Social Isolation Selectively Increases Anxiety in Mice without Affecting Depression-like Behavior

It is hypothesized that a number of environmental factors affect animals'' behavior. Without controlling these variables, it is very hard for researchers to get not only reliable, but replicable data from various behavioral experiments testing animals'' cognitive as well as emotional functions. For example, laboratory mice which had restricted environment showed different synaptic potentiation properties with wild mice (Zhao MG et al., 2009). While performing behavioral experiments, however, it is sometimes inevitable that the researcher changes the animals'' environments, as by switching the cages in which experimental animals are housed and separating animals raised together into small experimental groups. In this study, we investigated the effect of environmental changes on mice''s emotional behaviors by socially isolating them or reducing the size of their cage. We found that social isolation selectively increases the animals'' levels of anxiety, while leaving depression-like behaviors unchanged. On the other hand, alteration of the housing dimensions affected neither their anxiety levels nor their depression-like behaviors. These results suggest that environmental variables may have a prominent impact on experimental animals'' emotional behaviors and possibly their psychological states, leading to bias in the behavioral data produced from experiments.     

Sildenafil,a phosphodiesterase type 5 inhibitor,reduces antidepressant-like activity of paroxetine in the forced swim test in mice

BackgroundSildenafil, a selective phosphodiesterase 5 (PDE5) inhibitor, has recently been reported to influence the antidepressant activity of some antidepressant drugs. The present study was undertaken to investigate the involvement of the nitric oxide/cyclic guanosine 3',5'-monophosphate/PDE5 (NO/cGMP/PDE5) signaling pathway in the antidepressant activity of paroxetine and to assess the interaction between paroxetine and sildenafil, in the forced swim test in mice.MethodsSwim trials were conducted by placing mice in glass cylinders filled with water for 6 min. Total behavioral immobility was measured during the last 4 min of the test. Changes in locomotor activity were measured with photoresistor actimeters. Serum and brain paroxetine concentrations were assayed by the HPLC method.ResultsParoxetine at a dose of 1 mg/kg significantly decreased immobility time in the forced swim test, while sildenafil (5, 10 and 20 mg/kg) in a dose-dependent manner reduced the antidepressant activity of paroxetine. Pharmacokinetic studies did not show any significant changes in paroxetine concentration in serum and brain tissue as compared to paroxetine treatment alone.ConclusionsThe results suggest that paroxetine may exert its antidepressant action by decreasing cGMP levels and sildenafil, as a drug which has the opposite effect on the processes mediated via the NO/cGMP/PDE5 signaling pathway, may decrease the efficacy of paroxetine. However, the co-administration of paroxetine with sildenafil resulted in a potent reduction (80%) of locomotor activity, which suggests that the reversal of antidepressant action of paroxetine may have been a result of locomotor deficits. Further studies are required to explain the mechanism underlying this phenomenon.     

Influence of the phosphodiesterase type 5 inhibitor, sildenafil, on antidepressant-like activity of magnesium in the forced swim test in mice

Magnesium, which acts as an antagonist of N-methyl-D-aspartate (NMDA) subtype of glutamate receptors, exerts antidepressant-like activity in animal models of depression. The present study was undertaken to elucidate the influence of sildenafil, a phosphodiesterase type 5 inhibitor, on the anti-immobility action of magnesium in the forced swim test in mice. Swim sessions were conducted by placing mice in glass cylinders filled with water for 6 min and the duration of the behavioral immobility during the last 4 min of the test was evaluated. Locomotor activity was measured with photoresistor actimeters. Serum and brain magnesium levels were assayed spectrophotometrically. Magnesium at a dose of 30 mg/kg, i.p. significantly decreased the immobility time while sildenafil (5, 10 and 20 mg/kg, i.p.) in a dose-dependent manner reduced the antidepressant-like activity of magnesium. The co-administration of magnesium with sildenafil at the highest dose entirely abolished the antidepressant-like effect of magnesium and caused a statistically significant increase in immobility duration as compared to the control group. Combination of magnesium with sildenafil resulted in a potent reduction (80%) of locomotor activity and pharmacokinetic studies showed a significant increase of magnesium concentration in serum (as compared to magnesium treatment alone) without changes within brain tissue in mice treated with magnesium and sildenafil. When given alone, sildenafil caused a significant increase in magnesium levels in both serum and brain. Our results indicate that a simultaneous treatment with magnesium and sildenafil results in hypermagnesemia in laboratory animals. However, the mechanism underlying this effect remains elusive.     

