-like activity of acutely administered antidepressants, although the sensitivity of these models is usually limited to SSRIs and other drugs affecting 5-HT uptake. The predictive validity of models of "anxiety", such as the plus-maze and light-dark transition tests or stress-induced hyperthermia, appears to be limited to BDZ-related drugs. Far less work has been done on chronic administration of antidepressants in animal anxiety models. Unless and until such studies have been undertaken, the true predictive value of the anxiety models will remain unknown.

Contrasting phenotypes of C57BL/6JOlaHsd, 129S2/SvHsd and 129/SvEv mice in two exploration-based tests of anxiety-related behaviour

Knockout mice are typically generated on a mixed genetic background and, as such, detailed behavioural characterisation of these background strains is essential to the valid interpretation of mutant phenotypes. In this context, recent research has revealed significant differences in anxiety-like behaviour among the most commonly used background strains (C57BL/6J and various 129 substrains), leading to the possibility that at least certain mutant phenotypes may not after all be due to the targeted mutation. However, these findings derive largely from behavioural test batteries in which there may well be an experiential confound, while the widely reported hypolocomotor profile of most 129 substrains may compromise the principal indices of anxiety-like behaviour. In the present study, we have compared the behavioural profiles of three commonly used background strains (C57BL/6JOlaHsd, 129/SvEv and 129S2/SvHsd) in two of the most popular animal models of anxiety—the elevated plus-maze (EPM) and light/dark exploration (LDE) tests. Naive animals were used for each procedure, ethological scoring methods were employed throughout, and the inbred phenotypes were also compared with that of an outbred strain (Swiss–Webster) widely employed in test validation and behavioural pharmacology. Our results show that, despite their hypolocomotor profile, both 129 substrains display higher levels of anxiety-like behaviour (conventional and/or ethological measures) relative to the C57BL/6JOlaHsd strain. Furthermore, all three inbred strains were less active in both tests when compared with the outbred Swiss–Webster strain. However, whereas C57BL/6JOlaHsd mice displayed lower levels of anxiety-like behaviour than their Swiss–Webster counterparts (both tests), 129S2/SvHsd (but not 129/SvEv) mice exhibited evidence of higher anxiety, particularly in the LDE test. The implications of these findings are discussed in relation to both the behavioural and pharmacological phenotyping of mutant mice.

Dorsal and ventral hippocampal cholinergic systems modulate anxiety in the plus-maze and shock-probe tests

There is emerging evidence that increased acetylcholine levels in brain reduce anxiety. More specifically there is evidence that some of these anxiolytic effects of acetylcholine are modulated by the hippocampus. In the present study we examined the roles of the cholinergic systems in the dorsal and ventral hippocampus in two animal models of anxiety: the elevated plus-maze and the shock-probe burying tests. We found that microinfusions (10 μg/0.5 μl) of the acetylcholinesterase inhibitor physostigmine in either the dorsal or the ventral hippocampus increased rats’ open arm exploration in the plus-maze test, and decreased burying behavior in the shock-probe test. Interestingly, infusions in the ventral, but not the dorsal hippocampus also increased the number of contacts rats made with the shock-probe. Overall, the results suggest that cholinergic stimulation in the dorsal and ventral hippocampus modulate anxiety, but that only the ventral hippocampal cholinergic system is involved in the passive avoidance of painful stimuli.

Pharmacology of flibanserin.

Flibanserin has preferential affinity for serotonin 5-HT(1A), dopamine D(4k), and serotonin 5-HT(2A) receptors. In vitro and in microiontophoresis, flibanserin behaves as a 5-HT(1A) agonist, a very weak partial agonist on dopamine D(4) receptors, and a 5-HT(2A) antagonist. In vivo flibanserin binds equally to 5-HT(1A) and 5-HT(2A) receptors. However, under higher levels of brain 5-HT (i.e., under stress), flibanserin may occupy 5-HT(2A) receptors in higher proportion than 5-HT(1A) receptors. The effects of flibanserin on adenylyl cyclase are different from those of buspirone and 8-OH-DPAT, two other purported 5-HT(1A) receptor agonists. Flibanserin reduces neuronal firing rate in cells of the dorsal raphe, hippocampus, and cortex with the CA1 region being the most sensitive in the brain. Flibanserin-induced reduction in firing rate in the cortex seems to be mediated through stimulation of postsynaptic 5-HT(1A) receptors, whereas the reduction of the number of active cells seems to be mediated through dopamine D(4) receptor stimulation. Flibanserin quickly desensitizes somatic 5-HT autoreceptors in the dorsal raphe and enhances tonic activation of postsynaptic 5-HT(1A) receptors in the CA3 region. Flibanserin preferentially reduces synthesis and extracellular levels of 5-HT in the cortex, where it enhances extracellular levels of NE and DA. Flibanserin displays antidepressant-like activity in most animal models sensitive to antidepressants. Such activity, however, seems qualitatively different from that exerted by other antidepressants. Flibanserin seems to act via direct or indirect stimulation of 5-HT(1A), DA, and opioid receptors in those animal models. Flibanserin does not display consistent effects in animal models of anxiety and seems to exert potential antipsychotic effects. Flibanserin may induce some sedation but does not induce observable toxic effects at pharmacologically relevant doses.

