Imidacloprid insecticide exposure induces stress and disrupts glucose homeostasis in male rats

In the present study, we evaluated the stress response in adult rats who were administered imidacloprid (IMI) orally in two doses (0.5 and 1.0 mg/kg bw for 60 days). It led to an alteration in the levels of cortisone and catecholamines and induced behavioral deficits, particularly in the animals exposed to the dose of 1.0 mg/kg. IMI was further analyzed for the effect on glucose homeostasis in developing and adult rats at a dose of 1.0 mg/kg bw where it elicited a hyperglycemic effect. Moreover, we observed an alteration in the mRNA levels of glucose transporters. Histopathological and immunohistochemical data displayed structural perturbations in pancreatic tissue with a decline in the expression of insulin and GLUT4, particularly in the developing rats. Collectively, IMI treatment resulted in stress represented by behavioral and biochemical changes, particularly at a dose of 1.0 mg/kg bw. Moreover, IMI perturbed the glucose regulation through hyperglycemic activity in both developing and adult rats, an observation clearly evident in the developing rats.     

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.     

The effects of ifenprodil on the activity of antidepressant drugs in the forced swim test in mice

BackgroundAccording to reports in the literature, more than 30% of depressive patients fail to achieve remission. Therapy with the conventional antidepressant drugs may induce the serious adverse reactions. Moreover, its benefits may be seen at least 2–4 weeks after the first dose. Therefore, the alternative strategies for prevention and treatment of depression are sought. The main aim of our study was to assess the effects of ifenprodil given at a non-active dose (10 mg/kg) on the activity of antidepressant agents from diverse pharmacological groups.MethodsThe antidepressant-like effect was assessed by the forced swim test in mice.ResultsIfenprodil potentiated the antidepressant-like effect of imipramine (15 mg/kg) and fluoxetine (5 mg/kg) while did not reduce the immobility time of animals which simultaneously received reboxetine (2.5 mg/kg) or tianeptine (15 mg/kg).ConclusionThe concomitant administration of certain commonly prescribed antidepressant drugs that affect the serotonergic neurotransmission (i.e., typical tricyclic antidepressants and selective serotonin reuptake inhibitors) with a negative modulator selectively binding to the GluN1/N2B subunits of the NMDA receptor complex (i.e., ifenprodil) may induce a more pronounced antidepressant-like effect than monotherapy. However, these findings still need to be confirmed in further experiments.     

Oral treatment with ACCUTANE does not increase measures of anhedonia or depression in rats

Reports of depression and/or suicide with ACCUTANE^® (13-cis-retinoic acid (13-cis-RA)) use prompted studies in a rodent model to ascertain its potential effects. Previously, there were no effects on measures of anhedonia (intake of a saccharin-flavored solution) and depression (forced swim test (FST) behaviors) in rats treated with 7.5 or 22.5 mg/kg 13-cis-RA [S.A. Ferguson, F.J. Cisneros, B. Gough, J.P. Hanig, K.J. Berry, Chronic oral treatment with 13-cis-retinoic acid (isotretinoin) or all-trans-retinoic acid does not alter depression-like behaviors in rats, Toxicol. Sci. 87 (2005) 451–459.]. Here, dose and temporal thresholds were investigated by increasing the maximum 13-cis-RA dose to 30 mg/kg, extending treatment duration, and measuring behaviors repeatedly. Beginning on post-natal day 59, male and female Sprague–Dawley rats were gavaged with soybean oil, 7.5 or 30 mg/kg/day of 13-cis-RA for approximately 19 weeks. FST behaviors were measured after 24, 82, and 131 treatment days and saccharin intake (0.03% solution) was measured at baseline and after 14, 35, 56, and 112 treatment days. Body weight and food intake were not altered by treatment. FST durations of swim, climb/struggle, and immobility were unaffected by 13-cis-RA at any time during treatment. More males than females required “rescue” in the FST but there was no treatment effect on number of rats requiring early removal. 13-cis-RA treatment had no effects on saccharin intake at any time. Given that the 7.5 mg/kg dose produces serum levels which parallel those of humans [S.A. Ferguson, P.H. Siitonen, F.J. Cisneros, B. Gough, J.F. Young, Steady state pharmacokinetics of oral treatment with 13-cis-retinoic acid or all-trans-retinoic acid in male and female adult rats, Basic Clin. Pharmacol. Toxicol 98 (2006) 582–587.], these results are quite relevant. Combined with previous results, these results provide further evidence that 13-cis-RA does not produce behavioral alterations indicative of depression in rats.     

