Animal Models Of Anxiety Disorders Research Articles

Recent advances in anxiety disorders: Focus on animal models and pathological mechanisms.

Anxiety disorders have become one of the most severe psychiatric disorders, and the incidence is increasing every year. They impose an extraordinary personal and socioeconomic burden. Anxiety disorders are influenced by multiple complex and interacting genetic, psychological, social, and environmental factors, which contribute to disruption or imbalance in homeostasis and eventually cause pathologic anxiety. The selection of a suitable animal model is important for the exploration of disease etiology and pathophysiology, and the development of new drugs. Therefore, a more comprehensive understanding of the advantages and limitations of existing animal models of anxiety disorders is helpful to further study the underlying pathological mechanisms of the disease. This review summarizes animal models and the pathogenesis of anxiety disorders, and discusses the current research status to provide insights for further study of anxiety disorders.

Valproate Adjuvant Cognitive Behavioral Therapy in Panic Disorder Patients With Comorbid Bipolar Disorder: Case Series and Review of the Literature.

Anxiety disorders are the most common comorbid psychiatric disorders in patients with bipolar disorder. Managing anxiety symptoms in comorbid conditions is challenging and has received little research interest. The findings from preclinical research on fear conditioning, an animal model of anxiety disorder, have suggested that memory reconsolidation updating (exposure-based therapy) combined with valproate might facilitate the amelioration of fear memories. Here, three cases of successful amelioration of agoraphobia and panic symptoms through valproate adjuvant therapy for cognitive behavioral therapy in patients who failed to respond to two to three consecutive standard pharmacotherapy trials over several years are described. To the best of the author’s knowledge, this is the first attempt to combine CBT with valproate in patients with panic disorder, agoraphobia, and comorbid bipolar disorder. Additionally, the background preclinical research on this combination therapy based on the reconsolidation-updating mechanism, the inhibition of histone deacetylase 2, and critical period reopening, off-label use of valproate in panic disorder, plasticity-augmented psychotherapy, and how to combine valproate with CBT is discussed.

Modeling anxiety in healthy humans: a key intermediate bridge between basic and clinical sciences.

Animal models of anxiety disorders are important for elucidating neurobiological defense mechanisms. However, animal models are limited when it comes to understanding the more complex processes of anxiety that are unique to humans (e.g., worry) and to screen new treatments. In this review, we outline how the Experimental Psychopathology approach, based on experimental models of anxiety in healthy subjects, can mitigate these limitations and complement research in animals. Experimental psychopathology can bridge basic research in animals and clinical studies, as well as guide and constrain hypotheses about the nature of psychopathology, treatment mechanisms, and treatment targets. This review begins with a brief review of the strengths and limitations of animal models before discussing the need for human models of anxiety, which are especially necessary to probe higher-order cognitive processes. This can be accomplished by combining anxiety-induction procedures with tasks that probe clinically relevant processes to identify neurocircuits that are potentially altered by anxiety. The review then discusses the validity of experimental psychopathology and introduces a methodological approach consisting of five steps: (1) select anxiety-relevant cognitive or behavioral operations and associated tasks, (2) identify the underlying neurocircuits supporting these operations in healthy controls, 3) examine the impact of experimental anxiety on the targeted operations in healthy controls, (4) utilize findings from step 3 to generate hypotheses about neurocircuit dysfunction in anxious patients, and 5) evaluate treatment mechanisms and screen novel treatments. This is followed by two concrete illustrations of this approach and suggestions for future studies.

MODERN METHODS OF ANXIETY ASSESSMENT of RODENTS BY TESTS BASED ON UNCONDITIONal BEHAVIOR MODELS

Aim.The main aim of this research is to overview some main methods of anxiety assessment of animals by the behavioral tests based on the unconditional models. Animal models of anxiety disorders are actively used for studying their etiology and pathogenesis and for their treatment and prevention. This review describes some basic unconditional methods of anxiety disorders assessment in laboratory animals: open field test, light-dark box test / light-dark exploration box, elevated plus-maze and Suok test. The principles of conducting this test, regulated parameters and their link with anxiety-level are described.Conclusion.A modern researcher possesses different methods of modeling anxiety disorders in rodents. The tendency to an in-depth assessment of the behavioral reactions is noted. The use of the described models allows us to reveal and analyze the anxiolytic activity of new pharmacological drugs and non-pharmacological methods of pathological anxiety management. The most important aspect of performing this research is the correct matching of received data and normal and pathological human physiology features.

