Behavioral effects of dietary cholesterol in rats tested in experimental models of mild stress and cognition tasks

Abnormalities in serum cholesterol levels of patients with mood disorders have been identified in epidemiological studies. However, evidence for an influence of dietary cholesterol on behavioral models is poor. Here, we investigated the behavioral changes of Wistar male rats fed a 2% cholesterol-enriched diet for 2 months in experimental models of depression and anxiety, such as the forced swim test (FST) paradigm and the novelty-induced grooming sampling test (NGT). The correlation between behavioral depression and impaired cognitive capacity was also examined testing rats in the Morris water maze (MWM) task one day after the FST. Different groups of rats fed various dietary regimens, were subjected to acute or repeated treatment (14 days) with clomipramine hydrochloride (50 or 25 mg/kg), diazepam (1 mg/kg) or with the peripheral benzodiazepine receptors (PBRs) antagonist, isoquinoline PK11195 (1 mg/kg) injected intraperitoneally (i.p.). Rats fed the cholesterol-enriched diet showed a significant decrease of grooming score in the NGT and of immobility time in the FST in comparison to animals fed a standard diet. Furthermore, the anxiolytic and antidepressant effects of diazepam and clomipramine were not affected by the different diets. Only after repeated treatment, PK11195 impaired the performance of animals fed a standard diet in the FST, and exhibited an anxiolytic-like profile in animals fed either the cholesterol-enriched or the standard diet. The improved performance in the FST was followed by a better learning performance in the acquisition phase of the MWM. These results suggest that effects of cholesterol-enriched diet on the behavioral reaction of rats in experimental models of mild stress may involve PBRs. They deserve attention in order to clarify the clinical correlation between plasma cholesterol levels and mood disorders in humans.     

Additional evidence for anxiolytic- and antidepressant-like activities of saredutant (SR48968), an antagonist at the neurokinin-2 receptor in various rodent-models

Central tachykinins have been shown to play a role in the modulation of stress-related behaviours. Saredutant, a tachykinin NK2 receptor antagonist, displayed mixed anxiolytic- and antidepressant-like activities in rodents. The present study aimed at further characterizing its psychotropic properties. Saredutant was tested in the rat social interaction test to further confirm its anxiolytic-like activity, and in a variety of behavioural models sensitive to antidepressant drugs. In the rat social interaction test, saredutant (20 mg/kg, i.p.) significantly increased the time spent in interaction, as did the prototypical anxiolytic agents, diazepam (1 mg/kg, i.p.) and buspirone (1 mg/kg, s.c.), but not the antidepressant, fluoxetine. In a differential reinforcement of low rate-72s task, saredutant (3 mg/kg, i.p.) displayed an antidepressant-like activity by increasing reinforced response rate and percentage of responses emitted in the inter-response time bin [49-96 s]. In bulbectomized rats, saredutant (20 mg/kg, i.p.) restored the deficit of acquisition of passive avoidance. In rat pups separated from their mother, saredutant (3-10 mg/kg, s.c.) reduced ultrasonic distress calls. Finally, in the chronic mild stress paradigm in mice, a 29-day treatment regimen with saredutant (10 mg/kg, i.p.) attenuated stress-induced physical degradation. Importantly, in the depression models, the effects of saredutant were comparable to those obtained under similar experimental conditions by reference antidepressants such as fluoxetine or imipramine. Together, these results suggest further that the NK2 receptor may represent an attractive target for the treatment of both depressive and anxiety disorders.     