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.     

Involvement of α-MSH in the social isolation induced anxiety- and depression-like behaviors in rat

Although physical isolation of rats is known to cause anxiety- and depression-like symptoms, the underlying mechanisms are not fully understood. We have attempted to define the role of endogenous melanocortins (MC) in the manifestation of these symptoms. Weaning rats were socially isolated for 6 weeks and subjected to behavioral paradigms like elevated plus maze (EPM), social interaction, and forced swim test (FST). While socially isolated rats spent less time in social interaction, and showed significantly decreased activity in the open arms of the EPM, the immobility time in FST was significantly increased thus reflecting anxiety- and depression-like phenotypes. Intracerebroventricular injection of HS014 (5 or 10 nmol/rat), selective antagonist of MC4 receptors, attenuated these symptoms. This suggested the involvement of endogenous alpha-melanocyte stimulating hormone (α-MSH) in anxiety and depression. With a view to determining the neuroanatomical substrates in which the endogenous α-MSH may process the related information, profile of the peptide in paraventricular (PVN), arcuate (ARC), dorsomedial hypothalamic-dorsal (DMNd) and -ventral (DMNv) nuclei, and central nucleus of amygdala (CeA) was investigated with immunohistochemistry. While social isolation significantly reduced α-MSH-immunoreactivity profile in all these components, re-socialization of the socially isolated rats, over a period of 72 h, resulted in full recovery of the α-MSH-immunoreactivity profile; the symptoms of anxiety- and depression-like behaviors were also fully attenuated. We suggest that α-MSH in the PVN, ARC, DMNd, DMNv and CeA, acting via MC4 receptors, are involved in manifestation of affective disorders like anxiety and depression.     

Inter-individual differences in novelty-seeking behavior in rats predict differential responses to desipramine in the forced swim test

RATIONALE: Antidepressant medications are effective only in a subpopulation of patients with depression, and some patients respond to certain drugs, but not others. The biological bases for these clinical observations remain unexplained. OBJECTIVE: To investigate individual differences in response to antidepressants, we have examined the effects of the norepinephrine reuptake inhibitor desipramine (DMI) and the selective serotonin reutake inhibitor fluoxetine (FLU) in the forced swim test (FST) in rats that differ in their emotional behavior. METHODS: As response to novelty correlates with numerous other measures of emotionality and substance abuse, we contrasted animals that are high responders (HR) in a novel environment with animals that are low responders (LR) and asked whether the two groups exhibit differential responses to DMI (10mg/kg) and FLU (20mg/kg). RESULTS: At the behavioral level, DMI caused a significant decrease in immobility in LR animals only, while FLU caused a significant reduction in immobility in both groups. Moreover, at the neural level, DMI treatment led to a decrease in FST-induced c-fos messenger RNA levels in medial prefrontal cortex (PFC) and paraventricular nucleus of the hypothalamus (PVN) in LR but not HR animals. CONCLUSIONS: Taken together, our results suggest that the HR-LR model is a useful tool to investigate individual differences in responses to norepinephrine reuptake inhibitors (NRIs) and that a differential activation of PFC and/or PVN could underlie some of the inter-individual differences in the efficacy of NRIs.     

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.     