Acute and repeated exposure with the nitric oxide (NO) donor sodium nitroprusside (SNP) differentially modulate responses in a rat model of anxiety

The nitric oxide (NO) donor sodium nitroprusside (SNP) actually is under investigation for the treatment of schizophrenia. That anxiety disorders are noted to occur commonly in schizophrenia patients is known. Contradictory results were reported however, concerning the effects of SNP in animal models of anxiety disorders. The present study investigated the effects of acute and repeated administration of SNP on anxiety-like behaviour in rats assessed in the light/dark test. The effects of SNP on motility in a locomotor activity chamber were also investigated in rats. Acute administration of 1 mg/kg SNP 30 but not 60 min before testing induced anxiolytic-like behaviour which cannot be attributed to changes in locomotor activity. Conversely, a single injection of 3 mg/kg SNP at 30 min before testing depressed rats' general activity, while at 60 min this dose did not influence performance of animals either in the light/dark or in the motor activity test. Repeated application of SNP (1 and 3 mg/kg, for 5 consecutive days) did not alter rodents' performance in the above described behavioural paradigms. The present results suggest that the effects exerted by SNP in the light/dark test in rats are dose, time and treatment schedule-dependent. The current findings propose also a narrow therapeutic window for SNP in this animal model of anxiety.

PS06. Prefrontal dopamine-dependent plasticity mediates relapse in an animal model of anxiety disorders

PS06. Prefrontal dopamine-dependent plasticity mediates relapse in an animal model of anxiety disorders

The nitric oxide donor molsidomine induces anxiolytic-like behaviour in two different rat models of anxiety

Experimental evidence indicates the implication of the nitric oxide (NO) in anxiety. Contradictory results were reported however, concerning the effects of NO donors in animal models of anxiety disorders. The present study investigated the effects of the NO donor molsidomine on anxiety-like behaviour and compared them with the anxiolytic diazepam in rats. For this purpose, the light/dark and the open field tests were used. The effects of molsidomine on motility were also assessed. Intraperitoneal (i.p.) administration of molsidomine (1 and 4mg/kg) did not influence rats' performance either in the light/dark or in the open field test. Administration of 2mg/kg molsidomine significantly prolonged the time spent in the light chamber in the rats compared with the vehicle-treated animals, did not affect the first latency to enter the dark chamber and did not influence the number of transitions between the light and dark compartments of the apparatus. In the open field test, rats that received 2mg/kg molsidomine spent more time in the central zone of the apparatus and exhibited an increment of rearing episodes compared with control and to molsidomine 1 and 4mg/kg-treated rats. Nevertheless, molsidomine, at any dose tested, did not alter locomotor activity compared with vehicle-treated rats in a motility test. The present results indicate that the 2mg/kg molsidomine induced anxiolytic-like effects in the light/dark and open field tests in the rat cannot be attributed to changes in locomotor activity. The magnitude of the molsidomine (2mg/kg)-induced anxiolytic-like effects was not different to that produced by the benzodiazepine anxiolytic diazepam (1mg/kg).

Developmental rodent models of fear and anxiety: from neurobiology to pharmacology

Anxiety disorders pose one of the biggest threats to mental health in the world, and they predominantly emerge early in life. However, research of anxiety disorders and fear-related memories during development has been largely neglected, and existing treatments have been developed based on adult models of anxiety. The present review describes animal models of anxiety disorders across development and what is currently known of their pharmacology. To summarize, the underlying mechanisms of intrinsic 'unlearned' fear are poorly understood, especially beyond the period of infancy. Models using 'learned' fear reveal that through development, rats exhibit a stress hyporesponsive period before postnatal day 10, where they paradoxically form odour-shock preferences, and then switch to more adult-like conditioned fear responses. Juvenile rats appear to forget these aversive associations more easily, as is observed with the phenomenon of infantile amnesia. Juvenile rats also undergo more robust extinction, until adolescence where they display increased resistance to extinction. Maturation of brain structures, such as the amygdala, prefrontal cortex and hippocampus, along with the different temporal recruitment and involvement of various neurotransmitter systems (including NMDA, GABA, corticosterone and opioids) are responsible for these developmental changes. Taken together, the studies described in this review highlight that there is a period early in development where rats appear to be more robust in overcoming adverse early life experience. We need to understand the fundamental pharmacological processes underlying anxiety early in life in order to take advantage of this period for the treatment of anxiety disorders.