The neurokinin NK2 antagonist, saredutant, ameliorates stress-induced conditions without impairing cognition

The current work extends our previous findings in stress-related disorders, but also addresses the impact of a neurokinin-2 (NK2) antagonist on cognition. Besides efficacy in mood disorders, an NK2 antagonist may have the potential to lack the disinhibitory components and adverse side effects associated with existing clinical treatments. Saredutant (3-30 mg/kg, per os, p.o.) was tested for anxiolytic-like potential in three mouse models: holeboard, stress-induced hyperthermia (SIH) and four-plate. In the holeboard model saredutant (30 mg/kg) showed a trend to increase head dipping without affecting general activity. In the SIH model, saredutant demonstrated a significant reduction in stress-induced temperature at 30 mg/kg, while the number of punished crossings in the four-plate was increased at all doses tested (3-30 mg/kg). While chlordiazepoxide (CDP) demonstrated anxiolytic-like effects in these models, the adverse side effects of benzodiazepines, such as sedation, disinhibition and cognitive deficits are well-documented. Saredutant produced no detrimental effect in three models of cognition: Morris Water Maze (MWM) in rats, spontaneous alternation in a Y-maze in mice and novel objection recognition in mice. In contrast, the benzodiazepine, diazepam (DZM), produced cognitive impairments. NK2 receptor antagonists like saredutant may therefore yield beneficial effects for mood disorders without the adverse effects of current treatments.     

Protective effect of Withania somnifera dunal root extract against protracted social isolation induced behavior in rats

This study investigated the effect of Withania somnifera Dunal (WS) root extract and diazepam in social isolation induced behavior such as anxiety and depression in rats. Rats were isolated for 6 weeks and the assessment of changed behavior were done on elevated plus maze (EPM) and forced swim test (FST). Isolation reared rats spent less time into the open arms on EPM and significantly increased immobility time in FST compared to group housed rats. WS (100, 200 or 500 mg/kg, oral) and diazepam (1 or 2 mg/kg, ip) dose dependently increased the time spent and entries into the open arms on EPM test and showed the anxiolytic activity. Subeffective dose of WS (50 mg/kg, oral) potentiated the anxiolytic action of diazepam (0.5, 1 or 2 mg/kg, ip). WS (100, 200 or 500 mg/kg, oral) also reduced the immobility time in FST, thus showed antidepressant effect in both group housed and social isolates. The investigations support the use of WS as a mood stabilizer in socially isolation behavior in Ayurveda.     

Saredutant, an NK2 receptor antagonist, has both antidepressant-like effects and synergizes with desipramine in an animal model of depression

Previous work established that saredutant, an NK2 receptor antagonist, has antidepressant and anxiolytic-antistress effects in a variety of rodent models. The purpose of the present investigation was two-fold: to confirm the antidepressant-like effects of saredutant using a genetic animal model of depression, the Flinders Sensitive Line (FSL) rat, and to assess whether saredutant might synergize with desipramine to produce antidepressant-like effects at doses not seen with the individual compounds. For the main study the FSL rats and the control Flinders Resistant Line (FRL) rats were treated with various doses of saredutant (1, 3, and 10 mg/kg in FSL, 3 mg/kg in the FRL), the tricyclic desipramine (5 mg/kg) as a positive control, or vehicle for 14 consecutive days and then tested in the social interaction and forced swim tests about 22 h later. For the synergism study, the FSL rats were treated with subeffective doses of saredutant (1 mg/kg) or desipramine (2.5 mg/kg) or both for 14 consecutive days and then the behavior tests were performed. Saredutant, like desipramine, increased social interaction (at 10 mg/kg) reduced immobility (at 3 and 10 mg/kg), and had no effect on locomotor activity in the FSL rats, but did not affect any of these variables in the FRL rat. Neither saredutant (1 mg/kg) nor desipramine (2.5 mg/kg) affected any variable by themselves; however, their combination significantly lowered swim test immobility. These findings confirm the antidepressant-like effects of saredutant in a genetic animal model of depression. Moreover, they suggest that saredutant might also act as an add-on therapy for individuals who are not fully responding to their antidepressant treatment.     