CART Peptides Regulate Psychostimulants and May be Endogenous Antidepressants

CART peptides are endogenous neurotransmitters that are involved in a variety of physiologic functions. Injection of CART 55-102 into the nucleus accumbens produces no effect, but when co-administered with cocaine, it reduces the locomotor and rewarding properties of cocaine. In a human study, subjects carrying a missense mutation of the CART gene exhibited increased anxiety and depression. Also, several animal studies support the idea that CART is involved in anxiety and depression, and they also suggest several possible mechanisms by which this may occur. Thus, there is interesting evidence that CART peptides play a role in anxiety and depression, and that CART peptides may be endogenous antidepressants.     

New 8-aminoalkyl derivatives of purine-2,6-dione with arylalkyl,allyl or propynyl substituents in position 7, their 5-HT1A, 5-HT2A,and 5-HT7 receptor affinity and pharmacological evaluation

BackgroundOur previous studies in a group of arylpiperazine derivatives of 1,3-dimethyl-3,7-dihydro-purine-2,6-diones, aimed at chemical diversification of the purine-2,6-dione by introduction of hydrophobic substituent in a 7- or 8- position or elongation of the linker length between arylpiperazine and purine core, allowed a selection of potent 5-HT_1A, 5-HT_2A and 5-HT₇ receptor ligands displaying anxiolytic and antidepressant properties. Continuing our research in this field, in the present studies we designed a new series of 8-aminoalkylamino (15–35) and 8-arylpiperazinylpropoxy (36–42) derivatives of 7-substituted 1,3-dimethyl-3,7-dihydropurine- 2,6-dione as potential 5-HT_1A, 5-HT_2A and 5-HT₇ receptor ligands with potential psychotropic activity.MethodsRadioligand binding assays were employed for determining the affinity and the selectivity profile of the synthesized compounds for native 5-HT_1A, 5-HT_2A, and cloned 5-HT₆ and 5-HT₇ receptors. The functional activity of the selected compounds at 5-HT_1A and 5-HT_2A receptors was tested in the commonly used in vivo models. Antidepressant and anxiolytic properties were evaluated in the forced swim (FST) and the four-plate test (FPT) in mice, respectively.ResultsAmong the evaluated series, selected 7-benzyl-8-((4-(4-(3-chlorophenyl)piperazin-1-yl)butyl)amino)-1,3-dimethyl- 1H-purine-2,6(3H,7H)-dione (21), a mixed 5-HT_1A/5-HT_2A/5-HT₇ receptor ligand, produced an antidepressant-like effect in FST, and exerted anxiolytic-like activity in FPT. Another pharmacologically evaluated compound 42 (a mixed 5-HT_1A/5-HT₇ ligand) slightly, but non-significantly attenuated the immobility time of mice in FST and was devoid of activity in FPT.ConclusionsStudy revealed advantage of mixed 5-HT_1A/5-HT_2A/5-HT₇ receptor ligands over 5-HT_1A/5-HT₇ agents to display antidepressant- and anxiolytic-like activity. Modification of arylalkyl/allyl substituent in position 7 of purine-2,6-dione opens possibility for designing new 5-HT ligands with preserved π electron system and lower molecular weight.     