Differential roles of the dorsal and ventral hippocampus in predator odor contextual fear conditioning

The study of fear memory is important for understanding various anxiety disorders in which patients experience persistent recollections of traumatic events. These memories often involve associations of contextual cues with aversive events; consequently, Pavlovian classical conditioning is commonly used to study contextual fear learning. The use of predator odor as a fearful stimulus in contextual fear conditioning has become increasingly important as an animal model of anxiety disorders. Innate fear responses to predator odors are well characterized and reliable; however, attempts to use these odors as unconditioned stimuli in fear conditioning paradigms have proven inconsistent. Here we characterize a contextual fear conditioning paradigm using coyote urine as the unconditioned stimulus. We found that contextual conditioning induced by exposure to coyote urine produces long-term freezing, a stereotypic response to fear observed in mice. This paradigm is context-specific and parallels shock-induced contextual conditioning in that it is responsive to extinction training and manipulations of predator odor intensity. Region-specific lesions of the dorsal and ventral hippocampus indicate that both areas are independently required for the long-term expression of learned fear. These results in conjunction with c-fos immunostaining data suggest that while both the dorsal and ventral hippocampus are required for forming a contextual representation, the ventral region also modulates defensive behaviors associated with predators. This study provides information about the individual contributions of the dorsal and ventral hippocampus to ethologically relevant fear learning.

Animal models of anxiety disorders and stress

Anxiety and stress-related disorders are severe psychiatric conditions that affect performance in daily tasks and represent a high cost to public health. The initial observation of Charles Darwin that animals and human beings share similar characteristics in the expression of emotion raise the possibility of studying the mechanisms of psychiatric disorders in other mammals (mainly rodents). The development of animal models of anxiety and stress has helped to identify the pharmacological mechanisms and potential clinical effects of several drugs. Animal models of anxiety are based on conflict situations that can generate opposite motivational states induced by approach-avoidance situations. The present review revisited the main rodent models of anxiety and stress responses used worldwide. Here we defined as "ethological" the tests that assess unlearned/unpunished responses (such as the elevated plus maze, light-dark box, and open field), whereas models that involve learned/punished responses are referred to as "conditioned operant conflict tests" (such as the Vogel conflict test). We also discussed models that involve mainly classical conditioning tests (fear conditioning). Finally, we addressed the main protocols used to induce stress responses in rodents, including psychosocial (social defeat and neonatal isolation stress), physical (restraint stress), and chronic unpredictable stress.

Fear Conditioning Assay in Mouse

[Abstract] The study of fear memory is important for understanding various anxiety disorders in which patients experience persistent recollections of traumatic events. These memories often involve associations of contextual cues with aversive events; consequently, Pavlovian classical conditioning is commonly used to study contextual fear learning. A form of contextual fear conditioning that is becoming increasingly important as an animal model of anxiety disorders uses predator odor as a fearful stimulus. Innate fear responses to predator odors are well characterized and reliable; however, attempts to use these odors as unconditioned stimuli in fear conditioning paradigms have been highly dependent on experimental setup and have produced inconsistent behavioral results. Here we present a contextual fear conditioning paradigm using coyote urine as the unconditioned stimulus, which has been shown to produce consistent contextual freezing in response to fear learning (Wang et al., 2012).

Basal anxiety-like behavior predicts differences in dendritic morphology in the medial prefrontal cortex in two strains of rats

Basal differences in the brain may account for why some individuals are more vulnerable to stress than others. Although trait anxiety behavior varies greatly in human populations, most animal models of anxiety disorders tend to focus on the development of anxiety after a stressful experience. In this study, adult male Sprague-Dawley and Lewis rats were grouped according to baseline anxiety-like behavior in the open field, measured by time spent and distance traveled in the center. Individuals that fell one standard deviation above and below the mean, approximately the top and bottom 15%, were selected for the Low and High Anxiety groups. Pyramidal neurons from layer II/III of the prelimbic region of the medial prefrontal cortex were iontophoretically loaded with Lucifer yellow dye and reconstructed. In both strains, animals in the High Anxiety group had smaller apical dendrites than those in the Low Anxiety group. No difference was found in basal dendrites. Sholl analysis revealed a strain difference in the distribution of dendritic material between anxiety groups. These results illustrate significant variability in dendritic morphology in the prefrontal cortex of healthy adult male rats prior to experimental manipulation that correlates with baseline levels of anxiety-like behavior.

Subchronic effects of fluoxetine on conditioned suppression produced by a hot air blast.