Selective blockade of NK2 or NK3 receptors produces anxiolytic- and antidepressant-like effects in gerbils

There is a growing interest in the potential anxiolytic- and antidepressant-like effects of compounds that target neurokinin receptors. Since the structure and the pharmacology of the human neurokinin receptor resembles that of gerbils, rather than that of mice or rats, we decided to investigate the anxiolytic- and /or antidepressant-like effects of NK1 (SSR240600), NK2 (saredutant) and NK3 (osanetant) receptor antagonists in gerbils. It was found that saredutant (3-10 mg/kg, p.o.) and osanetant (3-10 mg/kg, p.o.) produced anxiolytic-like effects in the gerbil social interaction test. These effects were similar to those obtained with the V1b receptor antagonist SSR149415 (3-10 mg/kg, p.o.), diazepam (1 mg/kg, p.o.) and buspirone (10 mg/kg, p.o.). Fluoxetine and SSR240600 were devoid of effects in this test. In the tonic immobility test in gerbils, saredutant (5-10 mg/kg, i.p.) and osanetant (5-10 mg/kg, i.p.) produced similar effects to those observed with fluoxetine (7.5-15 mg/kg, i.p.), SSR149415 (10-30 mg/kg, p.o.) and buspirone (3 mg/kg, i.p.). Diazepam and SSR240600 were inactive in this paradigm. In conclusion, the present study indicates further that NK2 and NK3 receptor antagonists may have therapeutic potential in the clinical management of anxiety and depression.     

Effects of acute or chronic administration of substituted benzamides in experimental models of depression in rats

The effects of substituted benzamides, sulpiride and raclopride on experimental models of depression were studied in male rats after acute or chronic administration in comparison to those of the classical antidepressant, clomipramine. In contrast to clomipramine (50 mg/kg), acute doses of sulpiride or raclopride (1 or 5 mg/kg) failed to change the behavioral response of animals tested in the despair (constrained swim) test or in the model of reserpine-induced changes in the open field behavior. These doses also did not modify the grooming response of rats exposed to a novel environment. Sulpiride or raclopride 10 mg/kg increased the immobility time in the despair test and reduced novelty-induced grooming. The repeated injection for 21 days of sulpiride or raclopride (1 or 5 mg/kg, but not 10 mg/kg) induced a reduction of the immobility period during the constrained swim test similar to that following the chronic treatment with clomipramine 50 mg/kg. This appeared to be a clear-cut reversed dose–response relationship for both substituted benzamides, being the dose potency 1 mg/kg>5 mg/kg>10 mg/kg. Raclopride was more potent than sulpiride in this respect. Furthermore, like clomipramine, sulpiride (1 or 5 mg/kg) and raclopride (1 mg/kg) antagonized reserpine-induced changes in the open field behavior and enhanced novelty-induced grooming. These results indicate that, in contrast to acute injection, repeated administration of small doses of the substituted benzamides, sulpiride or raclopride induce an effect similar to that of the classical antidepressant, clomipramine. The reverse dose–response relationship suggests that these drugs in small doses act on presynaptic dopamine D₂ receptors. This may be consistent with a postsynaptic action of greater doses that exert sedative effects and increase immobility time in the despair test.     

Anxiolytic and antidepressant-like effects of the hydroalcoholic extract from Aloysia polystachya in rats

Behavioral effects of a hydroalcoholic extract from leaves of Aloysia polystachya (Griseb.) Moldenke (Verbenaceae) were studied in female Sprague-Dawley rats. The extract was administered intraperitoneally and its effects on spontaneous motor activity (total motility, locomotion, rearing and grooming behavior) were monitored. Anxiolytic-like properties were studied in the elevated plus-maze (EPM) test and the possible antidepressant-like actions were evaluated in the forced swimming test (FST). The results revealed that high doses of the extract (25 and 50 mg/kg, i.p.) caused a significant decrease in total motility, locomotion, rearing and grooming behavior. All doses injected (from 1.56 to 50 mg/kg) increased the exploration of the EPM open arms in a similar way to that of diazepam (1 mg/kg, i.p.). In the FST, the extract (12.5, 25 and 50 mg/kg) was as effective as fluoxetine (10 mg/kg, i.p.) and imipramine (12.5 mg/kg, i.p.) in reducing immobility, along with a significant increase in swimming and climbing, respectively. These results suggest that some of the components of the hydroalcoholic extract of A. polystachya, such as thujone and carvone among others, may have sedative, anxiolytic and antidepressant-like properties which deserve further investigation.     