Chronic treatment with imipramine reverses immobility behaviour, hippocampal corticosteroid receptors and cortical 5-HT(1A) receptor mRNA in prenatally stressed rats

Prenatal stress in the rat induces enhanced reactivity of the hypothalamus-pituitary-adrenal (HPA) axis, disturbances in a variety of circadian rhythms and increased anxiety-like behaviour. Such abnormalities parallel those found in human depressed patients. Prenatally stressed (PS) rats could represent, therefore, an interesting animal model for the evaluation of the efficacy of pharmacotherapeutic intervention in psychiatric disorders that has often been addressed using control animals. In the present study, PS and non-stressed rats were chronically treated with the tricyclic antidepressant imipramine (10 mg/kg i.p. for 21 days) and assessed in the forced swim test. Glucocorticoid receptor binding sites in the hippocampus were measured and 5-HT(1A) receptor mRNA levels in the frontal cortex were also assessed. PS rats were characterised by increased immobility in the forced swim test, reduced hippocampal corticosteroid receptor binding and increased levels of cortical 5-HT(1A) mRNA. All these parameters were significantly reversed by chronic imipramine treatment. Conversely, no significant effects were observed for non-stressed rats. All these effects are consistent with the expected pharmacotherapy of depression-like abnormalities in PS rats. These results further indicate that PS rats are a relevant animal model of depression.     

Effect of acute and chronic treatment with QCF-3 (4-benzylpiperazin-1-yl) (quinoxalin-2-yl) methanone,a novel 5-HT3 receptor antagonist,in animal models of depression

The serotonin type 3 (5-HT₃) receptor is unique among the seven recognized serotonin receptor “families”. The existence serotonin type 3 receptor (5-HT₃) in neuro-anatomical regions stimulated the research interest for novel therapeutic targets such as anxiety, depression, nociception and cognitive function. In the current study, (4-benzylpiperazin-1-yl) (quinoxalin-2-yl) methanone (QCF-3), a novel 5-HT₃ receptor antagonist, with an optimal log P (the logarithm of the ratio of the concentrations of the un-ionized solute in the solvents is called log P) and significant pA2 value (is a negative logarithm of the molar concentration of antagonist required to reduce the effect of multiple dose agonist to that of single dose) was screened for its anti-depressant potential using rodent behavioral models of depression. Psycho-pharmacological investigations involved acute and chronic treatment (14 days) with QCF-3 and assessment of behavior during the forced swim test (FST) and tail suspension test (TST) in mice and olfactory bulbectomised rats. A dose response study in mice revealed an initial anti-depressant-like effect of QCF-3 (0.5–4 mg/kg, ip) in the FST and TST. Interaction studies showed that QCF-3 (1 and 2 mg/kg) significantly enhanced the antidepressant action of fluoxetine and bupropion in the FST and TST, respectively. QCF-3 (1 and 2 mg/kg) potentiated the 5-hydroxytryptophan (5-HTP) induced head twitches response in mice and reversed reserpine-induced hypothermia in rats. Further, OBX rats exhibited behavioral anomalies in the open field and hyper-emotionality tests that were attenuated by chronic QCF-3 treatment. In conclusion, this behavioral study describes an antidepressant-like effect of QCF-3 in rodent behavioral models of depression.     

Correlations between depression behaviors and sleep parameters after repeated corticosterone injections in rats

Aim： Disrupted sleep may be a prodromal symptom or a predictor of depressive disorders. In this study we investigated the relationship between depression symptoms and disrupted sleep using a novel model of stress-mimicked sleep disorders in rats. Methods： SD rats were injected with corticosterone （10, 20 or 40 mg/kg, sc） or vehicle for 7 d. Their sleep-wake behavior was monitored through implanted EEG and EMG electrodes. Their depressive behaviors were assessed using forced swim test, open field test and sucrose preference test. Results： The corticosterone-treated rats showed significantly reduced sleep time, disinhibition of rapid-eye-movement （REM） sleep and altered power spectra during non-REM sleep. All depressive behavioral tests did not show significant difference across the groups. However, individual correlation analysis revealed statistically significance： the immobility time （despair） was negatively correlated with REM sleep latency, slow wave sleep （SWS） time ratio, SWS bouts and delta power density, and it was positively correlated with REM sleep bouts and beta power density. Meanwhile, sucrose preference （anhedonia） was positively correlated with total sleep time and light sleep bouts, and it was negatively correlated with the REM sleep time ratio. Conclusion： In stress-mimicked rats, sleep disturbances are a predictor of depressive disorders, and certain symptoms of depression may be related to the disruption of several specific sleep parameters.     

