An animal model of copulatory disorder induced by social stress in male mice: effects of apomorphine and l-dopa

 We investigated the possible role of dopamine receptors in the mediation of copulatory disorder induced by defeat experience in male mice, using l-dopa and apomorphine. To generate the copulatory disorder, male mice were attacked 20 times daily for 5 consecutive days, as intruders in confrontation with an aggressive resident. Following the repeated exposure to defeat, virtually all intruder males failed to display copulatory behavior towards estrous females. Acute injection of apomorphine (25, 50, 75 μg/kg, SC) significantly increased both the incidence and the frequency of copulatory elements (mounting and intromission) in a dose-dependent manner. The combination of l-dopa with carbidopa, a dopa decarboxylase inhibitor, also increased significantly copulatory behavior, revealing an inverted U-shaped dose-effect curve. In both cases, locomotion and digging frequencies were significantly decreased. This evidence suggests that dopaminergic mechanisms are involved in the mediation of social stress-induced copulatory disorder. Received: 21 December 1996 / Final version: 25 April 1997     

Translational approaches to obsessive-compulsive disorder: from animal models to clinical treatment

Obsessive-compulsive disorder (OCD) is characterized by obsessions (intrusive thoughts) and compulsions (repetitive ritualistic behaviours) leading to functional impairment. Accumulating evidence links these conditions with underlying dysregulation of fronto-striatal circuitry and monoamine systems. These abnormalities represent key targets for existing and novel treatment interventions. However, the brain bases of these conditions and treatment mechanisms are still not fully elucidated. Animal models simulating the behavioural and clinical manifestations of the disorder show great potential for augmenting our understanding of the pathophysiology and treatment of OCD. This paper provides an overview of what is known about OCD from several perspectives. We begin by describing the clinical features of OCD and the criteria used to assess the validity of animal models of symptomatology; namely, face validity (phenomenological similarity between inducing conditions and specific symptoms of the human phenomenon), predictive validity (similarity in response to treatment) and construct validity (similarity in underlying physiological or psychological mechanisms). We then survey animal models of OC spectrum conditions within this framework, focusing on (i) ethological models; (ii) genetic and pharmacological models; and (iii) neurobehavioural models. We also discuss their advantages and shortcomings in relation to their capacity to identify potentially efficacious new compounds. It is of interest that there has been rather little evidence of 'false alarms' for therapeutic drug effects in OCD models which actually fail in the clinic. While it is more difficult to model obsessive cognition than compulsive behaviour in experimental animals, it is feasible to infer cognitive inflexibility in certain animal paradigms. Finally, key future neurobiological and treatment research areas are highlighted.     

New animal model of social behavioral deficit: reversal by drugs

A new model of social behavioral deficit and its reversal by drugs is described. Mice isolated for one week or more (isolated mice) behave differently from controls (grouped mice). When observed together under an inverted beaker, the isolated mice make significantly less escape attempts than the grouped mice. This behavioral deficit is a social one because it exists only when the isolated and grouped mice are tested together but not when they are tested singly. Several drugs impair this social behavioral deficit, particularly the 5-HT1B receptors agonists.     

单程延迟性应激诱导雌性大鼠创伤后应激障碍模型的建立

目的 采用雌性SD大鼠建立单程长时应激(SPS)模型,从表观效度和预测效度2方面考察其是否能作为创伤性应激障碍的动物模型。方法 雌性大鼠依次连续给予固定束缚(2 h)、强迫游泳(20 min)和乙醚麻醉各1次作为应激因子制备SPS模型,随后连续2周内每天1次ig 给予舍曲林10 mg·kg^-1。2周后给予足底电击刺激,次日环境重现,测定呆滞行为时间;高架十字迷宫实验测定进入开臂次数百分比和开臂滞留时间百分比;开场实验观察爬格次数和站立次数。结果 与正常对照组比较,模型组大鼠呆滞行为时间明显延长(P<0.01),进入开臂次数百分比和开臂滞留时间百分比显著降低(P<0.01);与模型组相比,舍曲林组大鼠呆滞行为时间显著降低,进入开臂次数百分比和开臂滞留时间百分比显著增加(P<0.05, P<0.01); 各组爬格次数和站立数与正常对照组无显著性差异。结论 通过SPS成功诱导建立雌性大鼠创伤性应激障碍动物模型。     

Present status and prospects about an animal model of post-traumatic stress disorder in rats using a shuttle box]

