Repeated quinpirole treatments produce neurochemical sensitization and associated behavioral changes in female hamsters

Rationale Repeated stimulation of dopaminergic pathways with dopamine receptor agonists can produce both neurochemical and behavioral sensitization.Objectives The present study was designed to examine whether repeated treatment with the D₂-like dopamine receptor agonist, quinpirole, would produce neurochemical sensitization of D₁ dopamine receptor-mediated processes and associated behavioral changes in female hamsters in a manner analogous to that previously used to sensitize heterologous dopamine signaling pathways in derived cell lines.Materials and methods Female hamsters received two injections of quinpirole (1.5 mg/kg) or saline each week for 7 weeks, during which time pouching behavior and body weight were monitored. Over the next 2 weeks, hamsters were tested for differences in prepulse inhibition of the acoustic startle response (PPI) and sexual behavior. Adenylate cyclase activation assays were then performed on dissected tissue from the nucleus accumbens and caudate–putamen.Results Repeated treatment with quinpirole increased pouching behavior and body weight and disrupted PPI. No changes in sexual activity in response to repeated quinpirole were found. Prior quinpirole treatment enhanced D₁ dopamine receptor-stimulated adenylate cyclase activity in the caudate–putamen that was blocked by co-incubation with the D₁ dopamine antagonist, SCH23390.Conclusions These results show that repeated activation of D₂-like receptors in vivo can produce changes in feeding behavior and sensory processing that is associated with sensitization of D₁ dopamine receptor-mediated signaling in the caudate–putamen.     

Juvenile rats in the forced-swim test model the human response to antidepressant treatment for pediatric depression

Rationale Currently, there are limited treatment options for major depressive disorder in children and adolescents compared to the options available for adults. Many effective treatments used for adult depression, such as the tricyclic antidepressants, lack efficacy when given to children and adolescents. Objective To more quickly identify compounds that could be effective for treating childhood and adolescent depression, a reliable preclinical animal behavioral test of antidepressant efficacy for pediatric depression is needed. The forced-swim test (FST) with juvenile rats was assessed to determine its reliability as a predictive model for pediatric depression. Materials and methods We adapted procedures from the adult FST to test 21-day-old juvenile rats. The 21-day-old animals were treated with three classes of antidepressant drugs before being assessed in the FST: the selective serotonin reuptake inhibitors escitalopram or fluoxetine; the tricyclic antidepressants desipramine or imipramine; and the monoamine oxidase inhibitor tranylcypromine. Results The 21-day-old rats showed dose-dependent changes in behaviors similar to those seen in adults when treated with escitalopram or fluoxetine. Tranylcypromine also decreased immobility in 21-day-old rats. Treatment with desipramine or imipramine, however, was not effective at reducing immobility in the 21-day-old rats. Conclusions The juvenile FST accurately predicts the efficacy of selective serotonin reuptake inhibitors and the lack of efficacy of tricyclic antidepressants in the treatment of depression in children and adolescents. This suggests that the FST using 21-day-old rats may help to develop better treatments for childhood and adolescent depression.     

Differential impact of audiogenic stressors on Lewis and Fischer rats: behavioral, neurochemical, and endocrine variations.

Exposure to intense noise can trigger a cascade of neuroendocrine events reminiscent of a stress response, including activation of the hypothalamic-pituitary-adrenocortical (HPA) axis. Using male Fischer and Lewis rats, which exhibit differences in their corticosterone response to stressors, this investigation assessed effects of acute noise exposure on neurochemical and neuroendocrine responses. In response to the noise exposure, Fischer rats displayed greater plasma adrenocorticotropin-releasing hormone (ACTH) and corticosterone responses than their Lewis counterparts. However, both strains responded with similar increases of plasma prolactin, suggesting that strain differences in the HPA response were not likely because of differences in noise perception. Post-mortem analyses revealed that noise exposure induced strain-dependent variations of corticotropin-releasing hormone (CRH) across several brain regions. These effects were evident irrespective of whether the rats were noise exposed in a familiar (home cage) or unfamiliar environment. In vivo, dynamic assessment of immunoreactive (ir)-CRH at the pituitary gland revealed that noise exposure elicited an immediate rise in ir-CRH among Fischer rats, relative to the delayed response in Lewis rats. Similarly, the rise in local interstitial corticosterone was more rapid and pronounced in Fischer rats. In contrast to these differences, ir-CRH released at the central nucleus of the amygdala (CeA) was gradual and protracted following noise exposure in both strains. Behaviorally, the Fischer rats displayed an active stress response, whereas the Lewis strain adopted freezing as a defensive style. The role of CRH in the genesis of the overall strain-dependent response to stressors is discussed.     