Gender differences in genetic mouse models evaluated for depressive-like and antidepressant behavior

Depression is a mental disease that affects complex cognitive and emotional functions. It is believed that depression is twice as prevalent in women as in men. This phenomenon may influence the response to various antidepressant therapies, and these differences are still underestimated in clinical treatment. Nevertheless, most of the current findings are based on studies on male animal models, and relatively few of these studies take possible gender differences into consideration. Advancements in genetic engineering over the last two decades have introduced many transgenic lines that have been screened to study the pathomechanisms of depression. In this mini-review, we provide a compendious list of genetically altered mice that underwent tests for depressive-like or antidepressant behavior and determine if and how the gender factor was analyzed in their evaluation. Furthermore, we compile the gender differences in response to antidepressant treatment. On the basis of these analyses, we conclude that in many cases, gender variability is neglected or not taken into consideration in the presented results. We note the necessity of discussing this issue in the phenotypic characterization of transgenic mice, which seems to be particularly important while modeling mental diseases.     

Evidences for the involvement of monoaminergic and GABAergic systems in antidepressant-like activity of garlic extract in mice

Objectives:

The present study was undertaken to investigate the effect of the ethanolic extract of Allium sativum L. (Family: Lilliaceae), commonly known as garlic, on depression in mice.

Materials and Methods:

Ethanolic extract of garlic (25, 50 and 100 mg/kg) was administered orally for 14 successive days to young Swiss albino mice of either sex and antidepressant-like activity was evaluated employing tail suspension test (TST) and forced swim test (FST). The efficacy of the extract was compared with standard antidepressant drugs like fluoxetine and imipramine. The mechanism of action of the extract was investigated by co-administration of prazosin (α1-adrenoceptor antagonist), sulpiride (selective D2-receptor antagonist), baclofen (GABA_B agonist) and p-CPA (serotonin antagonist) separately with the extract and by studying the effect of the extract on brain MAO-A and MAO-B levels.

Results:

Garlic extract (25, 50 and 100 mg/kg) significantly decreased immobility time in a dose-dependent manner in both TST and FST, indicating significant antidepressant-like activity. The efficacy of the extract was found to be comparable to fluoxetine (20 mg/kg p.o.) and imipramine (15 mg/kg p.o.) in both TST and FST. The extract did not show any significant effect on the locomotor activity of the mice. Prazosin, sulpiride, baclofen and p-CPA significantly attenuated the extract-induced antidepressant-like effect in TST. Garlic extract (100 mg/kg) administered orally for 14 successive days significantly decreased brain MAO-A and MAO-B levels, as compared to the control group.

Conclusion:

Garlic extract showed significant antidepressant-like activity probably by inhibiting MAO-A and MAO-B levels and through interaction with adrenergic, dopaminergic, serotonergic and GABAergic systems.     

Antidepressant-like effects of a novel 5-HT3 receptor antagonist 6z in acute and chronic murine models of depression

Aim:

To investigate the antidepressant-like effects of a novel 5-HT₃ receptor antagonist N-(benzo[d]thiazol-2-yl)-3-methoxyquinoxalin-2-carboxamide (6z) in acute and chronic murine models of depression.