Effects of rolipram on the elevated plus-maze test in rats: a preliminary study.

The objective of the present study was to assess the behavioural effects of rolipram, a specific cAMP phosphodiesterase (PDE4) inhibitor, in the elevated plus-maze (EPM) test in rats. Results showed that rolipram at the highest dose tested (0.1 mg/kg) increased the percentage of both time spent and entries into open arms, although a decrease of locomotor activity in the EPM test was also observed. In contrast, diazepam (3.0 mg/kg) exhibited the typical profile of an anxiolytic in the EPM test, increasing the percentage of time spent and entries into open arms as well as locomotor activity. A posterior statistical analysis, however, established that the effects of both rolipram and diazepam on parameters denoting anxiolytic-like activity were statistically independent from those reflecting locomotor activity reduction. Furthermore, the effects of both rolipram and diazepam were shown to be distinct from those exhibited by tricyclic antidepressant imipramine which did not show any anxiolytic-like effects in the EPM test, although a reduction of locomotor activity was also detected. Although these preliminary results suggest that rolipram may have some anxiolytic-like properties on the EPM test in rats, such an interpretation should be taken cautiously due to the observed effects on locomotor activity, which could complicate the interpretation of results from rolipram and other PDE4 inhibitors in the current test and in other anxiety animal models.     

Behavioral effects of the beta3 adrenoceptor agonist SR58611A: is it the putative prototype of a new class of antidepressant/anxiolytic drugs?

A large body of evidence corroborates the notion that deficiencies of serotonergic system are likely involved in the pathogenesis of both depression and anxiety. Activation of beta(3) adrenoceptors has been shown to increase brain tryptophan content suggesting an elevation of brain serotonin (5HT) synthesis. SR58611A is a selective beta(3) adrenergic agent possessing a profile of antidepressant activity in routine rodents' experimental models of depression. The present study was undertaken to evaluate in rodents the antidepressant properties of SR58611A and to assess its putative anxiolytic value in experimental models of depression and anxiety. Compared to the control group, SR58611A (0.1, 1, 5 or 10 mg/kg) caused a dose-dependent reduction in immobility of Wistar male rats in the forced swim test. The maximum dose appeared to be equivalent to an effective dose of clomipramine (50 mg/kg). In addition, acute injection of SR58611A induced in rats a dose-dependent decrease in grooming response to a novel environment (novelty-induced grooming test). For any dose, the effect was lower than that of diazepam (1 mg/kg). Chronic treatment with SR58611A resulted also in an increased social interaction time in the social interaction test without affecting motor activity of rats. Furthermore, similarly to diazepam a chronic treatment with the highest doses of SR58611A was followed by increased exploratory behavior in Swiss male mice exposed to the elevated plus maze test. These effects are mediated by beta(3) adrenoceptors since i.p. pretreatment with the selective beta(3) adrenoceptor antagonist SR59230A (5 mg/kg) blocked the effects of SR58611A. Finally, also the 5HT antagonist methysergide (2 mg/kg) prevented the antidepressant and anxiolytic-like activity of SR58611A indicating that 5HT transmission is strictly involved in its action.     