An organoselenium compound improves behavioral,endocrinal and neurochemical changes induced by corticosterone in mice

Rationale

3-(4-Fluorophenylselenyl)-2,5-diphenylselenophene (F-DPS) is a promising organoselenium compound that shows antidepressant-like properties related to interaction with the serotonergic system.

Objectives

In this study, a mouse model of anxiety/depressant-like behavior induced by long-term corticosterone treatment was used to evaluate behavioral, endocrinal, and neurochemical changes in mice and their possible modulation of F-DPS treatment.

Methods

Swiss mice were subjected to 4 weeks of corticosterone administration (20 μg/ml in drinking water) and a new therapeutic approach with F-DPS (0.1 mg/kg/day, intragastric route, during 1 week) was employed to modulate changes induced by corticosterone exposure.

Results

Treatment with corticosterone caused a significant depressant-like behavior in the forced swimming test and tail suspension test, which was accompanied by anxiety-like condition in the light–dark test and novelty suppressed-feeding; similarly to the classical antidepressant drug paroxetine, F-DPS treatment was effective in reversing these behavioral changes. Further, F-DPS normalized serum levels of corticosterone and adrenocorticotropic hormone, which were increased after corticosterone exposure. Corticosterone also significantly inhibited glutamate uptake in the prefrontal cortex of mice, whereas glutamate release was not modified. Besides normalizing glutamate uptake in the corticosterone-exposed mice, F-DPS promoted an inhibition of 5-HT uptake in the prefrontal cortex and hippocampus. In addition, hippocampal monoamine oxidase-A activity was also inhibited by F-DPS treatment.

Conclusions

These findings suggest a modulation of both serotonergic and glutamatergic systems by F-DPS after a long-term corticosterone exposure in mice, which may be involved in the antidepressant- and anxiolytic-like actions of this organoselenium compound.     

Total sleep deprivation decreases immobility in the forced-swim test.

Sleep deprivation can exert antidepressant effects in humans in less than 24 h, making it the fastest acting antidepressant treatment. However, it is rarely used clinically because the effect disappears once the subject goes back to sleep. An understanding of the neurobiological mechanisms underlying the antidepressant effect of sleep deprivation should help to develop new rapidly acting antidepressant strategies. In the present report, an animal model of depression (the forced-swim test) was used to determine whether the effects of total sleep deprivation parallel those obtained with antidepressant drugs. Using the disk-over-water method, rats deprived of sleep for 24 h exhibited increased swimming behavior when compared to cage control rats, mimicking the effects of serotonergic antidepressants. After 48 h, sleep-deprived rats exhibited increased swimming when compared to both cage control and stimulus control rats, demonstrating that the effect is due to sleep deprivation per se, and not to extraneous factors inherent in the sleep deprivation protocol (such as stress and movement). We believe that this paradigm can be used to study the neurobiological mechanisms of rapid antidepressant effects induced by sleep deprivation.     

Simultaneous analyses of the neurochemical and behavioral effects of the norepinephrine reuptake inhibitor reboxetine in a rat model of antidepressant action