Acute effect of ethanol on anxiety and 5-HT in the prefrontal cortex of rats

The anxiolytic effect of ethanol is generally accepted to be involved in the development of alcohol dependence. Because serotonin (5-HT) is said to be involved in both anxiety and alcohol dependence, in the present study the effect of acute ethanol administration on basal 5-HT release of the medial prefrontal cortex and its effect on 5-HT release in rats submitted to an animal model of anxiety, the elevated plus maze test, were detected in two rat strains showing a different anxiety-related behavior. Ethanol had an anxiolytic-like effect and induced an increase of basal 5-HT release in the medial prefrontal cortex in the home cage in the less anxious Wistar–Harlan rats. Both effects were not seen in the more anxious Wistar–BgVV rats. The exposure to the elevated plus maze test induced an increase of extracellular 5-HT in the more anxious Wistar–BgVV rats but not in the less anxious Wistar–Harlan rats. Ethanol did not change 5-HT release during the elevated plus maze test in both rat strains. Thus, the anxiolytic-like effect of ethanol in Wistar–Harlan rats was not primarily associated with a decrease of 5-HT release in the prefrontal cortex as it is seen with other anxiolytic agents like diazepam.

5-HT 1B mrna regulation in two animal models of altered stress reactivity

Background: Acute stress has profound effects on serotonergic activity, but it is not known whether alterations in the serotonin system can predispose individuals to exaggerated stress responses. We examined the regulation of 5-HT 1B and 5-HT 1A mRNA in two rodent models of differential sensitivity to stress: congenital learned helplessness (cLH) and handling and maternal separation (HMS). Methods: 5-HT 1B and 5-HT 1A mRNAs in brain tissue sections were quantitated by in situ hybridization from control, stress-sensitive, and stress-resistant male rats in the HMS model and stress-sensitive and stress-resistant rats (both males and females) in the cLH model. Dorsal raphe nucleus, striatum, and hippocampus were examined. Results: The main result was that dorsal raphe 5-HT 1B mRNA was substantially elevated (63–73%) in male rats in the stress-resistant group of both models compared with stress-sensitive animals. 5-HT 1B mRNA in female rats did not differ between groups in the cLH model. There were no differences in 5-HT 1A mRNA between HMS groups. Conclusions: These findings suggest that 5-HT 1B autoreceptor regulation is altered in animals with diminished stress reactivity. These results suggest that 5-HT 1B autoreceptors in unstressed and acutely stressed animals differ, indicating the importance of state versus trait changes in serotonin function in animal models of anxiety and depression.

Individual response profiles of male Wistar rats in animal models for anxiety and depression

Previous work has shown that systematic individual differences between male Wistar rats can be detected in tasks like the elevated plus-maze, or the open field. Here, we investigated whether individual profiles of anxiety, as measured with the plus-maze, may predict behavioral response profiles in other tasks where anxiety, aversion, or depressive behaviors are important. Male Wistar rats were initially screened: (A) in an open field; and (B) in an elevated plus-maze. Based on their plus-maze behavior, that is, the time spent in the open arms, the animals were divided into two subgroups with either ‘low’ or ‘high’ anxiety (LA or HA) levels. These subgroups were exposed to other experimental anxiety paradigms, namely object burying and two-way active avoidance, and an animal model of depression, the forced swim test. In the plus-maze, the percentage of time spent on, and the number of entries into the open arms were lower in HA than in LA rats. In the object burying task, HA rats showed more burying behavior of Tabasco-coated marbles, and in the active avoidance task, they showed slower acquisition of avoidance learning and higher escape latency as compared to LA rats. Finally, LA and HA rats behaved similarly in the forced swim test; however, the percentage changes of immobility time between test days 1 and 2 were negatively correlated to open field behavior, namely locomotor activity and center entries. On the other hand, the frequencies of rearing in the open field, which can also gauge functional differences between rats (for example responsiveness to novelty, psychomotor activation), were not substantially related to the behavioral profiles in the tests of anxiety and depression. These results show that individual differences of anxiety in the plus-maze can be predictive of behavior in other anxiety models, but not in forced swim test, indicating that they may be determined partly by similar functional and physiological mechanisms.