Evaluation of the anxiolytic-like effects of clomipramine in two rat strains with different anxiety vulnerability (Wistar and Wistar-Kyoto rats): participation of 5-HT1A receptors

The main aim of this study was to evaluate the anxiolytic-like effects of the serotonergic antidepressant, clomipramine (0.6-5.0 mg/kg), and the 5-HT1A agonist, (±)8-hydroxy-2-(di-n)-propil-aminotetraline hydrobromide (8-OH-DPAT; 0.01-0.5 mg/kg), in two strains of rat with different anxiety vulnerability: Wistar-Kyoto (WKY; with trait anxiety) and Wistar rats (control strain). The anxiety model used was the burying behavior test; decreases in burying, grooming of the snout, and freezing were interpreted as a reduction of anxiety-like levels. A second objective was to explore the participation of 5-HT1A receptors in the effects of clomipramine and 8-OH-DPAT. Behavior in the burying behavior test was strain dependent. In addition to the burying behavior, WKY rats showed high levels of freezing and grooming of the snout. Clomipramine and 8-OH-DPAT decreased the burying behavior in both strains of rats through a direct interaction with the 5-HT1A receptor. 8-OH-DPAT decreased freezing behavior in both strains through a mechanism that was not related to 5-HT1A receptors. Finally, clomipramine was able to block freezing and grooming behaviors only in WKY rats. In conclusion, strains with different anxiety vulnerability express different behavioral responses toward the same aversive stimulus, and the anxiolytic-like effects of clomipramine and 8-OH-DPAT are both behavior and strain dependent.     

Effect of a tachykinin NK(2) receptor antagonist, nepadutant, on cardiovascular and gastrointestinal function in rats and dogs

The effect of the tachykinin NK(2) receptor antagonist, nepadutant (MEN 11420 or (c[[(beta-D-GlcNAc)Asn-Asp-Trp-Phe-Dpr-Leu]c(2beta-5beta)])) was assessed on cardiovascular function (unanaesthetized rats and anaesthetized dogs) and gastrointestinal motor activity (fasted unanaesthetized dogs). The selective tachykinin NK(2) receptor agonist, [betaAla(8)]neurokinin A (4-10), up to 100 nmol/kg, i.v., did not produce changes on mean blood pressure or heart rate in unanaesthetized rats. Nepadutant did not affect blood pressure and heart rate up to 10 micromol/kg, whereas saredutant (SR 48968 or ((S)-N-methyl-N[4-(4-acetylamino-4-phenyl piperidino)-2-(3,4-dichlorophenyl)butyl] benzamide), a nonpeptide antagonist, produced a transient reduction of mean blood pressure and heart rate. Nepadutant up to 20 micromol/kg, i.v. neither caused changes of cardiovascular and respiratory parameters in anaesthetized dogs nor induced any changes in left ventricular systolic pressure, left ventricular dP/dt or of electrocardiogram (lead II) waveforms. Intravenous administration of neurokinin A (9 nmol/kg) in unanaesthetized dogs stimulated gastrointestinal motility for 20-25 min. Nepadutant at 0.1 micromol/kg suppressed the stimulant effects of neurokinin A but, up to a dose of 10 micromol/kg, did not produce significant changes in the basal migrating motor complexes. We conclude that tachykinin NK(2) receptors do not participate in the physiologic regulation of resting cardiovascular and respiratory functions and that they do not regulate the fasted pattern of gastrointestinal motility. The cardiovascular changes induced by the nonpeptide tachykinin NK(2) receptor antagonist, saredutant, likely arise from nonspecific effects unrelated to tachykinin NK(2) receptor blockade.     

The β3 adrenoceptor agonist,amibegron (SR58611A) counteracts stress-induced behavioral and neurochemical changes