Conditioned suppression is an animal model of anxiety disorders that has been broadly used to investigate the behavioral effects of different drugs. However, various methodological variables (e.g., the type of aversive stimulus) that supposedly interfere with the acquisition of conditioned suppression may also contribute to conflicting results among the studied drugs. Additionally, few studies have sought to investigate the effects of selective serotonin reuptake inhibitors (SSRIs). The present study investigated the effect of subchronic 5-day administration of 5 mg/kg fluoxetine in the retention of conditioned suppression produced by a hot air blast (HAB). The subjects were 12 albino Wistar rats distributed into an Experimental Group (EG) and Control Group (CG). After sessions were conducted to pair two stimuli, a sound and HAB, fluoxetine (EG) or saline (CG) was administered. Twenty-four hours after the last injection, a test session was conducted. The results showed no difference between groups. Fluoxetine (5 mg/kg) did not exert anxiolytic effects in this model of conditioned suppression produced by a HAB.

Animal models of anxiety disorders in rats and mice: some conceptual issues

Animal models can certainly be useful to find out more about the biological bases of anxiety disorders and develop new, more efficient pharmacological and/or behavioral treatments. However, many of the current "models of anxiety" in animals do not deal with pathology itself, but only with extreme forms of anxiety which are still in the normal, adaptive range. These models have certainly provided a lot of information on brain and behavioral mechanisms which could be involved in the etiology and physiopathology of anxiety disorders, but are usually not satisfactory when confronted directly with clinical syndromes. Further progress in this field will probably depend on the finding of endophenotypes which can be studied in both humans and animals with common methodological approaches. The emphasis should be on individual differences in vulnerability, which have to be included in animal models. Finally, progress will also depend on refining theoretical constructs from an interdisciplinary perspective, including psychiatry, psychology, behavioral sciences, genetics, and other neurosciences.

Changes in cue reactivity and attentional bias following experimental cue exposure and response prevention: a laboratory study of the effects of d-cycloserine in heavy drinkers

The effects of D-cycloserine (DCS) in animal models of anxiety disorders and addiction indicate a role for N-methyl D-aspartate (NMDA) receptors in extinction learning. Exposure/response prevention treatments for anxiety disorders in humans are enhanced by DCS, suggesting a promising co-therapy regime, mediated by NMDA receptors. Exposure/response prevention may also be effective in problematic drinkers, and DCS might enhance habituation to cues in these individuals. Since heavy drinkers show ostensible conditioned responses to alcohol cues, habituation following exposure/response prevention should be evident in these drinkers, with DCS enhancing this effect. The objective of this study is to investigate the effect of DCS on exposure/response prevention in heavy drinkers. In a randomised, double-blind, placebo-controlled study, heavy social drinkers recruited from the community received either DCS (125 mg; n = 19) or placebo (n = 17) 1 h prior to each of two sessions of exposure/response prevention. Cue reactivity and attentional bias were assessed during these two sessions and at a third follow-up session. Between-session drinking behaviour was recorded. Robust cue reactivity and attentional bias to alcohol cues was evident, as expected of heavy drinkers. Within- and between-session habituation of cue reactivity, as well as a reduction in attentional bias to alcohol cues over time was found. However, there was no evidence of greater habituation in the DCS group. Subtle stimulant effects (increased subjective contentedness and euphoria) which were unrelated to exposure/response prevention were found following DCS. DCS does not appear to enhance habituation of alcohol cue reactivity in heavy non-dependent drinkers. Its utility in enhancing treatments based on exposure/response prevention in dependent drinkers or drug users remains open.

Early life environment determines the development of adult phobic‐like fear responses in BALB/cAnN mice

Environmental factors may unleash genetically determined susceptibility to psychopathology. Great effort has been spent in identifying both the genetic basis and environmental sources of exaggerated fear in animal models of anxiety disorders. Here, we show that the origin of inbred mice, probably via subtle differences in breeding and rearing conditions, may have large consequences specifically on acquisition and retention of fear memories, while leaving anxiety-related behaviours unaffected. These effects could be seen in BALB/cAnN (BALB), but not in C57BL/6N (C57BL/6) mice, thus suggesting their dependency on the genetic background. Increased susceptibility for developing exaggerated fear responses was accompanied by decreased long-term depression and increased surface trafficking of the AMPA receptor GluR1 subunit at the level of the basolateral amygdala complex. Together, these data raise a novel caveat in the debate about the origins of variation in behavioural studies with experimental animals. Considering that there are currently no animal models which explicitly consider conceptual analogy to the specific gene-environment interactions observed in the aetiology of phobias, our study might suggest a novel approach and direction for further preclinical studies focusing on such aspects of phobic-like fears.