Abstract Rationale. The forced swimming test (FST) is a rodent behavioral assay widely used to predict clinical efficacy of putative antidepressants. Few studies have examined the effects of the FST on neurotransmitter levels and how antidepressant drug treatment may alter neurotransmitter levels and behavior simultaneously during the performance of a stressful task. Objectives. The present study examined the role of norepinephrine in mediating active behaviors in the FST after treatment with reboxetine, a selective norepinephrine reuptake inhibitor. Methods. High-pressure liquid chromatography was used to analyze microdialysis samples collected from awake, freely moving rats before, during and after exposure to the FST. Reboxetine (10 mg/kg) was given three times over a 24-h period prior to the test swim. Behavioral responses, including immobility, swimming and climbing, were counted during the 5-min test on day 1 and day 2. Results. The first exposure to swim stress elicited a 65% increase in extracellular norepinephrine (NE). A second exposure on day 2 elicited a 52% increase of NE and a behavioral profile characterized by increased immobility and a reduction of active behaviors. A subchronic course (three injections over 24 h) of treatment with reboxetine between the two swim exposures resulted in antidepressant-like activity, i.e., decreased immobility and increased climbing behavior on day 2. A significantly greater increase in extracellular NE (112%) was observed in the group of animals that received reboxetine injections. Conclusions. Treatment with reboxetine in a schedule commonly used in the FST resulted in a potentiated noradrenergic response to the swim challenge concomitant with behavioral alterations consistent with antidepressant-like activity. Electronic Publication     

Neuropeptide S attenuates neuropathological, neurochemical and behavioral changes induced by the NMDA receptor antagonist MK-801

Neuropeptide S (NPS) and its cognate receptor were reported to mediate anxiolytic-like and arousal effects. NPS receptors are predominantly expressed in the brain, especially in limbic structures, including amygdala, olfactory nucleus, subiculum and retrosplenial cortex. In contrast, the NPS precursor is expressed in only a few brainstem nuclei where it is co-expressed with various excitatory transmitters, including glutamate. The current study investigates interactions of the NPS system with glutamatergic neurotransmission. It has been suggested that dysfunctions in glutamatergic neurotransmission via N-methyl-d-aspartate (NMDA) receptors might be involved in the pathophysiology of schizophrenia since NMDA receptor antagonists, such as MK-801, have been shown to induce psychotic-like behavior in humans and animal models. Also, MK-801 is known to produce histological changes such as cytoplasmic vacuoles in retrosplenial cortex neurons where NPS receptors are highly expressed. In this study we show that NPS is able to alleviate neuropathological, neurochemical and behavioral changes produced by NMDA receptor antagonists. NPS treatment attenuated MK-801-induced vacuolization in the rat retrosplenial cortex in a dose-dependent manner that can be blocked by an NPS receptor-selective antagonist. NPS also suppressed MK-801-induced increases of extracellular acetylcholine levels in the retrosplenial cortex. In the prepulse inhibition (PPI) assay, animals pretreated with NPS recovered significantly from MK-801-induced disruption of PPI. Our study suggests that NPS may have protective effects against the neurotoxic and behavioral changes produced by NMDA receptor antagonists and that NPS receptor agonists may elicit antipsychotic effects.     

Clonidine infusions into the locus coeruleus attenuate behavioral and neurochemical changes associated with naloxone-precipitated withdrawal

Clonidine, an alpha-2-adrenergic agonist, suppresses signs of opiate withdrawal in animals and in man. Electrical or chemical stimulation of the nucleus locus coeruleus (LC) increases noradrenergic activity and brain concentration of the noradrenergic metabolite MHPG, and produces many signs of opiate withdrawal. Thus, clonidine's ability to attenuate withdrawal might be due to the reduction of noradrenergic neuronal activity originating in the LC, but additional alpha-2-adrenergic receptors throughout the body and other mechanisms may also play a role. The present study explored the neuroanatomical and pharmacological selectivity of alpha-2-adrenergic receptors of the LC in the anti-withdrawal action of clonidine. Experiment 1 tested the hypothesis that behavioral and biochemical measures of naloxone-precipitated withdrawal from morphine would be blocked by infusions of clonidine (0.6 or 2.4 μg/μl) into the LC. Significant reductions were observed in the occurrence of diarrhea, ptosis, weight loss and wet-dog shakes. Clonidine also reversed the naloxone-precipitated increase in hippocampus MHPG concentration. In experiment 2 subjects received an LC infusion or IP injection of a non-lipophilic alpha-2-agonist (ST-91), which does not penetrate the blood-brain barrier, or of clonidine into the dorsal parabrachial nucleus (DPB) to test the selectivity of the effects of clonidine infusions into the LC. ST-91 infusions into the LC reduced several of the observed withdrawal signs and increased others (e.g., jumping). Although peripheral injections of ST-91 attenuated some of the checked signs associated with naloxone-precipitated withdrawal, the frequency of wet-dog shakes was not reduced. ST-91 infusions into the LC, but not systemic ST-91 administration, prevented the withdrawal-induced increase in hippocampus MHPG concentration. Clonidine infused lateral to the LC into the DPB did not significantly attenuate withdrawal or reduce hippocampus MHPG levels. These results provide behavioral and biochemical evidence to support the suggestion that clonidine significantly attenuates naloxone-precipitated withdrawal through an interaction with noradrenergic neurons located in the vicinity of the LC.     