Methods:

5-HT₃ receptor antagonism was examined in guinea pig ileum in vitro. A tail suspension test (TST) was used as acute depression model to evaluate the antidepressant-like behavior in mice treated with 6z (0.5–2 mg/kg, ip). In chronic depression model, mice were exposed to a 4-week chronic unpredictable stress (CUS) protocol, and treated with 6z (0.5–2 mg·kg⁻¹·d⁻¹, po) or a positive drug fluoxetine (10 mg·kg⁻¹·d⁻¹, po) in the last 2 weeks, followed by behavioral and biochemical assessments.

Results:

The 5-HT₃ receptor antagonism of 6z (pA₂=7.4) in guinea pig ileum was more potent than that of a standard 5-HT₃ receptor antagonist ondansetron (pA₂=6.9). In acute depression model, 6z administration significantly decreased the immobility duration. In chronic depression model, 6z administration reversed CUS-induced depressive-like behavior, as evidenced by increased immobility duration in the forced swim test and sucrose preference in the sucrose preference test. Furthermore, chronic administration of 6z prevented CUS-induced brain oxidative stress, with significant reduction of pro-oxidant markers and elevation of antioxidant enzyme activity. Moreover, chronic administration of 6z attenuated CUS-induced hypothalamic-pituitary-adrenal axis hyperactivity, as shown by reduced plasma corticosterone levels. Similar results were observed in the fluoxetine-treated group.

Conclusion:

6z is a novel 5-HT₃ receptor antagonist with potential antidepressant-like activities, which may be related to modulating hypothalamic-pituitary-adrenal axis and attenuating brain oxidative damage.     

Seizure Susceptibility and Epileptogenesis in a Rat Model of Epilepsy and Depression Co-Morbidity

Although a strong co-morbidity exists clinically between epilepsy and depression, the cause of this co-morbidity remains unknown, and a valid animal model is crucial for the identification of underlying mechanisms and the development of a screening tool for novel therapies. Although some rodent models of epilepsy have been reported to display behaviors relevant to affective disorders, the seizure susceptibility of animals prone to depression-like behavior has not been characterized. Toward this end, we assessed several forms of seizure sensitivity and epileptogenesis in rats selectively bred for vulnerability (Swim Lo-Active; SwLo) or resilience (Swim High-Active; SwHi) to depression-like phenotypes. The SwLo rats exhibit decreased motor activity in a swim test and other depression-like phenotypes, whereas the SwHi rats display increased motor activity in a swim test. SwLo rats exhibited a decreased latency to limbic motor seizures following acute pilocarpine administration in the absence of differences in pilocarpine pharmacokinetics, and also had a decreased threshold to tonic seizures induced by electroshock. Approximately half of the SwLo rats, but none of the SwHi rats, had spontaneous limbic motor seizures 5 weeks following pilocarpine-induced status epilepticus. While the number of stimulations required to achieve full amygdala and hippocampal electrical kindling were similar in the two rat lines, SwLo rats had a lower final hippocampal kindling threshold and more wet dog shakes during both amygdala and hippocampal kindling. Combined, these results indicate that SwLo rats are a model of epilepsy and depression co-morbidity that can be used for investigating underlying neurobiological and genetic mechanisms and screening novel therapeutics.     

Antagonism of metabotropic glutamate group II receptors in the potential treatment of neurological and neuropsychiatric disorders

The metabotropic glutamate Group II receptors (mGlu2 and mGlu3 receptors) regulate the synaptic availability of glutamate and thus control the broad‐ranging neural transmission of glutamate as well as glutamate‐modulated transmission. The present review focuses on the potential role of Group II mGlu receptor antagonism in neurological and neuropsychiatric disorders. Recent findings have determined that agonists of metabotropic glutamate type 2/3 receptors (mGlu2/3) have antianxiety efficacy. Although it could be assumed that blockade of these receptors might engender anxiogenic responses, new data have indicted that these compounds produce antidepressant‐like, wake‐promoting, and pro‐cognitive effects in rodents. However, there are almost no data available to define the relative importance of mGlu2 versus mGlu3 receptors in these activities. Although there are some hints that antagonism of mGlu2/3 receptors could have additional therapeutic impact, the preponderance of data suggests that agonists of the mGlu2/3 receptors would be more likely to have efficacy in anxiety disorders, positive symptoms of schizophrenia, neurodegenerative disorders, and stroke, pain, and epilepsy. The pharmacology of antagonists of mGlu2/3 receptors suggests that such compounds could have a unique place in the medicinal arsenal for mood disorders as well as disorders of cognition and arousal. Given the activity surrounding the discovery of orally available antagonists for these receptors, there may be an opportunity for clinical investigation of these possibilities in the future. Drug Dev. Res. 67:757–769, 2006. © 2006 Wiley‐Liss, Inc.     

