Depression-like behaviors in tree shrews and comparison of the effects of treatment with fluoxetine and carbetocin.

Tree shrews, a species phylogenetically close to primates, are regarded as a suitable and naturalistic animal model for depression studies. However, psychological symptoms that are essential for depression diagnosis and treatment, such as helplessness and social withdrawal, have not been studied in this model. Therefore, in this study, we first investigated learned helplessness, social interaction and sucrose preference induced by two chronic stress paradigms: uncontrollable foot shocks (1-week foot shocks) and multiple unpredictable stimuli (1-week foot shocks and 3-week unpredictable stressors) in tree shrews. Our results showed that uncontrollable foot shocks could only induce learned helplessness in animals; whereas animals treated with multiple unpredictable stimuli exhibited more depression-like behaviors including social withdrawal, anhedonia and learned helplessness. These findings suggested that multiple unpredictable stimuli could effectively induce various depression-like behaviors in tree shrews. More importantly, we compared the antidepressant effects of fluoxetine and carbetocin, a long-acting oxytocin analog, on specific depression-like behaviors. Our present data displayed that, compared with fluoxetine, carbetocin was also effective in reversing learned helplessness, elevating sucrose preference and improving social interaction behaviors in depression-like animals. Therefore, carbetocin might be a potential antidepressant with applications in humans.

Tree shrew models: a chronic social defeat model of depression and a one-trial captive conditioning model of learning and memory.

Recent genome studies indicate that tree shrew is in the order or a closest sister of primates, and thus may be one of the best animals to model human diseases. In this paper, we report on a social defeat model of depression in tree shrew (Tupaia belangeri chinensis). Two male tree shrews were housed in a pair-cage consisting of two independent cages separated by a wire mesh partition with a door connecting the two cages. After one week adaptation, the connecting door was opened and a brief fighting occurs between the two male tree shrews and this social conflict session consisted of 1 h direct conflict (fighting) and 23 h indirect influence (e.g. smell, visual cues) per day for 21 days. The defeated tree shrew was considered the subordinate. Compared with naive animals, subordinate tree shrews at the final week of social conflict session showed alterations in body weight, locomotion, avoidance behavior and urinary cortisol levels. Remarkably, these alterations persisted for over two weeks. We also report on a novel captive conditioning model of learning and memory in tree shrew. An automatic trapping cage was placed in a small closed room with a freely-moving tree shrew. For the first four trials, the tree shrew was not trapped when it entered the cage and ate the bait apple, but it was trapped and kept in the cage for 1 h on the fifth trial. Latency was defined as the time between release of the tree shrew and when it entered the captive cage. Latencies during the five trials indicated adaptation. A test trial 24 h later was used to measure whether the one-trial trapping during the fifth trial could form captive memory. Tree shrews showed much longer trapping latencies in the test trial than the adaptation trials. The N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 (0.2 mg/kg, i.p.), known to prevent the formation of memory, did not affect latencies in the adaptation trails, but did block captive memory as it led to much shorter trapping latencies compared to saline treatment in the test trial. These results demonstrate a chronic social defeat model of depression and a novel one-trial captive conditioning model for learning and memory in tree shrews, which are important for mechanism studies of depression, learning, memory, and preclinical evaluation for new antidepressants.

Chronic psychosocial stress in tree shrews: effect of the substance P (NK1 receptor) antagonist L-760735 and clomipramine on endocrine and behavioral parameters.

RATIONALE: Substance P and its preferred receptor, the neurokinin 1 receptor (NK(1)R), have been proposed as possible targets for new antidepressant therapies, although results of a recently completed phase III trial failed to demonstrate that the NK(1)R antagonist MK-869 is more effective than placebo in the treatment of depression. METHODS: In the present study, we compared the effects of the NK(1)R antagonist L-760735 with the tricyclic antidepressant clomipramine on endocrine and behavioral parameters in chronically stressed tree shrews. Animals were subjected to a 7-day period of psychosocial stress before receiving daily oral administration of L-760735 (10 mg/kg/day) or clomipramine (50 mg/kg/day). The psychosocial stress continued throughout the treatment period of 21 days. Daily morning urine was collected to measure cortisol and norepinephrine levels. All animals were videotaped daily and three types of behavior were analyzed. RESULTS: Chronic psychosocial stress resulted in a significant increase of urinary cortisol and norepinephrine concentrations. Moreover, stressed animals displayed decreased marking behavior and locomotor activity, while grooming remained unaffected. Neither treatment with clomipramine nor L-760735 was able to normalize the stress-induced elevation of cortisol or norepinephrine. On the behavioral parameters, L-760735 had a time-dependent restorative influence on marking behavior close to normal levels, without affecting locomotor activity. Grooming behavior was significantly increased by the 3 weeks of drug treatment. CONCLUSIONS: These results suggest that L-760735 was able to counteract certain stress-induced behavioral alterations in an animal model of depression.