Strain differences in the behavioral effects of antidepressant drugs in the rat forced swimming test.

Wistar-Kyoto (WKY) rats provide a model of stress-induced depressive behavior, because they show enhanced vulnerability to the effects of stressors. The present study examined differences in the behavioral response to different types of antidepressant drugs between WKY and Sprague-Dawley (SD) rats in the forced swimming test (FST). WKY rats displayed significantly greater immobility than SD rats during their exposure to the FST. The noradrenergic antidepressant, desipramine, produced a dose-dependent reduction of immobility and increase of climbing behavior in the SD rats. In WKY rats, desipramine reduced immobility at a lower dose and produced increases of both swimming and climbing behavior. The serotonergic compounds, fluoxetine and 8-OH-DPAT, produced dose-dependent reductions of immobility and increases of swimming behavior in the FST in SD rats, but the response to the serotonergic drugs were blunted in WKY rats. These results indicate that genetic or constitutive differences may determine the distinct behavioral profiles for antidepressant compounds with selective pharmacological effects in different rat strains, and these effects may be related to genetic heterogeneity of antidepressant responses in depressed patients.     

A selective test for antidepressant treatments using rats bred for stress-induced reduction of motor activity in the swim test

Rationale and objective This paper describes a new procedure for detecting effective antidepressant treatments. The procedure uses the swim-test susceptible (Susceptible) rat which has been selectively bred to show decreased struggling behavior in a swim test after exposure to a mild stressor. The ability of treatments to block this decrease in swim-test activity was assessed as a method for detecting effective antidepressants. Results In both male and female Susceptible rats, chronic (14-day) treatment with different antidepressant drugs delivered via osmotic minipump [i.e., three tricyclics (desmethylimipramine, imipramine, amitriptyline), two selective serotonin reuptake inhibitors (fluoxetine and sertraline), a monoamine oxidase inhibitor (phenelzine), and two atypical antidepressants (venlafaxine and bupropion)] all prevented the stress-induced decrease in swim-test struggling normally shown by these rats. Electroconvulsive shock had a similar effect. Unlike antidepressant drugs, 14-day treatment with various nonantidepressant drugs [i.e., a stimulant (amphetamine), an anxiolytic (chlordiazepoxide), an antihistamine (chlorpheniramine), and an anticholinergic (scopolamine)] did not have this effect. Antidepressant drug treatment for 1 day (i.e., acute treatment) was also ineffective in this test. The procedure described above requires use of the Susceptible rat—swim test resistant rats (i.e., rats selectively bred to be resistant to decreased swim-test activity after exposure to stressful conditions) showed no significant differences in swim-test behavior between stress and nonstress conditions after 14-day drug treatment, and randomly bred Sprague–Dawley rats did not show a decrease in swim-test activity following exposure to the mild stressor that is the basis for the test. Conclusion These results suggest that the procedure described here, which uses a rat subject that has been bred for vulnerability to stressful conditions, may be a selective screening technique for effective antidepressant treatments.     