These experiments were made to study the mechanisms underlying the antidepressant-like effects of the β₃ adrenoceptor agonist amibegron (SR58611A). To this purpose, the expression levels of the hippocampal cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB), brain-derived neurotrophic factor (BDNF), B-cell lymphoma-2 (Bcl-2) and Bax proteins were assessed, by using western blot analysis, in rats tested in the forced swim test (FST). Under basal conditions (no previous exposure to stressors), different groups of male Wistar rats received acutely or repeatedly (once/day for 7 days) intraperitoneal (i.p.) injections of amibegron (1, 5 and 10 mg/kg), the tricyclic antidepressant (TCA) clomipramine (50 mg/kg), the selective serotonin reuptake inhibitor (SSRI) citalopram (15 mg/kg) or their vehicles. The influence of stress-related conditions was studied in rats subjected to acute (4 h) or repeated (4 h/day for 7 days) restraint stress, applied prior to the FST procedure. Compared to the control groups, both stressor procedures increased the immobility time in the FST and reduced hippocampal BDNF and Bcl-2/Bax ratio proteins expression, which were counteracted by amibegron (5 and 10 mg/kg) treatment. Opposite effects were found in the CREB expression, since it was lower after acute and higher after repeated stress procedure, respectively. Again, these effects were reversed by amibegron treatment. Different results were obtained in animals treated with clomipramine or citalopram. Hence, it is likely that the observed behavioral effects of amibegron could be due, at least in part, to its action on hippocampal expression of neurotrophic and/or anti-apoptotic factors, supporting the hypothesis that β₃ adrenoceptors may be a therapeutic target for the treatment of stress-related disorders.     

Effect of TV3326, a novel monoamine-oxidase cholinesterase inhibitor, in rat models of anxiety and depression

RATIONALE: A high incidence of depression is found in subjects with Alzheimer's disease (AD), in whom many antidepressants are contraindicated because they have anticholinergic activity. We have designed a new cholinesterase inhibitor TV3326 [( N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate] for the treatment of AD, which has neuroprotective activities and also blocks monoamine oxidase (MAO) A and B in the brain but not in the intestine after chronic administration. OBJECTIVES: To examine the antidepressant and anxiolytic potential of TV3326 in rats and compare them with those of its R isomer TV3279, which lacks MAO-inhibitory activity, and of amitriptyline and moclobemide. METHODS: Each of the drugs was administered orally, acutely or once daily for 2 weeks, and its effect was evaluated on the behavior of rats in the forced swim test (FST) and plus maze (EPM) test. RESULTS: Immobility in the FST was reduced by 56% after acute and chronic administration of amitriptyline (10 mg/kg) and by 42% after acute administration of moclobemide (20 mg/kg) and by 63% when this drug was given chronically. TV3326 (26 mg/kg) only reduced immobility (by 44%) when given chronically and inhibited brain MAO-A and -B by more than 66%. TV3279 had no significant effect in the FST. All the drugs except TV3326 increased anxiogenic activity in rats in EPM, as indicated by a more than 50% decrease in the time in open arms after chronic administration. CONCLUSIONS: TV3326 has potential antidepressant-like activity when given in a dose regimen that causes significant inhibition of brain MAO-A and -B. Together with its neuroprotective properties, this action could make TV3326 a potentially valuable drug for the treatment of dementia in patients with depression.     

Anticonflict effect of the glycineB receptor partial agonist, D-cycloserine, in rats. Pharmacological analysis

RATIONALE: Several studies have provided evidence that antagonists and partial agonists of glycine(B) receptors exhibit an anxiolytic-like activity in different animal models. OBJECTIVE: Using the conflict-drinking Vogel test in rats as a model, in the present study we examined the anxiolytic-like activity of D-cycloserine (DCS), a partial agonist of the glycine(B) site of the N-methyl-D-aspartate (NMDA) receptor complex. Diazepam was used as a reference drug. RESULTS: DCS (200 and 300 mg/kg) and diazepam (5 mg/kg) produced an anxiolytic-like effect in rats by increasing the number of shocks accepted. We also demonstrated that NMDA (15 mg/kg) reduced the anxiolytic-like activity of DCS (200 mg/kg), whereas glycine (800 mg/kg) and flumazenil (10 mg/kg) did not affect the anticonflict effect of DCS (200 mg/kg). The anticonflict effect of diazepam (5 mg/kg) was totally blocked by flumazenil (10 mg/kg). CONCLUSION: The obtained results have shown that DCS exhibits an anxiolytic-like activity which depends on NMDA receptors rather than on glycine(B) or benzodiazepine sites.     