Social stress in tree shrews as an animal model of depression: an example of a behavioral model of a CNS disorder.

Animal models are invaluable in preclinical research on human psychopathology. Valid animal models to study the pathophysiology of depression and specific biological and behavioral responses to antidepressant drug treatments are of prime interest. In order to improve our knowledge of the causal mechanisms of stress-related disorders such as depression, we need animal models that mirror the situation seen in patients. One promising model is the chronic psychosocial stress paradigm in male tree shrews. Coexistence of two males in visual and olfactory contact leads to a stable dominant/subordinate relationship, with the subordinates showing obvious changes in behavioral, neuroendocrine, and central nervous activity that are similar to the signs and symptoms observed during episodes of depression in patients. To discover whether this model, besides its "face validity" for depression, also has "predictive validity," we treated subordinate animals with the tricyclic antidepressant clomipramine and found a time-dependent recovery of both endocrine function and normal behavior. In contrast, the anxiolytic diazepam was ineffective. Chronic psychosocial stress in male tree shrews significantly decreased hippocampal volume and the proliferation rate of the granule precursor cells in the dentate gyrus. These stress-induced changes can be prevented by treating the animals with clomipramine, tianeptine, or the selective neurokinin receptor antagonist L-760,735. In addition to its apparent face and predictive validity, the tree shrew model also has a "molecular validity" due to the degradation routes of psychotropic compounds and gene sequences of receptors are very similar to those in humans. Although further research is required to validate this model fully, it provides an adequate and interesting non-rodent experimental paradigm for preclinical research on depression.

Examining novel concepts of the pathophysiology of depression in the chronic psychosocial stress paradigm in tree shrews.

Despite decades of research on psychiatric disorders, the aetiology and precise biological mechanisms that underlie depressive diseases are still poorly understood. There is increasing evidence that psychiatric disorders not only have a neurochemical basis but are also associated with morphological alterations in central nervous neurons and/or glial cells. Antidepressants may act by restoring structure as well as function of neural networks, meaning that they may, as a fundamental principle, affect neural plasticity underlying normal brain functioning. To examine these novel concepts of the pathophysiology of depression and antidepressant medication we have carried out a series of experiments using the chronic psychosocial stress paradigm in male tree shrews, an animal model with a high validity for the pathophysiology of depressive disorders, in which the animals were treated with the tricyclic antidepressant compound clomipramine. We found that one month of stress reduced cell proliferation in the dentate gyrus, and decreased the total hippocampal volume. Gene transcription analysis revealed that, under these experimental conditions, expression of genes known to be involved in processes of cell differentiation is suppressed. These effects of social conflict on hippocampal cells, including gene transcription, and on the entire hippocampal volume could be counteracted by chronic treatment with the antidepressant clomipramine. Stress also induced a constant hyperactivity of the hypothalamic-pituitary-adrenal axis, and suppressed both motor and marking behaviour. These neuroendocrine and behavioural stress-induced changes were also re-normalized by clomipramine.

Social stress in tree shrews: effects on physiology, brain function, and behavior of subordinate individuals.

Social stress is known to be involved in the etiology of central nervous disorders such as depression. In recent years, animal models have been developed that use chronic stress to induce neuroendocrine and central nervous changes that might be similar to those occurring in the course of the development of depressive disorders. The present review gives a summary of observations made in the tree shrew chronic social stress model. During periods of daily social stress, male tree shrews develop symptoms that are known from many depressed patients such as persistent hyperactivities of both the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system, disturbances in sleeping patterns, and reduced motor activity. Moreover, various physiological parameters indicate an acceleration of the over all metabolic rate in socially stressed tree shrews. Some of these parameters can be renormalized by antidepressants thus supporting the view of the tree shrew social stress paradigm as model for major depression. In the brains of socially stressed animals, monoamine receptors show dynamic changes that reflect adaptation to the persistent monoaminergic hyperactivity during periods of chronic stress. In addition to the changes in neurotransmitter systems, there are structural changes in neurons, e.g., retraction of the dendrites of hippocampal pyramidal neurons. Together, these processes are suggested as a cause of behavioral alterations that can be counteracted by antidepressants in this naturalistic social stress model.

Effects of cortisol on brain alpha2-adrenoceptors: potential role in stress.