A quantitative trait locus influencing anxiety in the laboratory rat.

A critical test for a gene that influences susceptibility to fear in animals is that it should have a consistent pattern of effects across a broad range of conditioned and unconditioned models of anxiety. Despite many years of research, definitive evidence that genetic effects operate in this way is lacking. The limited behavioral test regimes so far used in genetic mapping experiments and the lack of suitable multivariate methodologies have made it impossible to determine whether the quantitative trait loci (QTL) detected to date specifically influence fear-related traits. Here we report the first multivariate analysis to explore the genetic architecture of rodent behavior in a battery of animal models of anxiety. We have mapped QTLs in an F2 intercross of two rat strains, the Roman high and low avoidance rats, that have been selectively bred for differential response to fear. Multivariate analyses show that one locus, on rat chromosome 5, influences behavior in different models of anxiety. The QTL influences two-way active avoidance, conditioned fear, elevated plus maze, and open field activity but not acoustic startle response or defecation in a novel environment. The direction of effects of the QTL alleles and a coincidence between the behavioral profiles of anxiolytic drug and genetic action are consistent with the QTL containing at least one gene with a pleiotropic action on fear responses. As the neural basis of fear is conserved across species, we suggest that the QTL may have relevance to trait anxiety in humans.

Leptin suppression of hypothalamic NPY expression and feeding, but not amygdala NPY expression and experimental anxiety

Leptin decreases food intake through actions in the hypothalamus, partly through interactions with neuropeptide Y (NPY). However, NPY also produces behavioral antistress effects mediated inter alia through the amygdala. If leptin generally suppresses NPY function, the utility of leptin-mimics for treatment of obesity might be limited. Here, we therefore compared the effects of intracerebroventricular leptin on hypothalamic and amygdala NPY expression, as well as the respective related behaviors, i.e., feeding and experimental anxiety. Rats were injected intracerebroventricularly with leptin once daily for 6 days. Leptin-treated subjects consumed significantly less chow and had reduced body weight at the end of the treatment period compared to saline-treated controls. This was accompanied by a significant suppression of hypothalamic NPY expression. In contrast, the expression of NPY within the amygdala was unaffected by leptin. In parallel, in an established animal model of anxiety, the elevated plus-maze, no effect of leptin on anxiety-related behaviors was observed. In conclusion, leptin selectively affects the hypothalamic NPY system and its functional outflow, i.e., feeding and endocrine stress responses. Despite modifying endocrine responses, leptin treatment does not affect behavioral measures of experimental anxiety.

The influence of competitive status (winner/loser) on the behavior of male rats in three models of anxiety

AbstractStudies indicate that features such as prior stressful experience, strain, gender, and age can influence the behavior of rats in animal models of anxiety. In the present study, we examined the possible influence of competitive status (winner/loser) in three such models: the elevated plus‐maze, the open field, and the social interaction test. One hundred to 135‐day‐old male Wistar rats were conditioned to traverse a straight runway tube to obtain food. Subsequently, two rats were placed at the same time in the runway tube and, being unable to pass each other, one of them pushed the other to the opposite end‐box. The rats were categorized as winners or losers in this competition. One week after the straight runway tube test, the rats were submitted to the anxiety models, where it was observed that winner rats showed greater locomotor activity than the losers in the three models studied. Furthermore, winner rats showed less immobility and higher central and total locomotor activity in the open field and a greater duration of social interaction in the social interaction test. These results suggest that competitive status has an influence on the locomotor activity of rats in animal models of anxiety. However, whether competitive status influences anxiety as assessed in these models is unclear, and further investigations are warranted. Aggr. Behav. 28:164–171, 2002. © 2002 Wiley‐Liss, Inc.

Anxiolytic effects of mecamylamine in two animal models of anxiety.

Anxiolytic effects of mecamylamine in two animal models of anxiety.

The effects of cold, rotation, and genotype on the production of ultrasonic calls in infant mice.