Anti-depressant like effect of curcumin and its combination with piperine in unpredictable chronic stress-induced behavioral, biochemical and neurochemical changes

Curcumin, a yellow pigment extracted from rhizomes of the plant Curcuma longa (turmeric), has been widely used as food additive and also as a herbal medicine throughout Asia. The present study was designed to study the pharmacological, biochemical and neurochemical effects of daily administration of curcumin to rats subjected to chronic unpredictable stress. Curcumin treatment (20 and 40 mg/kg, i.p., 21 days) significantly reversed the chronic unpredictable stress-induced behavioral (increase immobility period), biochemical (increase monoamine oxidase activity) and neurochemical (depletion of brain monoamine levels) alterations. The combination of piperine (2.5 mg/kg, i.p., 21 days), a bioavailability enhancer, with curcumin (20 and 40 mg/kg, i.p., 21 days) showed significant potentiation of its anti-immobility, neurotransmitter enhancing (serotonin and dopamine) and monoamine oxidase inhibitory (MAO-A) effects as compared to curcumin effect per se. This study provided a scientific rationale for the use of curcumin and its co-administration with piperine in the treatment of depressive disorders     

Sex differences in forced-swim and open-field test behaviours after chronic administration of melatonin

The effects of melatonin administered chronically on forced-swim test and open-field test behaviours were examined in male and female rats. The forced-swim test has been shown to be sensitive to all major classes of antidepressants and evidence indicates that melatonin possesses putative antidepressive properties. Male and female Long-Evans rats received either a regimen of chronic administration of melatonin or the control condition for 14 days via the drinking water. On day 15, each animal was individually introduced into a swim chamber, and was scored for 15 min on the duration of swimming, struggling, and immobility. After 24 h, each animal was again tested in the forced-swim test for 10 min. On day 18, all animals were tested in the open-field test apparatus for 5 min. Results revealed that females consistently showed higher activity levels than males in the forced-swim and open-field tests. Melatonin significantly increased struggling in males on day 15, but failed to do so in females. Also, whereas melatonin-treated females showed higher levels of behavioural immobility during their first exposure to the forced-swim test, this effect was prevented upon a second exposure. In both males and females, melatonin decreased swimming in the forced-swim test while increasing open-field ambulatory behaviour. Therefore, it is unlikely that melatonin's mechanism of action is a general inhibitory effect on motor activity. Taken together, the results suggest that the effects of melatonin treatment on forced-swim test behaviours are sex- and test-dependent.     

A study on behavioral,neurotoxicological, and immunotoxicological effects of subchronic arsenic treatment in rats

Male Wistar rats were treated for 4, 8, and 12 wk with 3.33, 6.66, 13.3, or 26.6 mg/kg of inorganic arsenic (NaAsO(2)) per os by gavage. Changes in behavioral and electrophysiological parameters (spontaneous open-field exploration; electrocorticogram mean frequency and power spectrum; latency and duration of somatosensory, visual, and auditory evoked potentials; conduction velocity; and relative and absolute refractory period of a peripheral nerve) were determined. Treated rats exhibited hypoactivity of horizontal ambulation in the open field and showed depressed rates of grooming. The electrophysiological data, recorded from anesthetized rats, did not show any significant dose- and time-dependent changes. Changes in humoral immune response, tested after 4 wk of treatment, were not marked. The weight of organs responsible for immune response (thymus, spleen, adrenals), was significantly reduced, as were delayed-type hypersensitivity (DTH) reaction and mean cell volume (MCV) of red blood cells a hematological parameter. Plaque-forming cell (PFC) assay proved to be insensitive in this short-time exposure. These results suggest that subchronic low-level exposure to arsenic can affect immune responses and/or spontaneous behavior of rats.     

Cerebral and cerebellar neurochemical changes and behavioral manifestations in rats chronically exposed to marijuana smoke.