Wistar rats exposed to inescapable foot shocks (IS) for 2 wk exhibited PTSD-like bi-directional changes similar to avoidance/numbing and hyperarousal symptoms when placed in a shuttle box. Paroxetine administration after IS reduced the hyperarousal-like behavior, and its therapeutic effect on avoidance/numbing-like behavior was also significant. Further, F344 rats, which were more vulnerable to various kinds of stressors, showed more significant 'bi-directional changes' than Wistar rats. Thus, the paradigm we have developed could serve as a useful PTSD model because of its face, predictive, and construct validity. Moreover, the intensity of IS dose-dependently induced PTSD-like behaviors and hypo-activity in a shuttle box, similar to the 'avoidance/numbing' that reappeared in a square open field. These findings further support the construct validity of this paradigm. Both electro-convulsive shock treatment before and after IS ameliorated the PTSD-like behaviors in this model, so electro-convulsive therapy may be an effective method for prevention and medical treatment of PTSD in the future. On the other hand, pretreatment with fluvoxamine before IS did not have a significant effect, and its improving effect after IS was only observed for 'hyperarousal' behavior. Lastly, we recently developed a useful criterion, which is represented as a 'bi-directional index', for separating real PTSD rats from those exposed to IS.     

Spontaneous alternation behavior: an animal model for obsessive-compulsive disorder?

This study entailed the adoption of a well-established behavioral paradigm, spontaneous alternation, as a possible animal model for some of the symptoms observed in obsessive-compulsive disorder (OCD) in humans. Food-deprived rats were run in a T-maze in which both a black and a white goal box were equally baited with a small amount of chocolate milk. Each rat was given 7 trials every other day during which it was placed in the start box and allowed to make a choice. The mean number of choices until an alternation occurred was recorded. After a stable baseline of spontaneous alternation was achieved the effects of manipulating the serotonergic system were tested. Both the nonselective 5-HT agonist 5-MeODMT (1.25 mg/kg) and the more selective 5-HT1A agonist 8-OH-DPAT (2 mg/kg) disrupted spontaneous alternation. A course of chronic treatment (2 x 5 mg/kg for 21 days) with the selective 5-HT uptake blocking agent fluoxetine had a protective effect on the 5-MeODMT-induced disruption of spontaneous alternation behavior. Serotonergic manipulations of spontaneous alternation may be a simple animal model for the perseverative symptoms or indecisiveness seen in people diagnosed with OCD.     

Setting apart the affected: the use of behavioral criteria in animal models of post traumatic stress disorder.

Post-traumatic stress disorder (PTSD) affects about 20-30% of exposed individuals. Clinical studies of PTSD generally employ stringent criteria for inclusion in study populations, and yet in animal studies the data collection and analysis are generally expressed as a function of exposed vs nonexposed populations, regardless of individual variation in response. Prior data support an approach to animal models analogous to inclusion criteria in clinical studies. This series of studies sought to assess prevalence rates of maladaptive vs adaptive responses determined according to a more stringent approach to the concept of inclusion/exclusion criteria (cutoff behavioral criteria-CBC), consisting of two successive behavioral tests (elevated plus maze and acoustic startle response tests). The rats were exposed to stressors in two different paradigms; exposure to a predator and underwater trauma. The prevalence rates of maladaptive responses to stress in these two distinct models dropped over time from 90% in the acute phase to 25% enduring/maladaptive response at 7 days, to remain constant over 30 days. As setting the affected individuals apart from the unaffected approximates clinical studies, it might also help to clarify some of the pending issues in PTSD research.     

New approaches to combining pharmacotherapy and psychotherapy for posttraumatic stress disorder

Introduction: Posttraumatic stress disorder (PTSD) is a complex disorder associated with an intricate biological and psychological symptom profile and various common comorbidities. Despite an existing myriad of evidence-based and experimental treatments, PTSD is often difficult to treat. This reality necessitates a discussion of the potential of emerging treatments.

Areas covered: A literature search using PubMed and PsychInfo was done using the following keywords: randomized clinical trials, treatment guidelines, pharmacotherapy and psychotherapy, all in addition to PTSD. A comprehensive treatment review establishes that early intervention approaches have not yet been found to prevent PTSD in trauma survivors. However, psychotherapy research provides substantial support for cognitive behavioral therapies and eye movement desensitization and reprocessing for chronic PTSD, and psychopharmacological approaches are myriad – although at present there is FDA approval only for sertraline and paroxetine. However, the efficacy of these treatments varies and, unfortunately, not everyone will achieve remission.

Expert opinion: So far, the mental health field has tended to focus on either biological or psychological targets. We propose that maximizing treatment success may require an integrated approach that does not dichotomize biological and psychological aspects. Exciting new developments reflecting this perspective include psychopharmacologic augmentation strategies that enhance the mechanisms of psychotherapy.     