Effects of serotonin (5-HT)2 receptor ligands on depression-like behavior during nicotine withdrawal

A pronounced withdrawal syndrome including depressed mood prevents cigarette smoking cessation. We tested if blockade or activation of serotonin (5-HT)₂ receptors affected the time of immobility (as an indirect measure of depression-like behavior) in naïve animals and in those withdrawn from chronic nicotine in the forced swim test (FST). The antidepressant imipramine was used as a control. In the FST, the selective 5-HT_2A receptor antagonist M100,907 (1-2 mg/kg, but not 0.5 mg/kg), the selective 5-HT_2C receptor antagonist SB 242,084 (0.3-1 mg/kg, but not 0.1 mg/kg), the 5-HT_2C receptor agonists Ro 60-0175 (10 mg/kg, but not 3 mg/kg) and WAY 163,909 (1.5-10 mg/kg, but not 0.75 mg/kg) as well as imipramine (30 mg/kg, but not 15 mg/kg) decreased the immobility time while the non-selective 5-HT₂ receptor agonist DOI (0.1-1 mg/kg) was inactive in naïve rats. We found an increase in immobility time in rats that were withdrawn from nicotine exposure after 5 days of chronic nicotine treatment. This effect increased from day 1 until day 10 following withdrawal of nicotine, with maximal withdrawal effects on day 3. M100,907 (1 mg/kg), SB 242,084 (0.3 mg/kg), Ro 60-0175 (3 mg/kg), WAY 163,909 (0.75-1.5 mg/kg) and imipramine (15-30 mg/kg) shortened the immobility time in rats that had been removed from nicotine exposure for 3 days. Locomotor activity studies indicated that the effects of SB 242,084 might have been non-specific, as we noticed enhanced basal locomotion in naïve rats. This data set demonstrates that 5-HT_2A receptor antagonist and 5-HT_2C receptor agonists exhibited effects similar to antidepressant drugs and abolished the depression-like effects in nicotine-withdrawn rats. These drugs should be considered as adjuncts to smoking cessation therapy, to ameliorate abstinence-induced depressive symptoms.     

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.     

Neurochemical responses to antidepressants in the prefrontal cortex of mice and their efficacy in preclinical models of anxiety-like and depression-like behavior: a comparative and correlational study

Rational Marble burying and forced swimming behavior are widely used and sensitive tests for identifying clinically effective antidepressant drugs, although the underlying neurobiology of these behaviors is not fully elucidated. Objectives The objective of this study was to determine the relationship between the behavioral effects of antidepressant drugs and their ability to modulate extracellular neurotransmitter levels in the prefrontal cortex. Materials and methods The effects of fluoxetine, fluvoxamine, citalopram, imipramine, and desipramine (0 to 60 mg/kg by oral gavage, except fluoxetine at 0 to 40 mg/kg) were studied independently in CD-1 mice in the marble-burying task, forced swim task and on extracellular concentrations of serotonin, norepinephrine, and dopamine in the prefrontal cortex by freely moving microdialysis. Results Fluvoxamine, fluoxetine, and citalopram all suppressed marble-burying behavior, but produced no change in immobility time in the forced swim test. In contrast, imipramine and desipramine suppressed both marble-burying behavior and increased swimming time in the forced swim test, although desipramine mildly suppressed locomotor activity at the maximal dose. Fluvoxamine, fluoxetine, and citalopram all increased extracellular levels of cortical serotonin. Desipramine and imipramine increased extracellular dopamine levels. Fluoxetine, desipramine, and imipramine increased extracellular norepinephrine levels. Correlational analysis revealed a positive correlation between efficacy of drugs in the forced swim test and cortical extracellular dopamine levels, whereas a positive correlation was found between efficacy in the marble-burying test and extracellular serotonin levels. Conclusions Although marble burying and forced swimming behavior have strong predictive validity in tests of antidepressant action, each assay appears to be underpinned by entirely different neurochemical systems.     

