Antidepressant-like effects of 3,4-methylenedioxymethamphetamine in an animal model of depression

Increased synaptic serotonin (5-hydroxytryptamine) levels may underlie antidepressant-like effects of 3,4-methylenedioxymethamphetamine (MDMA) that may be more prominent in subjects with mood disturbance. The Flinders Sensitive Line (FSL) strain is an important animal model of depression. These rats are more immobile in the forced swimming test (FST), and their immobility is reversed by known antidepressants after prolonged administration. The objective of this study was to determine whether MDMA administration has a dose-dependent antidepressant-like effect in this animal model of depression. The effects of MDMA at 5 and 10 mg/kg following single and repeated administration were assessed in FSL rats using the FST. Sprague-Dawley rats were used as a control. During both FST sessions, saline-treated FSL rats were significantly more immobile than Sprague-Dawley rats (P<0.001). Acute MDMA administration had a dose-dependent antidepressant-like effect in FSL rats, which was most evident after 10 mg/kg. This effect was diminished after repeated administration. Methamphetamine 2 mg/kg, which was used as a positive control for locomotor activity induction, did not affect the depressive-like state in FSL rats. There were no changes in the cortical levels of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid after treatments. It is concluded that MDMA exhibited an antidepressant-like effect in FSL rats, which was most evident following acute administration.     

The effects of carbamazepine on two animal models of depression

Some clinical reports on antimanic, antidepressant and prophylactic effects of carbamazepine (CBZ) in manic-depressive illness have appeared since its initial use as an anticonvulsant drug. The present report deals with the effects of CBZ on two animal models of depression, namely the potentiation of amphetamine-induced anorexia, and the behavioral despair model. Carbamazepine (10, 20 or 40 mg/kg) neither modified the methamphetamine anorectic effect, nor induced anorexia when administered alone. Subacute and chronic administration of imipramine (4 or 15 mg/kg) decreased immobility of rats in the behavioral despair model. Subacute and chronic administration of CBZ (40 mg/kg) also decreased immobility, whereas the dose of 10 mg/kg CBZ was effective only after chronic treatment. It was concluded that CBZ is similar to atypical anti-depressants, since it did not potentiate the amphetamine-induced behavioral effect, but did have an effect on the behavioral despair model of depression.     

Inositol reduces depressive-like behaviors in two different animal models of depression

  Rationale: Myo-inositol is an isomer of glucose that is a precursor in the phosphatidylinositol (PIP) cycle, a source of two second messengers: diacylglycerol (DAG) and inositol triphosphate (IP₃). Clinical studies have reported that inositol is effective in relieving symptoms of depression. Objective: The present study examined the effects of inositol on two animal models of depression: the Porsolt forced swim test, a behaviorally based model; and the reserpine-induced immobility model, a pharmacologically based model. Methods and results: Chronic inositol injections (daily for 14 days) of 1.2 g/kg (but not at lower doses) reduced immobility time and increased struggle time in the Porsolt test compared with control animals. The same dose and treatment schedule also reduced complete immobility time but did not affect ambulatory activity in the reserpine test compared with controls. Chronic oral treatment with inositol (10% in food for 14 days) had effects similar to IP inositol in the Porsolt test. Conclusions: The effect of inositol in animal models of depression supports its possible importance as a new treatment for the disorder, and permits research on its mechanisms of action. Received: 31 August 1998 / Final version: 18 November 1998     

Lack of tolerance to imipramine or mianserine in two animal models of depression

Few clinical reports describe tolerance induced by antidepressants and this question is considered an unsolved problem for clinical use of this group of drugs. The present report deals with the effects of imipramine and mianserine on two animal models of depression, after acute or prolonged previous treatment with these antidepressants. Imipramine and mianserine potentiated amphetamine-induced anorexia both after acute administration or after prolonged previous treatment with each drug. Mianserine effects were not detected in the behavioral despair test and imipramine reduced rats immobility equally after acute and prolonged previous treatment. It was concluded that imipramine and mianserine do not induce detectable tolerance when previously administered to animals submitted to amphetamine anorexia or behavioral despair.     

