Efficacy of Chronic Antidepressant Treatments in a New Model of Extreme Anxiety in Rats (original) (raw)
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Pharmacological validation of a novel animal model of anticipatory anxiety in mice
Psychopharmacology, 1990
The current study investigates the action of anxiotytics, antidepressants, neuroleptics, antipyretics, muscle relaxants, antihypertensives and naloxone in a novel animal model of anxiety, based on the evidence that mice removed last from their cage develop hyperthermia (stress-induced hyperthermia, SIH) when compared to those removed first. Alprazolam (0.15-0.6 rag/ kg), chlordiazepoxide (25 mg/kg), estazolam (1 mg/kg), phenobarbital (20 mg/kg), ethanol (2 and 4 g/kg), buspirone (5 and 10 mg/kg) and prazosin (1 and 2 mg/kg), as well as repeatedly administered diazepam (5 mg/kg), inhibited SIH. In contrast, tofisopam (12.5-200 mg/kg), desipramine (15 and 30 mg/kg), amitriptyline (10 rag/ kg), fluoxetine (10 and 20 mg/kg), tranylcypromine (5 and 10 mg/kg), chlorpromazine (1 and 2 mg/kg), clozapine (2 and 4 mg/kg), pimozide (0.5 and 1 mg/kg), /sulpiride (15 and 30 mg/kg), l-propranolol (5 and 10 rag/ kg), acetyl salicylic acid (200 and 400 mg/kg), indomethacin (2.5 and 5 mg/kg), verapamil (2.5 and 5 mg/kg), captopril (25 and 50 mg/kg), dantrolene (10 and 20 rag/ kg), mephenesin (300 and 600 mg/kg), d-amphetamine (t and 4 mg/kg) and naloxone (2.5 and 15 mg/kg) were inactive, as were 10 mg/kg imipramine, amitriptyline and fluoxetine injected every day for 21 days. Reserpine at high doses (1.25 and 2.5 mg/kg) but not at a lower dose (0.62 mg/kg) prevented SIH, but in this case animals showed a behavioural syndrome which could have interfered with the occurrence of the hyperthermia.
Panic-like behaviors in Carioca High-and Low-conditioned Freezing rats
Psychology and Neuroscience, 2011
Panic disorder involves both recurrent unexpected panic attacks and persistent concern about having additional attacks. Electrical stimulation of the dorsal periaqueductal gray (dPAG) is an animal model of both panic attack and panic disorder, whereas contextual fear conditioning represents a model of anticipatory anxiety. Previous research indicated that anxiety has an inhibitory effect on panic attack-like behavior. However, still unclear is the role that anticipatory anxiety plays in panic disorder-like behaviors. This issue was investigated with two lines of animals selectively bred for high (Carioca High-Freezing) and low (Carioca Low-Freezing) freezing in response to contextual cues associated with footshock. The results suggest that although anticipatory anxiety might exert an inhibitory effect on the expression of panic attack, it might also facilitate the pathogenesis of panic disorder.
Effects of treatment with imipramine and clonazepam on an animal model of panic disorder
Biological Psychiatry, 1994
Case Report This is the report of a case of AlP who presented with episodic, variable psychiatric symptoms. DS, the 14-yearold patient, is the eldest of seven siblings from a rural joint family. Febrile illness had precipitated respiratory distress and death in one sister and three brothers of DS, when they were 2 1/2 years, 4 months, 3 months, and 21/2 years of age, respectively.
European Journal of Pharmacology, 2006
Selective serotonin and noradrenalin reuptake inhibitors such as fluoxetine and desipramine, respectively, are efficacious in the treatment of depression and chronic stress. Although they inhibit the reuptake of the biogenic monoamines soon after administration, therapeutic improvements occur only after 2 or 3 weeks. Freezing response and potentiated startle are common responses to moderate fear contextual conditioning. However, freezing but not startle is increased in rats that undergo intense fear conditioning. In this study, we evaluated the effects of acute and subchronic administration of fluoxetine and desipramine on these responses in testing sessions, as indices of fear in moderate and high fear conditioning. Fluoxetine did not show any significant effect on the moderate fear conditioning but reduced freezing and restored the startle response in rats under intense fear conditioning. In comparison, desipramine had no effect on the startle response when administered acutely or subchronically while freezing of the intense fear conditioning was reduced. Our findings indicate that intense contextual fear conditioning is sensitive to subchronic treatment with fluoxetine and resistant to desipramine. Fluoxetine appears to restore the serotoninergic function in brain areas recruited by intense contextual fear conditioning. These effects of fluoxetine may underlie its reported efficacy in the pharmacotherapy of panic disorders.