There has been a revival of interest recently in the ultrasonic calls of infant rodents as investigators are using them to assess neurobehavioral development and animal models of anxiety. We compared the rates of ultrasonic calling of infant mice of two genotypes in two situations, cold and rotation. The subjects of study were 169 mouse pups from 29 litters and of two F1 genotypes, C57BL/10J x DBA/2J and C57BL/10J x SJL/J. Half of each litter was recorded in a cool situation for 20 seconds and the other half was recorded while rotating at 10 rpm for 20 seconds. All pups were recorded on days of age 2 to 8. Rotation elicited calling at about twice the rate as cool temperature on each day of age and on average across days; situation (cold or rotation) accounted for over 50% of the variation between litters. Genotype also altered call rate, and on some days situation and genotype interacted. In studies of neurobehavioral development and the effects of pharmacological agents on infant mice, it is particularly important to understand the roles of the stimuli and genotypes employed.

Improvement in the selectivity and metabolic stability of the serotonin 5-HT(1A) ligand, S 15535: a series of cis- and trans-2-(arylcycloalkylamine) 1-indanols.

S 15535 (1) displays a distinctive profile of agonist and antagonist (weak partial agonist) activity at pre- and postsynaptic 5-HT(1A) receptors, respectively. It has proven to be active in several models predictive of anxiolytic, antidepressant, and procognitive properties. In an attempt to increase its selectivity and metabolic stability, and guided by the results of human metabolic studies, we prepared a series of cis- and trans-2-(arylcycloalkylamine) 1-indanols. Irrespective of the nature of the arylcycloalkylamine moiety or the presence of substituents on the indanol ring, trans isomers invariably showed the highest affinity for human, recombinant h5-HT(1A) receptors. Among them, compounds 39, 42, 45, 49, 52, 53, 54, 57, 61, 64, 67, and 70 displayed similar or higher affinity than the parent compound 1 (pK(i) > or = 9.1). Lack of selectivity toward alpha1-adrenoceptors has been frequently encountered with 5-HT(1A) ligands. While S 15535 itself presents reasonable selectivity (158-fold) in this respect, trans piperazine derivatives 4-trans,35, 39, 41, 47, 64, 68, 69, 70, 71 displayed even more pronounced selectivity vs alpha1-adrenoceptors, with the nitro derivative 70 being highly selective (1259-fold). However, among the set of trans piperidines prepared, only 64, which also bears a nitro on the indanol ring, displayed selectivity greater than the parent compound 1. All trans derivatives behaved as partial agonists at h5-HT(1A) receptors, as determined by their submaximal stimulation of [35S]GTPgammaS binding to a level comparable to that observed with S 15535. In metabolic stability studies in vitro using human microsomes and hepatocytes, only trans piperazines and, in particular, 35, 39, 41, 68, 69, and 70, showed an improvement relative to 1, whereas trans piperidines did not. Compounds 35, 39, 41, and 70, which combined both improved selectivity and metabolic stability, and which retained the distinctive pharmacological characteristics of S 15535, were evaluated in animal models of anxiety. Of these, 35, which showed the highest oral bioavailability in vivo in rats, was resolved into its two isomers 36 and 37. The eutomer 37 displayed 47% oral bioavailability in the rat and was potently active (0.1-0.5 mg/kg, s.c.) in the rat ultrasonic vocalization and social interaction models, predictive of anxiolytic activity. In conclusion, 2-(arylcycloalkylamine) 1-indanols represent a novel class of potent 5-HT(1A) ligands in which the presence of the hydroxyl group in the benzylic position enhances selectivity, while substituents on the phenyl ring of the indanol moiety improve both selectivity and metabolic stability.

Differential expression of Fos protein in the rat brain induced by performance of avoidance or escape in the elevated T-maze

Analysis of Fos protein expression was used to map brain areas activated by exposure of male Wistar rats to the elevated T-maze, an animal model of anxiety where tasks of inhibitory avoidance or one-way escape can be separately performed. The apparatus consists of three elevated arms — one enclosed and two open. In the inhibitory avoidance task — considered to represent learned fear — the time taken by rats to leave from the enclosed arm in three consecutive trials is measured. One-way escape task is measured by recording the time taken by animals to withdraw from the open arm and is thought to reflect innate fear. Control animals were placed three times at the end of the transversal arm of a T-maze composed of three enclosed arms and withdrawal latencies from this arm was similarly measured. Performance of avoidance task increased Fos-like immunoreactivity in the medial amygdaloid nucleus, in the anterior hypothalamic nucleus and in the median raphe nucleus. In contrast, performance of escape task enhanced Fos-like immunoreactivity in the basolateral amygdaloid nucleus and in the dorsal periaqueductal gray matter of the mesencephalon. Both behavioural tasks promoted an increase in Fos-like immunoreactivity in the paraventricular nucleus of the thalamus and in the dorsomedial hypothalamic nucleus. Therefore, the obtained results indicate that different sets of brain structures were, respectively, activated by inhibitory avoidance and one-way escape. This evidence supports the original hypothesis that two types of fear/anxiety are generated in the elevated T-maze.