Effects of the brain-penetrant and selective 5-HT6 receptor antagonist SB-399885 in animal models of anxiety and depression

The effects of a selective 5-HT(6) receptor antagonist, SB-399885 (N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide), were evaluated in behavioural tests sensitive to clinically effective anxiolytic- and antidepressant-compounds using diazepam and imipramine as reference drugs. In the Vogel conflict drinking test in rats, SB-399885 (1-3mg/kg i.p.) caused an anxiolytic-like activity comparable to that of diazepam (2.5-5mg/kg i.p.). An anxiolytic-like effect was also seen in the elevated plus-maze test in rats, where SB-399885 (0.3-3mg/kg i.p.) was slightly weaker than diazepam (2.5-5mg/kg i.p.). In the four-plate test in mice, SB-399885 (3-20mg/kg i.p.) showed an anxiolytic-like effect which was weaker than that produced by diazepam (2.5-5mg/kg i.p.). In the forced swim test in rats, SB-399885 (10mg/kg i.p.) significantly shortened the immobility time and the effect was stronger than that of imipramine (30mg/kg i.p.). In the forced swim test in mice, SB-399885 (20-30mg/kg i.p.) had an anti-immobility action, comparable to imipramine (30mg/kg i.p.) and also in the tail suspension test in mice, SB-399885 (10-30mg/kg i.p.) had an antidepressant-like effect, though was weaker than imipramine (10-20mg/kg i.p.). The tested 5-HT(6) antagonist (3-20mg/kg i.p.) shortened the walking time of rats in the open field test and, at a dose of 30mg/kg i.p. reduced the locomotor activity of mice. SB-399885 (in doses up to 30mg/kg i.p.) did not affect motor coordination in mice and rats tested in the rota-rod test. Such data indicate that the selective 5-HT(6) receptor antagonist SB-399885had specific effects, indicative of this compound's anxiolytic and antidepressant potential.     

Stressors affect the response of male and female rats to clomipramine in a model of behavioral despair (forced swim test)

Aim of the present study was to evaluate the effects of physical stressors (electric foot-shocks) on effect of the antidepressant drug, clomipramine and plasma corticosterone levels in male and female rats tested in a model of behavioral despair (forced swim test,). Male and female rats of the Wistar strain were injected with clomipramine (50 mg/kg, i.p.) or saline. A group of animals also received electric shocks of different intensity and duration of 24, 5 and 1 h before being subjected to forced swim test. At the end of behavioral procedures, vaginal smears were assessed in all female animals and data on immobility time were plotted according to the ovarian cycle phase. After decapitation, corticosterone plasma levels were measured by radioimmunoassay in both male and female rats. Application of mild shocks (5 ms, 0.1 mA) significantly reduced immobility time in forced swim test of untreated male rats and augmented clomipramine effect on this parameter. Moderate shocks of higher intensity or duration (5 ms, 1.0 mA) also resulted in decreased immobility time of untreated male rats, but in reduced effect of clomipramine treatment. Furthermore, application of severe shocks (10 ms, 1.0 mA) increased the immobility time in untreated animals and totally abolished clomipramine effect in forced swim test. Untreated non-shocked female rats in proestrous and estrous phases exhibited a longer immobility time as compared to diestrous animals. Immobility time appeared to be generally higher when mild, moderate or severe shocks were applied prior to behavioral testing in proestrous and estrous animals, while the behavioral response of diestrous and metestrous animals did not differ from that of controls. Clomipramine effect on immobility time was generally reduced by application of shocks of every strengths. Stress-induced plasma corticosterone levels surge correlated with intensity and duration of shocks in both male and female rats, but clomipramine treatment generally blunted the hormonal response. However, severe shocks were followed by a surge of plasma corticosterone levels in both male and female clomipramine-treated rats.

These results demonstrate that duration and intensity of stressful stimuli may deeply affect the behavioral response of rats in forced swim test and influence clomipramine effect in this behavioral model depending on gender-based variables, probably of the hormonal type. Plasma corticosterone levels correlate with the behavioral response to clomipramine treatment suggesting that reactivity of hypothalamus–pituitary–adrenal axis to stress may be involved in the antidepressant effect of this drug.     