European Neuropsychopharmacology, 1994
In an attempt to develop new animal models of anxiety with face and predictive validity for the spectrum of human anxiety disorders, two new animal paradigms have been described, stress-induced hyperthermia (SIH) in mice and ultrasonic pup vocalizations (UV) in rats. In SIH mice develop enhanced body temperature in anticipation of an aversive event. This SIH can be antagonized by benzodiazepines, alcohol and 5-HTtA receptor agonists, but not by specific 5-HT reuptake inhibitors (SSRIs) or 5-HT3 receptor antagonists. When rat pups are separated from their mother and littermates they produce ultrasonic sounds, indicative of a separation distress. Benzodiazepines, 5-HT~A receptor agonists and SSRIs decrease this calling, whereas 5-HT3 receptor antagonists have no effect. Antidepressants in general do not decrease pup calling because in contrast to the SSRIs, noradrenergic uptake blockers enhance calling. These two animal models of anxiety can be added to the range of anxiety models and will be of help in predicting new putative anxiolytic drugs.
2011
Increasing evidence suggests that specific physiological measures may serve as biomarkers for successful treatment to alleviate symptoms of pathological anxiety. Studies of autonomic function investigating parameters such as heart rate (HR), HR variability and blood pressure (BP) indicated that HR variability is consistently reduced in anxious patients, whereas HR and BP data show inconsistent results. Therefore, HR and HR variability were measured under various emotionally challenging conditions in a mouse model of high innate anxiety (high anxiety behaviour ; HAB) vs. control normal anxiety-like behaviour (NAB) mice. Baseline HR, HR variability and activity did not differ between mouse lines. However, after cued Pavlovian fear conditioning, both elevated tachycardia and increased fear responses were observed in HAB mice compared to NAB mice upon re-exposure to the conditioning stimulus serving as the emotional stressor. When retention of conditioned fear was tested in the home cage, HAB mice again displayed higher fear responses than NAB mice, while the HR responses were similar. Conversely, in both experimental settings HAB mice consistently exhibited reduced HR variability. Repeated administration of the anxiolytic NK1 receptor antagonist L-822429 lowered the conditioned fear response and shifted HR dynamics in HAB mice to a more regular pattern, similar to that in NAB mice. Additional receiveroperating characteristic (ROC) analysis demonstrated the high specificity and sensitivity of HR variability to distinguish between normal and high anxiety trait. These findings indicate that assessment of autonomic response in addition to freezing might be a useful indicator of the efficacy of novel anxiolytic treatments.
European Neuropsychopharmacology, 2005
The amplitude of the whole-body acoustic startle response is reliably enhanced when elicited in the presence of foreground signals, such as light, previously paired with footshocks. It has been shown that this enhancement is evident by moderate fear levels, but is less affected by high fear levels. Potentiation of the acoustic startle reflex has also been reported in the presence of background cues previously associated with footshocks. However, the effects of anxiolytic drugs on different levels of fear elicited by moderate and intense contextual fear conditioning associated with startle reflex have not been examined yet. To approach this issue, we examined the effects of the anxiolytic, midazolam, on two intensities of contextual fear; freezing behavior and the startle response to loud noise. First, we compared the magnitude of the freezing behavior and the startle amplitude during the testing sessions in groups of rats submitted to fear conditioning using 0.3 and 0.6 mA as unconditioned stimuli (10 stimuli of 1 s each, intertrial interval from 60 to 180 s). Afterwards, the effects of midazolam (0.5 and 1.0 mg/kg) were assessed in these two conditions. Rats showed a potentiated startle reflex and a significant freezing behavior to moderate fear conditioning, which were both attenuated by midazolam. Higher levels of fear conditioning caused more intense freezing behavior without enhancing the startle reflex. Whereas midazolam reduced this freezing response, the startle response was unaffected. These results are indicative that anxiolytic-sensitive freezing and fear-potentiated startle are triggered by moderate contextual fear conditioning, while contextual conditioning with the use of high footshocks causes a distinct pattern of behavioral responses, which is only partially affected by midazolam. Due to the differential sensitivity to midazolam of these two patterns of startle responses generated as a function of the intensity of contextual fear conditioning, it is proposed that they represent moderate and intense aversive states that may be related to anxiety or panic/ phobic conditions, respectively.