Antidepressant-like effects of a novel pentapeptide,nemifitide, in an animal model of depression

Background Nemifitide is a novel peptide analog of melanocyte-inhibiting factor (MIF) that has been reported to relieve depressive symptoms in a very short period.Objectives The Flinders Sensitive Line (FSL) rat, a genetic animal model of depression with innate exaggerated immobility in the forced swim test, was used to obtain more detailed information about the antidepressant-like effects of nemifitide.Methods The FSL rats were treated chronically with various doses of nemifitide or reference antidepressants desipramine and fluoxetine for 5 or 14 days and the forced swim test was conducted 22–24 h after the last treatment.Results Nemifitide significantly increased swimming in the FSL rats at both low (0.025–0.3 mg/kg) and high (3.0–15.0 mg/kg) doses but not at intermediate (0.4–2.4 mg/kg) doses. Nemifitide (0.3 mg/kg) and desipramine (5.0 mg/kg) significantly increased swimming in the FSL rats after just 5 days of treatment, but fluoxetine (5.0 mg/kg) did not. Nemifitide (0.3 mg/kg) and fluoxetine (5.0 mg/kg) had long-lasting effects, but desipramine (5.0 mg/kg) did not.Conclusions These findings support the value of developing nemifitide and its analogs as potential antidepressants.     

Antidepressant-like effects of CRF1 receptor antagonist SSR125543 in an animal model of depression

Much interest has been expressed in the antidepressant potential of nonpeptide, orally active corticotropin-releasing factor (CRF) receptor antagonists in recent years. Therefore, the present investigation examined the antidepressant-like effects of the novel CRF(1) receptor antagonist SSR125543 on the exaggerated swim test immobility in the Flinders Sensitive Line rat, a genetic animal model of depression. Chronic treatment with SSR125543 (3, 10, 20, 30 mg/kg, i.p.) for 14 days significantly increased swimming in the Flinders Sensitive Line rats. The reference serotonin reuptake inhibitor fluoxetine (5 mg/kg, i.p.) and the tricyclic antidepressant desipramine (5 mg/kg, i.p.) also significantly increased swimming, as expected. The higher doses of SSR125543 (20 and 30 mg/kg) also significantly increased the abnormally low level of social interaction behavior in the Flinders Sensitive Line rats. Together, these findings indicate that the CRF(1) receptor antagonist SSR125543 has both antidepressant- and anxiolytic-like effects in the Flinders Sensitive Line rats.     

The validity of animal models of depression

Eighteen animal, models of depression are reviewed in relation to three sets of validating criteria. Of the 18 models, five could only be assessed for predictive, validity, seven could be assessed for predictive and face validity, and six could potentially have predictive, face and construct validity. Some traditional models (reserpine reversal, amphetamine potentiation) are rejected as invalid; the models with the highest overall validity are the intracranial self-stimulation, chronic stress and learned helplessness models in rats, and the primate separation model.     

Antidepressant-like properties of oral riluzole and utility of incentive disengagement models of depression in mice

Rationale  

The neuroprotective agent riluzole has antidepressant-like properties in humans, but its mechanisms of action are unclear. Despite the increasing utility of transgenic and knockout mice in addressing such issues, previous studies aimed at characterizing biochemical mechanisms have been conducted in rats.     

Antidepressant-like action of 5-HT1A agonists and conventional antidepressants in an animal model of depression

Previous results have suggested that behavioural adaptation to restraint might be promoted by post-restraint stimulation of 5-HT1A receptors. Therefore, rats were restrained for 2 h and injected with vehicle or 60-1,000 micrograms/kg of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) s.c. Vehicle-treated restrained rats showed reduced locomotor activity and increased defaecation in an open field test the day after the end of restraint. A single injection of 250 or 1,000 micrograms/kg 8-OH-DPAT attenuated these effects. The above locomotor deficits were also attenuated by chronic pretreatment with the antidepressants desipramine and sertraline but not by a single treatment with desipramine or the benzodiazepine anxiolytic drugs chlordiazepoxide and diazepam; none of these treatments unambiguously reversed stress-induced increases in defaecation. Evidence suggests that the above action of 8-OH-DPAT is mediated by 5-HT1A receptors since it was antagonised by the 5-HT1A antagonist spiperone but not by the 5-HT2 antagonist ketanserin and was not mimicked by the 5-HT1B agonist RU 24969. However, the 5-HT1A agonists buspirone and TVXQ 7821 (ipsapirone) and the non-specific 5-HT agonist quipazine all possess similar properties to 8-OH-DPAT in this test. The results suggest that 5-HT1A agonists may have rapid antidepressant properties.     