Measuring normal and pathological anxiety-like behaviour in mice: a review

Measuring anxiety-like behaviour in mice has been mostly undertaken using a few classical animal models of anxiety such as the elevated plus-maze, the light/dark choice or the open-field tests. All these procedures are based upon the exposure of subjects to unfamiliar aversive places. Anxiety can also be elicited by a range of threats such as predator exposure. Furthermore, the concepts of ‘state’ and ‘trait’ anxiety have been proposed to differentiate anxiety that the subject experiences at a particular moment of time and that is increased by the presence of an anxiogenic stimulus, and anxiety that does not vary from moment to moment and is considered to be an ‘enduring feature of an individual’. Thus, when assessing the behaviour of mice, it is necessary to increase the range of behavioural paradigms used, including animal models of ‘state’ and ‘trait’ anxiety. In the last few years, many mice with targeted mutations have been generated. Among them some have been proposed as animal models of pathological anxiety, since they display high level of anxiety-related behaviours in classical tests. However, it is important to emphasise that such mice are animal models of a single gene dysfunction, rather than models of anxiety, per se. Inbred strains of mice, such as the BALB/c line, which exhibits spontaneously elevated anxiety appear to be a more suitable model of pathological anxiety.

Summary of a National Institute of Mental Health workshop: developing animal models of anxiety disorders.

There exists a wide range of animal models and measures designed to assess anxiety or fearfulness. However, the relationship between these models and clinical anxiety symptoms and syndromes is unclear. The National Institute of Mental Health convened a workshop to discuss the relationship between existing behavioral models of anxiety and the clinical profile of anxiety disorders. A second goal of this workshop was to outline various approaches towards modeling components of anxiety disorders. To briefly describe epidemiological and behavioral manifestations of clinical anxiety syndromes and how they relate to commonly employed animal models of anxiety. To describe approaches and considerations for developing, improving, and adapting anxiety models to better understand the neurobiology of anxiety. Clinicians, psychiatrists and clinical and basic neuroscientists presented data exemplifying different approaches towards understanding anxiety and the role of animal models. Panel members outlined what they considered to be critical issues in developing and employing animal models of anxiety. This review summarizes the discussions and conclusions of the workshop including recommendations for improving upon existing models and strategies for developing novel models. The probability of developing comprehensive animal models that accurately reflect the relative influences of factors contributing to anxiety disorder syndromes is quite low. However, ample opportunity remains to better define and extend existing models and behavioral measures related to specific processes that may be disrupted in anxiety disorders and to develop new models that consider the impact of combined factors in determining anxious behaviors.

The light-enhanced startle paradigm as a putative animal model for anxiety: effects of chlordiazepoxide, flesinoxan and fluvoxamine.

Recently, a new putative animal model of anxiety, "light-enhanced startle" was introduced. By placing a rat in a brightly lit environment, which is a naturally aversive stimulus to rats, the amplitude of the startle response to a startle-eliciting noise burst is increased. The present study aimed to determine the predictive validity of the light-enhanced startle as a putative model for anxiety. The effects of the GABA(A)-benzodiazepine receptor agonist chlordiazepoxide (CDP), the 5-HT1A receptor agonist flesinoxan and the specific 5-HT reuptake inhibitor fluvoxamine on light-enhanced startle were studied. Both CDP and flesinoxan decreased startle potentiation, whereas fluvoxamine was devoid of any effects on potentiation. Effects on baseline startle amplitude were only seen after CDP administration. The present experiment provides evidence for the predictive validity of the light-enhanced startle as an animal model for anxiety. Due to the use of an unconditioned anxiogenic stimulus, the light-enhanced startle offers several benefits over animal models that depend on conditioning. Drug effects can be ascribed more directly to effects on anxiety, as opposed to memory retrieval and, as shown in this study, non-specific drug effects can easily be detected without the interference of contextual fear.