Anxiety Disorders, 2011
The concept of anxiety disorders has changed dramatically over the years as more clinical and experimental evidence has been collected. In the clinical setting, anxiety disorders www.intechopen.com Anxiety Disorders 122 departed from a single construct that ranged in intensity from normal to pathological or neurotic levels. A major shift in this view occurred with Klein's pioneering work (Klein, 1964; Klein & Fink, 1962), which showed that imipramine had a selective effect in the treatment of panic disorder. Moreover, certain anxiety disorders have been suggested to differ from each other in the primary object or specificity of threat. Fear of a circumscribed and well-defined object is a characteristic of specific phobias, whereas diffuse and chronic sustained anxiety is the main feature of GAD. The 3 rd edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III; American Psychiatric Association, 1980) introduced the current descriptive symptom-based approach to mental disorders with well-defined, explicit diagnostic criteria. This new classification incorporated distinct nosological entities, such as panic disorder, specific and social phobias, GAD, posttraumatic stress disorder, and obsessive-compulsive disorder. In the DSM-III, GAD was left as a residual diagnosis of worry, to be made only in the absence of other anxiety and depressive syndromes. Consequently, this residual category carried low diagnostic reliability. With the publication of the DSM-IV (American Psychiatric Association, 1994) and International Classification of Diseases and Related Health Problems (ICD-10; World Health Organization, 1992), these anxiety disorder categories remained basically the same. However, the diagnosis of GAD shifted from a residual category in the DSM-III to an independent anxiety disorder type in the DSM-IV. Free-floating anxiety was associated with the worry construct, which in turn produced several symptoms, such as muscle tension, fatigue, restlessness, concentration difficulties, and irritability. According to the DSM-IV, excessive and unrelenting worry is generally associated with impairments in academic, social, and personal functioning and related to multiple domains or activities. To be considered a pathological feature of GAD, worry must occur more days than not for a period of at least 6 months.
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2012
Several studies have shown that the α 1-adrenoreceptor is involved in controlling extracellular serotonin levels. The administration of the α 1-adrenoreceptor antagonist prazosin was shown to decrease extracellular serotonin levels in the hippocampus, the prefrontal cortex and the raphe nucleus, while the administration of the α 1-adrenoreceptor agonist cirazoline was shown to increase serotonin levels. Furthermore, the elevation of serotonin levels induced by the selective serotonin reuptake inhibitor (SSRI) citalopram was attenuated by prazosin. Thus, α 1-adrenoreceptor antagonists may affect SSRI-induced increases in extracellular serotonin levels and their antidepressive and anxiolytic effects. However, little is known about the influence of α 1adrenoreceptor antagonists on the behavioral pharmacological effects of SSRIs. The conditioned fear stressinduced freezing behavior is an animal model of anxiety and can detect the anxiolytic effect of SSRIs. To clarify whether an α 1-adrenoreceptor antagonist affects the anxiolytic action of SSRIs, we examined the effects of the co-administration of the α 1-adrenoreceptor antagonist prazosin and the SSRI citalopram using the contextual conditioned fear stress model. Low-dose prazosin (0.03 mg/kg) significantly attenuated the citalopram (3 mg/kg)-induced decrease in conditioned freezing. Moreover, high-dose (0.5 mg/kg), but not low-dose (0.03 mg/kg), prazosin significantly attenuated citalopram (10 mg/kg)-induced decreases in conditioned freezing. These drugs did not affect the spontaneous motor activity of the rats. Therefore, these results suggest that blocking the α 1-adrenoreceptor decreases the anxiolytic effect of citalopram.