Antidepressant-like effect of artemin in mice: a mechanism for acetyl-l-carnitine activity on depression

Rationale

Depression may be associated with altered plasticity of the nervous system. The importance of neurotrophic factor levels is strongly suggested, and the neuronal-related family is extensively studied with respect to glial-derived one.

Objectives

Aimed to contribute to the study of nervous plasticity modulation as therapeutical target in mood disorders, the role of the glial-derived factor artemin (ARTN) in depression and in the pharmacodynamics of the antidepressant and trophic compound acetyl-l-carnitine (ALCAR) was evaluated.

Methods

Male mice were treated with 100?mg?kg^?1 ALCAR daily for 7?days; 0.6???g/mouse ARTN was acutely injected intracerebroventricularly. Gene knockdown of ARTN and GDNF family receptor alpha (GFRalpha3) was obtained by oligonucleotide antisense strategy. The forced swimming test was performed to evaluate antidepressant-like effects.

Results

Repeated ALCAR administration increased ARTN levels in spinal cord, hippocampus, and prefrontal cortex. No modulatory effect was detected on BDNF and glial cell line-derived neutrotrophic factor (GDNF). ARTN, 30?min after administration, showed a dose-dependent antidepressant-like effect. ALCAR needed a 7-day treatment to reach a comparable effect; nevertheless, both substances were able to induce a phosphorylation of the GDNF family receptor Ret. A decrease of the free ARTN level by a specific ARTN antibody impaired the antidepressant-like effect of acute ARTN and repeated ALCAR. Gene knockdown of ARTN or, alternatively, of its receptor GFRalpha3 fully prevented ALCAR effectiveness.

Conclusions

A mechanism for the antidepressant property of ALCAR is proposed, and the novelty of the possible role of ARTN in depression is suggested.     

Development of animal models of treatment-resistant depression in rats]

Psychoendocrinological studies have focused on the hypothalamic-pituitary-adrenal axis in patients with depression. We have already reported that in rats, repeated adrenocorticotropic hormone (ACTH) treatment blocks the effect of tricyclic antidepressants in decreasing immobility time in a forced swim test, a widely used animal experiment for predicting antidepressant activity. Furthermore, chronic coadministration of lithium or carbamazepine, an agent that potentiates the actions of antidepressants in patients with depression, including those with treatment-resistant depression, significantly decreased the duration of immobility, even when given concurrently with ACTH. Recently, clinical and animal studies have shown that neurogenesis/neuroprotection in the adult brain is important for the therapeutic actions of antidepressants. We indicated that repeated ACTH treatment decreased the expression of BDNFmRNA and the number of newborn cells in the rat hippocampus. Namely, we recognized that ACTH-treated rats served as a useful animal model of tricyclic antidepressant treatment-resistant conditions.     

抑郁症动物模型的研究与应用

疾病研究和新药开发有赖于有效的实验性动物模型的建立和应用.该文阐述了目前在药理学研究中常用的几类抑郁症动物模型,并对模型的原理及其应用作了介绍,最后对未来发展抑郁症动物模型提出了一些设想.     

The validity of animal models of predisposition to depression

Some animal models of depression, including the majority of the more recently introduced models, are better characterized as models of predisposition to depression. In the first part of this paper, we show that the basis for such a model could be either a procedure that increases the ease with which an analogue of major depression may be evoked, or a presentation analogous to dysthymia (chronic mild depression). We then consider how the concepts of predictive, face, and construct validity apply to such models. Next, we review the validity of the available models of predisposition to depression, which derive from genetics, genomics, developmental manipulations, and brain lesioning. Finally, we compare the performance of the different models, using a novel scoring system that formalizes the evaluation of animal models against each of the three sets of validation criteria.     

Anti-diabetic activity of Emblica officinalis in animal models

The aqueous extract of Emblica officinalis Gaertn. (syn: Phyllanthus emblica L.) (Euphorbiaceae) seeds was investigated for its anti-diabetic activity in animal models. Streptozotocin (STZ)-induced type 2 diabetes models were used for the study. The standardized doses of 100, 200, 300, and 400?mg kg^?1 body weight of the extract were administered orally to normal and diabetic rats in order to define its glycemic potential. The maximum fall of 27.3% (p?<?0.001) in the blood glucose level of normal rats was observed at 6?h during fasting blood glucose studies, with the dose of 300?mg kg^?1 identified as the most effective dose. The same dose produced a fall of 25.3% (p?<?0.001) in the same models during the glucose tolerance test (GTT) at 3?h after glucose administration. However, the dose of 300?mg kg^?1 of aqueous seed extract in sub- and mild-diabetic animals produced a maximum fall of 34.1 and 41.6% (p?<?0.01), respectively, during the GTT at 3?h after glucose administration. This evidence clearly indicates that the aqueous extract of E. officinalis seeds has definite hypoglycemic potential as well as anti-diabetic activity.     