Beneficial effect of Hypericum perforatum on depression and anxiety in a type 2 diabetic rat model

Recent studies have revealed diverse therapeutically interesting pharmacological properties of a standardized Hypericum perforatum extract (HpE) potentially useful for treatments of patients with metabolic and psychiatric disorders. Consequently, the presented experiments were designed to test usefulness of the extract for the treatment of comorbid conditions of mood disturbances and anxiety in diabetic rats. Type 2 diabetes mellitus was induced in overnight fasted rats by a single i.p. injection of streptozotocin (STZ; 65 mg/kg), 15 min after an i.p. injection of nicotinamide (120 mg/kg). HpE was administered orally (100 and 200 mg/kg b.w..) to diabetic animals for 14 days. Anxiolytic activity was evaluated using open-field exploration test (OFT) and elevated plus maze (EPM) test. Antidepressant activity was assessed using Porsolt's forced swim test (FST). Fasting blood glucose levels in different groups were analyzed on the 14th day. Diabetic rats showed significant increase in anxiety in OFT and EPM compared to non diabetic normal control rats. Diabetic rats treated with HpE have shown significant anxiolytic activity in OFT and EPM test. In FST, immobility period of vehicle treated diabetic rats was significantly increased (p < 0.05) compared to normal control rats. Treatment with HpE significantly decreased (p < 0.001) immobility period compared to vehicle treated diabetic control rats. HpE treatment significantly reduced elevated blood glucose levels in diabetic rats. The presented observations strongly suggest that HpE could be suitable alternative therapeutic option for prevention, as well as treatment, of comorbidities caused by, or associated with, depression, anxiety and diabetes.     

Antidepressant-like effect of asiaticoside in mice

In the present study, the potential antidepressant properties of asiaticoside were investigated in male mice in three tests -- splash test in the unpredictable chronic mild stress (CMS) model, tail suspension test (TST), forced swimming test (FST) -- with clomipramine being a positive control. In the splash test, asiaticoside (10 mg/kg, PO) and clomipramine (50 mg/kg, PO) significantly augmented the frequency of grooming behavior in stressed mice. In the tail suspension test, asiaticoside (10, 20 mg/kg, PO) and clomipramine (50 mg/kg, PO) significantly decreased immobility time. In the forced swimming test, asiaticoside (10, 20 mg/kg, PO) and clomipramine (50 mg/kg, PO) significantly decreased immobility time. These results suggest that asiaticoside may have antidepressant-like action.     

Anxiolytic-Like Effect of baicalin and its additivity with other anxiolytics

Baicalin, a naturally occurring flavonoid, was previously reported to exert anxiolytic-like effects in the Vogel conflict test. In the present study, the anxiolytic effects of baicalin alone and in combination with other anxiolytics were tested in mice using the elevated plus-maze (EPM). Baicalin treatment (7.5 - 30 mg/kg) significantly increased entries into and time spent in open arms, indicative of an anxiolytic-like effect. Motor-depressive and myorelaxant side effects commonly associated with anxiolytics were not observed with baicalin at effective anxiolytic doses in the hole-board and horizontal wire tests, respectively. Co-administration of baicalin (3.75 mg/kg) with dl-tetrahydropalmatine ( dl-THP; 0.25 mg/kg), an anxiolytic-hypnotic alkaloid, both at sub-effective doses, induced an additive effect resulting in considerable anxiolysis. Similarly, an additive anxiolytic-like effect was observed with baicalin (3.75 mg/kg) and diazepam (DZ; 0.5 mg/kg). Results obtained from this study demonstrate the potential of baicalin as a candidate anxiolytic and its possible application in multidrug therapy. Abbreviations. BZS:benzodiazepine-binding site EPM:elevated plus-maze DZ:diazepam GABA (A):type A gamma-aminobutyric acid dl-THP: dl-tetrahydropalmatine.