A stimulatory effect of intraaccumbens injections of noradrenaline on the behavior of rats in the forced swim test

Intraaccumbens injections of catecholamines noradrenaline and dopamine, though not of serotonin, stimulated locomotion by rats in an open field, 10–15 min later. Similar effects were observed 5 min after microinjection of apomorphine whereas clonidine only attenuated locomotor activity. On the other hand, intraaccumbens administration of phenylephrine, isoproterenol and quipazine, in doses similar to an effective dose of noradrenaline, did not alter rat open field behavior. The escape-directed activity of rats in the forced swim test (FST) was stimulated 5 min after local administration of noradrenaline, phenylephrine, isoproterenol or apomorphine only. No effects in the FST were observed 15 min after noradrenaline injection or after intracaudate noradrenaline administration. The stimulatory effects of intraaccumbens noradrenaline injection in the FST were antagonized by the local pretreatment of rats with phentolamine, though not with propranolol. Accordingly, it is possible to conclude that both catecholamines, but not serotonin, play complex and probably distinct roles within the nucleus accumbens in the stimulation of activity by rats in the FST and the open field test.     

Nerve growth factor (NGF) has novel antidepressant-like properties in rats

Nerve growth factor, a neurotrophin, may have other functions, including a role in depressive disorders. The present study sought to determine whether NGF would (1) have antidepressant-like effects and (2) behave similarly to or differently from other well-recognized antidepressants. Over a broad dose-range, NGF reduced the exaggerated swim test immobility exhibited by the Flinders Sensitive Line (FSL) rats, but at a standard dose of 40 ng/ml, it was not as effective as desipramine (DMI, 5 mg/kg). The low social interaction behavior and locomotor activity of the FSL rats were less affected by NGF than was the immobility. Acute treatment with NGF did not induce c-fos expression in brain regions known to be activated by other acute antidepressants. The fact that chronic treatment with DMI blunted the corticosterone response to fluoxetine was replicated in this study. However, chronic treatment with NGF did not alter this response. Similarly, chronic treatment with fluoxetine blunted 5-HT_1A and 5-HT_2A receptor-mediated responses, whereas chronic treatment with NGF was without effect. Thus, NGF has antidepressant-like effects but does not appear to have biochemical actions typical of other antidepressants.     

The effects of new sigma (σ) receptor ligands,PB190 and PB212, in the models predictive of antidepressant activity

BackgroundA number of σ receptor ligands have been demonstrated to possess antidepressant-like effect in some experimental paradigms (e.g. forced swim test, tail suspension test, olfactory bulbectomy model, conditioned fear stress). The objective of the present study was to find out whether PB190 and PB212, new σ₁ receptor ligands, show the effects in some models predictive of antidepressant activity.MethodsThe impact of PB190 and PB212 on the immobility time in the forced swim test (FST) and tail suspension test (TST) was assessed in C57BL/6J male mice. Extracellular bradykinin triggers a transient increase in intracellular calcium concentration by activating the phospholipase C/IP₃ pathway. The intracellular calcium concentration was estimated with the dual wavelength ratiometric probe Fura-2.ResultsIn the FST model, PB190 showed a moderate antidepressant-like effect (only in the dose of 3 mg/kg) which was enhanced by joint treatment with amantadine (AMA), 10 mg/kg (inactive per se). The decrease in the immobility time induced by the combined treatment with PB190 and AMA was counteracted by PB212 and by BD1047, a σ₁-receptor antagonist. The in vitro studies indicated that Ca²⁺-response was increased by 1 μM PB190, like by the σ₁-agonist (+)-pentazocine, while 1 μM PB212 behaved line σ₁-antagonist, BD1063. On the other hand, 100 μM PB190 negatively affected the Ca²⁺-response after bradykinin.ConclusionsThe obtained results: 1/indicated that in the in vivo conditions PB190 behaved as a σ₁-receptor agonist while PB212 counteracted its effect, confirming the in vitro data; 2/gave support to the hypothesis that σ₁-receptors might be one of possible mechanisms by which drugs induce antidepressant-like activity; 3/revealed that this effect may be potentiated by NMDA receptor antagonists, e.g. AMA.     