Groups of male and female Fischer rats were exposed to marijuana cigarette smoke via an automatic smoking machine. Inhaled Δ⁹-tetrahydrocannabinol doses of 0.7, 2, and 4 mg/kg were relevant to man and were given for 12, 18, 27, 57, and 87 days. Another group of rats treated for 87 days was studied after a recovery of 20 days. Control animals inhaled smoke produced by placebo cigarettes. In the first week of exposure, 20% of lower-dosed rats were hyperactive and 50% at the high dose were prostrate or ataxic upon removal from the inhalator. Behavioral aberrations ameliorated within a few hours except for the depression exhibited by males at the high dose. Tolerance to CNS inhibition developed in 1–2 weeks. CNS stimulation, as manifested by hypersensitivity and hyperactivity, progressively involved more animals, primarily females, in all groups during Days 27–57. Tolerance to CNS stimulation developed thereafter. Fighting was displayed by 90% of females and 50% of males at 4 mg/kg by weeks 6–7. Neurotoxicity was expressed by involuntary vertical jumping, predominantly among high-dosed males in weeks 3 and 8. Normal behavior was displayed after cessation of treatment. At necropsy, homogenates of cerebrum and cerebellum were prepared and were analyzed for protein, RNA and acetylcholinesterase (AChE) activity. Cerebral AChE activity in females increased 33–71% after 12 exposures, decreased 10–23% after 57 exposures and rose 12% after 87 exposures. Cerebellar enzyme activity initially increased 15–35% in animals of both sexes during the subchronic phase but declined in females after 27 exposures. The extent of change in enzyme activity was generally reduced with continued treatment. Cerebellar RNA increased approximately 20% in rats of both sexes, but at different time intervals during the subchronic phase, and remained elevated in females at 87 days. Neurochemical changes were sex related and coincided with behavioral manifestations, and some changes extended into the recovery period. Inhalation findings were similar to those obtained earlier by the oral route; however, females demonstrated a greater facility to adapt to the cumulative toxic effects of marijuana smoke.     

Effect of subchronic caffeine treatment on MK-801-induced changes in locomotion, cognition and ataxia in mice

N-Methyl-D-aspartate (NMDA) receptor antagonists cause hyperlocomotion and cognitive deficits in rodents, and caffeine-tolerant mice show diminished locomotor response to NMDA receptor antagonists. The aim of this study was to evaluate the effect of subchronic caffeine treatment on MK-801-induced hyperlocomotion, ataxia and cognitive deficits, as well as amphetamine-induced hyperlocomotion in mice. Mice were treated subchronically with caffeine (0, 0.1, 0.3 and 1 mg/ml and 1, 3 and 7 days) and evaluated for locomotor activity, working memory (delayed alternation test), long-term memory (inhibitory avoidance task) and ataxia. Hyperlocomotion induced by MK-801 (0.25 mg/kg i.p.) was diminished after 3 days and almost abolished after 7 days of caffeine treatment at the 1 mg/ml dose, and this effect was also dose-dependent. Ataxia induced by 0.5 mg/kg MK-801 was not affected by caffeine treatment, but a short-lived hyperlocomotor effect was observed. Performance deficit in the inhibitory avoidance task induced by MK-801 (0.01 mg/kg) was prevented in mice treated with caffeine for 7 days at 1 mg/ml, and perseverative errors in the T-maze by MK-801 (0.4 mg/kg) were attenuated. The locomotor effect of amphetamine (5 mg/kg) was unaffected by subchronic caffeine treatment. The findings that hyperlocomotion and cognitive effects induced by MK-801 can be specifically influenced by reduced adenosinergic activity agree with a model of adenosine hypofunction in schizophrenia, since NMDA receptor antagonists are pharmacological models for this disorder.     

Repeated neonatal separation results in different neurochemical and behavioral changes in adult male and female Mongolian gerbils

We assessed whether daily separation of Mongolian gerbils (Meriones unguiculatus) from mothers and siblings during postnatal days 4-20 would produce behavioral and neurochemical changes in adulthood that parallel some features of depression in humans. Neonatal separation altered the behavior of adult females in the open field test but not in the tail suspension test, and did not affect behavior of males. Separated males, but not females, showed a significant decrease in hippocampal brain derived neurotrophic factor (BDNF) relative to controls. Western blot and optical densitometry measurements in the hippocampus did not reveal significant group differences in synaptophysin levels in either sex, but there was a tendency toward decreased levels of synaptophysin in the entire hippocampus as well as the CA1 hippocampal subregion of separated males. Repeated separation of neonates from mothers and siblings led to subtle behavioral and neurochemical changes during adulthood that were expressed differently in male and female gerbils.