New approaches to combining pharmacotherapy and psychotherapy for posttraumatic stress disorder

INTRODUCTION: Posttraumatic stress disorder (PTSD) is a complex disorder associated with an intricate biological and psychological symptom profile and various common comorbidities. Despite an existing myriad of evidence-based and experimental treatments, PTSD is often difficult to treat. This reality necessitates a discussion of the potential of emerging treatments. AREAS COVERED: A literature search using PubMed and PsychInfo was done using the following keywords: randomized clinical trials, treatment guidelines, pharmacotherapy and psychotherapy, all in addition to PTSD. A comprehensive treatment review establishes that early intervention approaches have not yet been found to prevent PTSD in trauma survivors. However, psychotherapy research provides substantial support for cognitive behavioral therapies and eye movement desensitization and reprocessing for chronic PTSD, and psychopharmacological approaches are myriad - although at present there is FDA approval only for sertraline and paroxetine. However, the efficacy of these treatments varies and, unfortunately, not everyone will achieve remission. EXPERT OPINION: So far, the mental health field has tended to focus on either biological or psychological targets. We propose that maximizing treatment success may require an integrated approach that does not dichotomize biological and psychological aspects. Exciting new developments reflecting this perspective include psychopharmacologic augmentation strategies that enhance the mechanisms of psychotherapy.     

The immediate early gene Arc is associated with behavioral resilience to stress exposure in an animal model of posttraumatic stress disorder.

Mechanisms involved in adaptative and maladaptive changes in neural plasticity and synaptic efficacy in various brain areas are pivotal to understanding the physiology of the response to stress and the pathophysiology of posttraumatic stress disorder (PTSD). Activity-regulated cytoskeletal-associated protein (Arc) is an effector immediate early gene (IEG) which has direct effects on intracellular homeostatic functions. Increased expression of Arc has been associated with increased neuronal activity and with consolidation of long-term memory. It may thus play an important role in mediating experience-induced reorganization and/or development of synaptic connections. This study sought to characterize the pattern of expression of mRNA for the Arc gene in selected brain areas of test subjects classified according to their individual pattern of behavioral response to a stressor, correlated with circulating levels of corticosterone (as a physiological marker of stress response). The hippocampal CA1 and CA3 subregions of individuals whose behavior was minimally or partially disrupted in response to predator scent stress demonstrated significantly increased levels of mRNA for Arc, compared to unexposed controls. The group whose behavior was severely disrupted demonstrated no such upregulation. Consistent with the hypothesis that the Arc gene has a promoting effect on neuronal function and/or structural changes, the lack of Arc expression in the behaviorally and physiologically more severely affected individuals raises the possibility that Arc may be associated with resilience and/or recovery after stress exposure.     

Olanzapine treatment for post-traumatic stress disorder: an open-label study.

Post-traumatic stress disorder (PTSD) is a common and increasingly diagnosed mental illness. Recent pharmacotherapeutic research on treatments for this condition has focused on antidepressant drugs with serotonergic actions. However, the presence of intrusive, psychotic-like symptoms in a substantial portion of PTSD patients raises the possibility that antipsychotics with serotonergic properties might also prove useful in treating PTSD. We conducted an open-label 8-week study of olanzapine treatment in veterans with combat-induced PTSD. Primary outcome measures in this study were the Clinician Administered PTSD Scale (CAPS) and the Clinical Global Impressions Improvement scale. Secondary outcome measures included the Hamilton Rating Scales for Depression (HRSD) and Anxiety (HRSA). Forty-eight patients enrolled in the study, and 30 completed the 8-week trial. Results of intent-to-treat and completer analyses demonstrated that all outcome measures improved significantly during treatment. Secondary analyses indicate that improvement in the intrusive symptom cluster of the CAPS was independent of improvement on the HRSD and HRSA. In conclusion, the study indicates that olanzapine treatment is useful in alleviating the symptoms of combat-induced PTSD.     