Long-term imipramine withdrawal induces a depressive-like behaviour in the forced swimming test

Chronic antidepressant treatments enhance dopaminergic neurotransmission in the mesolimbic dopamine system. We suggested that this potentiation might underlie both the antidepressant therapeutic effect and the antidepressant-induced switch from depression to mania. In a recent study we have shown a reversal of the imipramine-induced dopaminergic supersensitivity after 40 days of chronic imipramine withdrawal. We interpreted this result suggesting that the mood-switches observed in bipolar patients following antidepressant treatment and subsequent withdrawal, i.e. mania followed by rebound depression, might depend upon parallel changes in the mesolimbic dopamine system sensitivity. On this basis, one might predict a depressive-like behaviour after long-term interruption of a chronic treatment with imipramine. To test this hypothesis we examined the behaviour of rats treated with chronic imipramine 40 days after treatment interruption in an animal model of depression, the forced swimming test. The results show that animals treated with chronic imipramine, 40 days after treatment interruption, display a depressive-like behaviour in the forced swimming test, as indicated by their increased immobility with respect to the control group.     

Convulsant activity of a non-peptidic delta-opioid receptor agonist is not required for its antidepressant-like effects in Sprague-Dawley rats

Abstract Rationale. Non-peptidic δ-opioid receptor agonists possess antidepressant-like activity in the forced swim assay in the rat. These compounds have also previously been shown to possess convulsant properties in mice. Objective. The aim of the present study was to examine whether such convulsions occurred in rats and to investigate if δ-mediated convulsant activity was necessary for the mediation of δ-opioid agonist-induced antidepressant-like activity. Methods. The peripheral administration of δ-opioid receptor agonists to male Sprague-Dawley rats was followed by a period of observation for convulsant activity. Following this period and 60 min after δ-opioid agonist administration, rats were tested in the forced swim assay. Results. The non-peptidic δ-opioid receptor agonists (+)-4-[(R)-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyphenyl)methyl]-N,N-diethylbenzamide (SNC80) and (+)-4-[(R)-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide dihydrochloride [(+)BW373U86] both produced dose-dependent convulsant activity in rats and decreased immobility in the forced swim assay. The δ-opioid receptor antagonist naltrindole prevented the convulsant activity of (+)BW373U86 and its effects in the forced swim assay. This suggested a δ-opioid mechanism for both effects. Midazolam prevented convulsions but did not prevent activity in the forced swim assay. Rats tolerant to the convulsive effects of (+)BW373U86 still displayed antidepressant-like effects. Conclusion. δ-Mediated convulsions do occur in rats and can be prevented without affecting the δ-mediated effects in the forced swim assay. Therefore the convulsant activity of (+)BW373U86 and possibly other non-peptidic δ-agonists is not required for activity in the forced swim assay. Electronic Publication     

Forced swim test behavior in postpartum rats

This study was undertaken to determine whether depression-like behavior can be observed in gonadally intact females that have experienced normal pregnancy. When tested on the forced swim test (FST) on postpartum days 1-7, previously pregnant rats spent slightly more time immobile, significantly less time swimming and diving, and defecated more than virgin controls. Subchronic treatment with nomifensine (DA reuptake inhibitor, 2.5 mg/kg) but not sertraline (serotonin reuptake inhibitor, 10 mg/kg) or desipramine (norepinephrine reuptake inhibitor, 10 mg/kg) significantly decreased immobility on postpartum day 2. In rats pre-exposed to the FST in mid-pregnancy, neither subchronic nor chronic treatment with desipramine or sertraline decreased immobility on postpartum day 2; in contrast, chronic desipramine significantly decreased immobility in virgin controls. These results indicate that postpartum female rats, compared to virgin controls, show a reduction in some “active coping behaviors” but no significant increase in immobility when tested during the early postpartum period, unlike ovariectomized females that have undergone hormone-simulated pregnancy (HSP). Additionally, immobility that is increased by FST pre-exposure is not readily prevented by treatment with standard antidepressant medications in postpartum females. Depression-like behaviors previously observed in females that have undergone HSP may result from the more dramatic changes in estradiol, prolactin or corticosterone that occur during the early “postpartum” period, compared to the more subtle changes in these hormones that occur in actual postpartum females.     