Pharmacological Profile of Lurasidone, a Novel Antipsychotic Agent with Potent 5-Hydroxytryptamine 7 (5-HT7) and 5-HT1A Receptor Activity

Lurasidone [(3aR,4S,7R,7aS)-2-[(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexylmethyl]hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride; SM-13496] is an azapirone derivative and a novel antipsychotic candidate. The objective of the current studies was to investigate the in vitro and in vivo pharmacological properties of lurasidone. Receptor binding affinities of lurasidone and several antipsychotic drugs were tested under comparable assay conditions using cloned human receptors or membrane fractions prepared from animal tissue. Lurasidone was found to have potent binding affinity for dopamine D(2), 5-hydroxytryptamine 2A (5-HT(2A)), 5-HT(7), 5-HT(1A), and noradrenaline alpha(2C) receptors. Affinity for noradrenaline alpha(1), alpha(2A), and 5-HT(2C) receptors was weak, whereas affinity for histamine H(1) and muscarinic acetylcholine receptors was negligible. In vitro functional assays demonstrated that lurasidone acts as an antagonist at D(2) and 5-HT(7) receptors and as a partial agonist at the 5-HT(1A) receptor subtype. Lurasidone showed potent effects predictive of antipsychotic activity, such as inhibition of methamphetamine-induced hyperactivity and apomorphine-induced stereotyped behavior in rats, similar to other antipsychotics. Furthermore, lurasidone had only weak extrapyramidal effects in rodent models. In animal models of anxiety disorders and depression, treatment with lurasidone was associated with significant improvement. Lurasidone showed a preferential effect on the frontal cortex (versus striatum) in increasing dopamine turnover. Anti-alpha(1)-noradrenergic, anticholinergic, and central nervous system (CNS) depressant actions of lurasidone were also very weak. These results demonstrate that lurasidone possesses antipsychotic activity and antidepressant- or anxiolytic-like effects with potentially reduced liability for extrapyramidal and CNS depressant side effects.

S.11.05 Functional MRI in small animals: applications to animal models of anxiety disorders

S.11.05 Functional MRI in small animals: applications to animal models of anxiety disorders

Early emergence of increased fearful behavior in prenatally stressed rats

We have been studying the mildly prenatally stressed (PS) rat as a potentially useful animal model of anxiety disorders. Previously we have demonstrated that there are anatomical and biochemical alterations in the amygdalas of adult PS offspring and that these offspring show increased fearful behaviors. However, human data indicate that anxiety disorders often present first in early childhood and then persist throughout adolescence and adulthood. To determine if PS rats also model this characteristic of human anxiety disorders, here we asked whether behavioral indices of increased fear would be detectable at an early age. We tested the hypotheses that young PS rats would show increased behavioral fearfulness in response to an acute stressor and that this would increase with age. A mild prenatal stressor, consisting of removal of the dam from the home cage and administration of a subcutaneous injection of 0.1 ml of 0.9% saline daily, was administered during the last week of pregnancy. Offspring were tested in the defensive–withdrawal apparatus before and after exposure to restraint stress at 25, 45 and 60 days of age. PS animals showed increased defensive–withdrawal behavior following the stressor and were more fearful following restraint when compared to controls (CON). This was significant at P45 and increased to P60. Hence, fearful behaviors in PS rats emerge prior to sexual maturation and increase in magnitude thereafter, further validating our model as a means to investigate the underpinnings of anxiety disorders.

Stress and central Urocortin increase anxiety-like behavior in the social interaction test via the CRF 1 receptor

Corticotropin releasing factor (CRF) and Urocortin are important neurotransmitters in the regulation of physiological and behavioral responses to stress. Centrally administered CRF or Urocortin produces anxiety-like responses in numerous animal models of anxiety disorders. Previous studies in our lab have shown that Urocortin infused into the basolateral nucleus of the amygdala produces anxiety-like responses in the social interaction test. Subsequently, in the current study we prepared a specific CRF 1 receptor antagonist ( N-Cyclopropylmethyl-2,5-dimethyl- N-propyl- N'-(2,4,6-trichloro-phenyl)-pyrimidine-4,6-diamine, NBI3b1996) to examine in this paradigm. This CRF 1 receptor antagonist inhibited the ex vivo binding of 125I-sauvagine to rat cerebellum with an ED 50 of 6 mg/kg, i.p. NBI3b1996 produced a dose-dependent antagonism of Urocortin-induced anxiety-like behavior in Social Interaction test with an ED 50 of 6 mg/kg, i.p. The compound had no effect on baseline social interaction. In addition, the CRF 1 receptor antagonist prevented the stress-induced decrease in social interaction. These results provide further support for the CRF 1 receptor in anxiety-like behavior and suggest this pathway is quiescent in unstressed animals.