Nefazodone treatment for chronic posttraumatic stress disorder: an open trial

Currently, there is no standard treatment for posttraumatic stress disorder (PTSD) because of a deficit of systematic treatment trials. The symptom overlap with other mood and anxiety disorders that respond to antidepressants and the results of a limited number of antidepressant trials indicate promise for psychopharmacologic treatment. Several open trials and one controlled trial with selective serotonin reuptake inhibitors have reported improvement in the symptomatology of PTSD. In this study, a relatively new serotonergic antidepressant, nefazodone, was tested as a treatment for PTSD. Veterans with chronic PTSD (N = 36) were enrolled in an 8-week open-label trial of nefazodone. The primary outcome measure was the Clinician-Administered PTSD Scale (CAPS). Thirty-one patients completed at least 4 weeks of treatment, which was considered to be an adequate trial, and 26 patients completed the 8-week study. During treatment, there was a significant decrease in the total CAPS score and in each of three CAPS subscale scores, with most of the improvement occurring during the first 4 weeks. Comparable improvements were also seen on the Hamilton Rating Scales for Anxiety and for Depression. Nefazodone treatment was well tolerated by this patient population, with only four patients discontinuing because of adverse effects. In summary, nefazodone treatment improved the symptoms of PTSD, including the core symptoms. Placebo-controlled studies should be undertaken to further elucidate the efficacy of nefazodone in the treatment of PTSD.     

A distinct pattern of intracellular glucocorticoid-related responses is associated with extreme behavioral response to stress in an animal model of post-traumatic stress disorder

BackgroundActivation of glucocorticoid receptors (GR) increases expression of the mitogen-activated protein kinase (MAPK) pathway leading to increased expression of Zif/268, an effector immediate early gene involved in cellular growth, intracellular signaling, and synaptic modification. Glucocorticoids induce expression of Zif/268 through two distinct mechanisms: a rapid-onset, MAPK-independent pathway and a slower-onset, MAPK-dependent mechanism.MethodThis study investigated both rapid and long-term expression of GR protein in the cytosolic extract, its translocation to the nucleus, and expression of mRNA for the Zif/268 gene in selected brain areas, associated with circulating levels of corticosterone, in an animal model of PTSD. Trauma cue-triggered Zif/268 expression was assessed eight days after stress exposure.ResultsThe results demonstrated a pattern of response that was common to all exposed individuals at 30 min after exposure, characterized by a significant elevation in GR translocation to the nucleus and elevated levels of Zif/268 mRNA in the hippocampus. A distinct pattern associated with extreme behavioral response (EBR) was revealed upon further bioassay of behavioral response groups, classified according to their individual patterns of behavioral response at seven days. These EBR individuals displayed significantly higher circulating corticosterone and nuclear GR levels, compared to minimal behavioral responders and controls. No difference in Zif/268 mRNA levels was observed between the exposed and naïve animals.ConclusionFollowing the uniform acute response, the patterns of GR protein levels and Zif/268 mRNA levels are associated with degree of behavioral disruption. Since the slower-onset mechanism for glucocorticoid-induced Zif/268 expression depends on activation of the MAPK pathway, the pattern observed only in EBR rats may be related to disruptions of this pathway.     

New models for assessing carcinogenesis: an ongoing process

Traditionally, the use of rodent models in assessing the carcinogenic potential of chemicals has been expensive and lengthy, and the relevance of the carcinogenic effect to humans is often not fully understood. Today, however, with the rapid advances in molecular biology, genetically altered mice containing genes relevant to humans (e.g. oncogenes, tumor suppressor genes) and reporter genes (e.g. lacI) provide powerful tools for examining specific chemical–gene interactions thereby allowing a better understanding of the mechanisms of carcinogenesis in a shorter period of time. This paper will cover an overview of ongoing validation efforts, followed by examples of studies using several genetically engineered models including the p53^def mouse model and the Big Blue^® transgenic mouse model. Specifically, examples where transgenic models were integrated into the testing program based on specific hypotheses dealing with genetic alterations in cancer genes and reporter genes will be discussed. The examples will highlight possible ways genetically altered mice may be integrated into a comprehensive research and testing strategy and thereby provide an improved estimation of human health risks.     

An animal model of posttraumatic stress disorder and its validity: effect of paroxetine on a PTSD model in rats]

To better understand neuroscientific aspects of posttraumatic stress disorder (PTSD), it is necessary to establish an animal model of PTSD in which behavioral changes persist after initial traumatization. We administered inescapable footshock (IS) to male Wistar rats in a shuttle-box (inescapable stress session), and after 2 weeks we performed an avoidance/escape task session in the shuttle-box using signal lights as anxiogenic external stimuli. Rats exposed to IS beforehand exhibited PTSD-like bi-directional behavioral changes, that is, "avoidance/numbing" (e.g. decreased activity, reactivity, and interest in surroundings) and "hyperarousal" (e.g. irritability and exaggerated responsiveness to external stimuli). Concretely speaking, in a relatively calm situation, spontaneous locomotion decreased during a 5-min adaptation period just before the avoidance/escape task session. On the other hand, in a stressful situation after starting the task session, not only avoidance responses to external stimuli (signal lights) but also gate-crossings during inter-trial interval increased. Accordingly, the paradigm used here could serve as a useful model of PTSD. We administered paroxetine (PRX) to rats just after IS for 2 weeks to examine its chronic effect on our animal model. Two weeks of PRX treatment significantly reduced hyperarousal-like behaviors, but no effect on avoidance/numbing-like ones was manifested.     