The effects of CRF antagonists,antalarmin, CP154,526, LWH234, and R121919, in the forced swim test and on swim-induced increases in adrenocorticotropin in rats

Rationale Exposure to extreme stress has been suggested to produce long-term, detrimental alterations in the hypothalamic–pituitary–adrenal (HPA) axis leading to the development of mental disorders such as depression. Therefore, compounds that block the effects of stress hormones were investigated as potential therapeutics for depression.Objectives In the present study, we compared the potential antidepressant-like effects of four CRF antagonists, antalarmin, CP154,526, R121919, and LWH234 (at 3, 10, and 30 mg/kg i.p., 60 min prior to the forced swim test) and the corresponding effect on swim-induced HPA activation to better elucidate the relation between HPA activity and antidepressant activity.Methods The antidepressant-like effects of the CRF antagonists and known antidepressants were determined in the rat forced swim test, and blood samples were obtained before and after swimming for the evaluation of adrenocorticotropin-releasing hormone (ACTH) levels.Results Antalarmin, CP154,526, and R121919 did not produce antidepressant-like effects in the forced swim test although these compounds decreased swim-induced increases in ACTH to various extents. In contrast, LWH234 reduced immobility in the forced swim test, without altering the swim-stress-induced ACTH response. However, this compound antagonized restraint-induced ACTH release.Conclusions These data suggest that reducing stress-induced increases in HPA activity alone may not be sufficient to produce antidepressant-like activity; however, reductions in HPA activity may contribute to antidepressant actions of some treatments. In addition, it is proposed that CRF antagonists may alter differentially the HPA axis depending on the type of stressor used or behavioral measure evaluated.     

Effects of neuroleptics displaying antidepressant activity on behavior of rats in the forced swimming test

Levomepromazine, thioridazine and cis-chlorprothixene, neuroleptics with antidepressant activity, trans-chlorprothixene, the therapeutically inactive isomer of chlorprothixene, clozapine, an atypical neuroleptic, and imipramine, a classical antidepressant, were studied in the forced swimming test in rats after single or chronic administration. Levomepromazine (1.5 mg/kg), clozapine (2.5 and 5.0 mg/kg) and imipramine (10 mg/kg) after single administration, 1 hr before the test, shortened the period of the immobility. After chronic administration only imipramine (10 mg/kg orally, twice daily, for 10 days) diminished the immobility. Levomepromazine, thioridazine, cis-chlorprothixene and trans-chlorprothixene (1.5 mg, orally, twice daily, for 10 days), 15-18 hr after the last dose did not influence the immobility, although the behavioral parameters in the open field test were not depressed. It is concluded that the forced swimming test is not a suitable pharmacological model for revealing antidepressant activities of certain neuroleptics that are useful in treating certain forms of human depression.     

Effects of desipramine and alprazolam in the forced swim test in rats after long-lasting termination of chronic exposure to picrotoxin and pentylenetetrazol

Rats were treated for 5 weeks with three subconvulsant doses of picrotoxin (PTX) and pentylenetetrazol (PTZ) per week to induce a persistent reduction of the GABA_A receptor function which results in chemical kindling. Fifteen days after termination of this treatment schedule, the effect of desipramine (DMI) and alpraxolam (ALP) on immobility time in the forced swim test (FST) was evaluated. Chronic PTX and PTZ did not alter the immobility time. Acute PTX and PTZ reduced the immobility of rats chronically treated with vehicle but not of those exposed chronically to PTX and PTZ. Chronic PTX did not influence the anti-immobility effect of DMI, but blocked that of ALP. Chronic PTZ markedly potentiated the anti-immobility effect of DMI but blocked that of ALP. Concomitant administration of chlordiazepoxide prevented the effects of chronic PTX and PTZ. These findings suggest that a long-lasting reduction in GABA_A receptor function, unlike acute reduction, does not play an important role in the mobility of rats in the FST and in the anti-immobility effect of DMI while it blocks that of ALP.