It has been proposed that behavioural changes induced by chronic psychosocial stress in male tree shrews might be related to alterations in the central nervous alpha2-adrenoceptor system. In the noradrenergic centres of the brain, alpha2-adrenoceptors function as autoreceptors regulating noradrenaline release. Chronic stress downregulates these receptors in several brain regions. Since during stress, the activity of the hypothalamus-pituitary-adrenal axis is increased leading to high concentrations of plasma glucocorticoids, we investigated whether the effects of chronic stress can be mimicked by cortisol treatments. Two experiments were performed: a short-term treatment (males were injected i.v. with 1.5 mg cortisol and brains were dissected 2 h later) and a long-term treatment (animals received the hormone in their drinking water for 5 days; daily uptake 3-7 mg). The short-term treatment (injection), similar to the stress effects, downregulated alpha2-adrenoceptors in several brain regions. In contrast, the long-term oral treatment induced regional receptor upregulation. These data show: (i) that glucocorticoids regulate alpha2-adrenoceptors in the brain; (ii) that the duration and/or the route of cortisol application determines the results: and (iii) that chronic stress effects are not only due to the long-term glucocorticoid exposure, but also to other elements of the stress response.

Chronic psychosocial stress and antidepressant treatment in tree shrews: time-dependent behavioral and endocrine effects.

Social defeat has been shown to cause a number of behavioral, physiological, and central nervous changes in male tree shrews. The present study was designed to assess: (i) a potential time lag in the occurrence of behavioral alterations (locomotor activity, self-grooming, marking behavior, food and water intake, and avoidance behavior) after stress and long-term antidepressant treatment; and (ii) to investigate potential interactions between behavioral and endocrine variables (urinary cortisol and norepinephrine). Male tree shrews were submitted to chronic psychosocial stress for 39 days. In this paradigm, the stress-induced behavioral and endocrine alterations in subordinate animals are based exclusively on the central nervous interpretation of the continuous visual presence of the dominant conspecific. During the last 29 days of stress exposure, the tricyclic antidepressant clomipramine was administered daily to the subordinate animals (50 mg/kg, p.o). Results from this group were compared with three other experimental groups: one group was just stressed, one group received only clomipramine, and one group only vehicle. To determine the time-dependent effects of psychosocial stress and clomipramine treatment, behavior was recorded immediately after and 9 h after daily social encounters. Depending on the observation time, significant differences between the effects of psychosocial stress and antidepressant treatment were found. Generally, the effect of stress on behavioral parameters tended to be less distinct immediately after the social encounter compared to the later observation time. Furthermore the drug had a time-dependent restorative influence on marking and grooming behavior, locomotor activity, avoidance behavior, as well as on urinary cortisol, and norepinephrine excretion. Correlation analysis revealed significant interdependencies between locomotor activity, marking behavior, and avoidance behavior on 1 day with cortisol and norepinephrine quantified in the morning urine of the following day. These findings indicate that experimental manipulations, stress, and psychotropic drug application have a time lag on bio-behavioral parameters which should be considered when studying animal behavior in response to stressors and/or to drug treatment.

Memory performance in tree shrews: effects of stressful experiences.

Male tree shrews were exposed to alternating non-stressful and stressful conditions, and their memory performance was tested during three different stress periods and after rest periods of various lengths using a modified holeboard. This paradigm circumvents confounding factors, e.g. food or water deprivation, transport to a special testing arena, and excludes the development of automatic cognitive processes by complex memory tasks. In experimental tree shrews, psychosocial conflict caused elevated cortisol levels during the stress phases. While this resulted in an impairment of the stress-sensitive declarative memory during the second stress phase, no memory deficit was found during the first and third stress phase. Despite normalized cortisol levels, significant memory deficits in experimental animals were observed even 10 weeks after the last stressful experience. The alternating order of stressful events revealed that the negative correlation between the level of adrenal steroid hormones and memory performance does not account for the long-lasting effects of psychosocial stress in tree shrews.

Psychosocial stress in tree shrews: clomipramine counteracts behavioral and endocrine changes.

Male tree shrews (Tupaia belangeri) provide an animal model to study the neurobehavioral consequences of chronic psychosocial stress. When living in visual and olfactory contact with a male conspecific by which it has been defeated, the subordinante tree shrew shows dramatic behavioral, physiological, and neuroendocrine changes. Because the over all pattern of these changes resemble a depression-like symptomatology, we investigated to what extent the behavioral and endocrine changes in subordinate animals can be reversed by treatment with the tricyclic antidepressant clomipramine. In the present study, animals were subjected to a 10-day period of psychosocial conflict to elicit stress-induced behavioral and endocrine alterations before the onset of drug treatment, and psychosocial stress continued throughout the treatment period of 30 days. Clomipramine was administered orally once daily at a dose of 50 mg/kg. The drug had a time-dependent restorative influence on marking and grooming behavior, locomotor activity, risk assessment, as well as on urinary cortisol and norepinephrine excretion. It, thus, appears that the clomipramine treatment counteracts the behavioral and endocrine effects of chronic psychosocial stress in tree shrews, and the time course of recovery corresponds closely to that observed when treating depressed patients in the clinic.