Quetiapine as an adjunctive treatment for post-traumatic stress disorder: an 8-week open-label study

This study evaluated the effectiveness of quetiapine for subjects with post-traumatic stress disorder (PTSD) who were already on a stable dose of a selective serotonin reuptake inhibitor (SSRI) but had significant PTSD symptoms. Fifteen subjects were enrolled in an 8-week open-label trial for PTSD in which quetiapine was added to an SSRI. Subjects were on a stable dose of the SSRI for at least 6 weeks before study entry and had a Clincian-Administered PTSD Scale (CAPS) score of greater than or equal to 50 at study baseline. The mean age of subjects was 49 years (eight men and seven women). The average duration of PTSD was 29 years, one-third of subjects had combat-related PTSD, and two-thirds had noncombat PTSD. The mean dose prescribed in the study was 216 mg per day. The initial median CAPS score was 80, indicating severe PTSD. The addition of a modest dose of quetiapine provided significant relief from PTSD symptoms with a 42% overall improvement in PTSD symptoms based on the CAPS and significant improvement along each dimension of symptoms: re-experiencing (Z=-3.24, P=0.0012), hyperarousal (Z=-3.30, P=0.001) and avoidance (Z=-2.13, P=0.03). Subjects rated themselves as 45% improved on average on the Davidson Trauma Scale and reported a 44% decrease in their level of disability and impairment as reflected by the Sheehan Disability Scale. Subjects with PTSD who had significant PTSD symptoms when on an SSRI benefited from the addition of quetiapine. Patients improved significantly on all three clusters of PTSD symptoms: re-experiencing, hyperarousal and avoidance.     

A strategic approach to vaccine development: animal models,monitoring vaccine efficacy,formulation and delivery

One of the most pressing issues in animal and human medicine currently is the need to develop new and more effective vaccines, against an ever increasing range of infectious diseases. Traditional vaccines have involved the use of killed microorganisms, live attenuated cultures or antigenic extracts. In spite of extensive research, there have been very few newly developed vaccines for humans or animals, over the past 20 years. Recent developments in our understanding of the pathways of immunity required to produce protection against different infections, allow immunological principles to be incorporated into the design new and better vaccines. This paper outlines the key variables that need to be taken into consideration when developing a new vaccine. Three critical areas will be considered in the review: (1) use of an appropriate experimental animal model of infection; (2) targeting appropriate immune markers for protection; (3) design of optimal vaccine formulation and delivery systems.     

Glucocorticoids for the treatment of post-traumatic stress disorder and phobias: a novel therapeutic approach

Post-traumatic stress disorder (PTSD) and phobias belong to the most common anxiety disorders and to the most common psychiatric illnesses in general. In both disorders, aversive memories are thought to play an important role in the pathogenesis and symptomatology. Previously, we have reported that elevated glucocorticoid levels inhibit memory retrieval in animals and healthy humans. We therefore hypothesized that the administration of glucocorticoids might also inhibit the retrieval of aversive memory, thereby reducing symptoms in patients with PTSD and phobias. In recent clinical studies, we found first evidence to support this hypothesis. In patients with PTSD, low-dose cortisol treatment for one month reduced symptoms of traumatic memories without causing adverse side effects. Furthermore, we found evidence for a prolonged effect of the cortisol treatment. Persistent retrieval and reconsolidation of traumatic memories is a process that keeps these memories vivid and thereby the disorder alive. By inhibiting memory retrieval, cortisol may weaken the traumatic memory trace, and thus reduce symptoms even beyond the treatment period. In patients with social phobia, we found that a single oral administration of cortisone 1 h before a socio-evaluative stressor significantly reduced self-reported fear during the anticipation-, exposure-, and recovery phase of the stressor. In subjects with spider phobia, repeated oral administration of cortisol 1 h before exposure to a spider photograph induced a progressive reduction of stimulus-induced fear. This effect was maintained when subjects were exposed to the stimulus again two days after the last cortisol administration, indicating that cortisol facilitated the extinction of phobic fear. In conclusion, by a common mechanism of reducing the retrieval of aversive memories, glucocorticoids may be suited for the treatment of PTSD as well as phobias. More studies are needed to further evaluate the therapeutic efficacy of glucocorticoids in the treatment of anxiety disorders and to explore the potential of combining glucocorticoid treatment with psychotherapy.