Effects of amperozide in two animal models of anxiety

The novel psychotropic agent amperozide (amp) was investigated in two different rat anxiety models, Vogel's conflict test (VT) and Montgomery's conflict test (MT). In the VT, amp in lower doses (0.2-0.6 mg/kg subcutaneously) increased the number of shocks accepted, as compared to controls. Pretreatment with the specific benzodiazepine receptor antagonist Ro 15-1788 (10.0 mg/kg orally) or the GABA-A receptor antagonist bicuculline (2.0 mg/kg intraperitoneally) antagonized the anticonflict effect of amp (0.4 mg/kg subcutaneously). At the highest dose tried (2.0 mg/kg subcutaneously) amp instead decreased the number of shocks accepted. Both 0.4 mg/kg and 2.0 mg/kg of amp raised the shock threshold, as compared to controls. The latter dose also decreased the motivation to drink. Pretreatment with Ro 15-1788 (10.0 mg/kg orally) did not significantly change the shock threshold or the drinking motivation, as compared to the group receiving amp alone. In the MT, amp (0.05-0.1 mg/kg subcutaneously) increased the percentage time spent in the open arms, while no changes were seen in the number of entries made into these arms. After higher doses (0.4-0.8 mg/kg subcutaneously) no differences, as compared to controls, were observed. Amp (1 nM-10microM) exhibited no affinity for 3H-flunitrazepam binding sites in mouse forebrain membranes in vitro. Taken together, the present data suggest that amp in low doses produces anticonflict (anxiolytic-like) effects. These effects appear to be mediated through an indirect (via 5-HT and/or DA systems?) activation of the GABA/benzodiazepine chloride ionophore receptor complex.     

Activity of diltiazem and nifedipine in some animal models of depression

The effect of two calcium channel inhibitors, diltiazem and nifedipine in animal models of depression: a) behavioral despair test and b) behavioral deficit produced by uncontrollable footshock was investigated. Additionally, the influence of both drugs on mouse killing (muricide) behavior induced by chronic isolation was studied. Both drugs given in single doses increased the active behavior of rats in behavioral despair test. Nifedipine but not diltiazem was partially effective in the test when administered chronically (14 days). Both drugs also attenuated stress-induced behavioral depression in the open field and forced swim test. Diltiazem was markedly more active in the former whereas nifedipine in the latter test. Neither compound influenced killing behavior in muricidal rats. Our data support the notion that calcium channel inhibitors may possess antidepressant activity, although there appear to exist certain differences in their scope of action depending on the model applied.     

Functional magnetic resonance imaging reveals similar brain activity changes in two different animal models of schizophrenia

Rationale and objectives

In schizophrenia research, most of the functional imaging studies have been performed in psychotic patients, but little is known about brain areas involved in the expression of psychotic-like symptoms in animal models. The objective of this study was to visualize and compare brain activity abnormalities in a neurodevelopmental and a pharmacological animal model of schizophrenia.

Methods

Blood perfusion of specific brain areas, taken as indirect measure of brain activity, was investigated in adult rats following either neonatal ventral hippocampal lesion or acute administration of phencyclidine. Quantitative perfusion magnetic resonance imaging was performed on five frontal brain slices using the continuous arterial spin labeling technique. The mean perfusion was calculated in several brain structures, which were identified on anatomical images.

Results

Lesioned animals exhibiting deficits in prepulse inhibition of the startle reflex showed a significant blood perfusion increase in the nucleus accumbens, basolateral amygdala, ventral pallidum, entorhinal–piriform cortex, orbital prefrontal cortex, and in the bed nucleus of the stria terminalis, and a decrease of perfusion in the temporal cortex. Similar effects were seen following acute phencyclidine administration in naïve animals.

Conclusion

Our data point out specific cortical and subcortical brain areas involved in the development of psychotic-like symptoms in two different animal models of schizophrenia. The observed brain activity abnormalities are reminiscent of classical neuroimaging findings described in schizophrenic patients.