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.     

Neurogenesis-Independent Antidepressant-Like Effects on Behavior and Stress Axis Response of a Dual Orexin Receptor Antagonist in a Rodent Model of Depression

Growing evidence indicates that an increase of orexin (or hypocretin) signaling is involved in the pathophysiology of major depression, but little is known regarding the causal link between the orexinergic system and depressive-like states. Here we blocked orexin receptors in mice subjected to unpredictable chronic mild stress (UCMS) to investigate putative antidepressant-like effects of this treatment, as well as the underlying mechanisms. BALB/c mice were exposed to 9 weeks of UCMS and from the third week onward treated daily with fluoxetine (20 mg/kg per day, per os) or with the dual orexin receptor antagonist almorexant (100 mg/kg per day, per os). The effects of UCMS regimen and pharmacological treatments were assessed by physical measures and behavioral testing. The dexamethasone suppression test was performed to examine the integrity of the negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis, and immunohistochemical markers were used to assess cell proliferation (Ki-67), immature newborn neurons (doublecortin), and mature newborn neurons (5-bromo-2′-deoxyuridine/NeuN) in the dorsal and ventral parts of the hippocampus. Our results show that 7 weeks of fluoxetine or almorexant treatments counteract the UCMS-induced physical and behavioral alterations. Both treatments prevented the HPA axis dysregulation caused by UCMS, but only fluoxetine reversed the UCMS-induced decrease of hippocampal cell proliferation and neurogenesis, while chronic almorexant treatment decreased cell proliferation and neurogenesis specifically in the ventral hippocampus. Taken together, this is the first evidence that pharmacological blockade of the orexinergic system induces a robust antidepressant-like effect and the restoration of stress-related HPA axis defect independently from a neurogenic action.     

Antidepressant-like activity of CGP 36742 and CGP 51176, selective GABAB receptor antagonists, in rodents

BACKGROUND AND PURPOSE: A crucial role for the GABAB receptor in depression was proposed several years ago, but there are limited data to support this proposition. Therefore we decided to investigate the antidepressant-like activity of the selective GABAB receptor antagonists CGP 36742 and CGP 51176, and a selective agonist CGP 44532 in models of depression in rats and mice. EXPERIMENTAL APPROACH: Effects of CGP 36742 and CGP 51176 as well as the agonist CGP 44532 were assessed in the forced swim test in mice. Both antagonists were also investigated in an olfactory bulbectomy (OB) model of depression in rats, while CGP 51176 was also investigated in the chronic mild stress (CMS) rat model of depression. The density of GABAB receptors in the mouse hippocampus after chronic administration of CGP 51176 was also investigated. KEY RESULTS: The GABAB receptor antagonists CGP 36742 and CGP 51176 exhibited antidepressant-like activity in the forced swim test in mice. The GABAB receptor agonist CGP 44532 was not effective in this test, however, it counteracted the antidepressant-like effects of CGP 51176. The antagonists CGP 36742 and CGP 51176 were effective in an OB model of depression in rats. CGP 51176 was also effective in the CMS rat model of depression. Administration of CGP 51176 increased the density of GABAB receptors in the mouse hippocampus. CONCLUSIONS AND IMPLICATIONS: These data suggest that selective GABAB receptor antagonists may be useful in treatment of depression, and support an important role for GABA-ergic transmission in this disorder.