The antidepressant-like effect of inosine in the FST is associated with both adenosine A1 and A2A receptors

Inosine is an endogenous purine nucleoside, which is formed during the breakdown of adenosine. The adenosinergic system was already described as capable of modulating mood in preclinical models; we now explored the effects of inosine in two predictive models of depression: the forced swim test (FST) and tail suspension test (TST). Mice treated with inosine displayed higher anti-immobility in the FST (5 and 50 mg/kg, intraperitoneal route (i.p.)) and in the TST (1 and 10 mg/kg, i.p.) when compared to vehicle-treated groups. These antidepressant-like effects started 30 min and lasted for 2 h after intraperitoneal administration of inosine and were not accompanied by any changes in the ambulatory activity in the open-field test. Both adenosine A₁ and A_2A receptor antagonists prevented the antidepressant-like effect of inosine in the FST. In addition, the administration of an adenosine deaminase inhibitor (1 and 10 mg/kg, i.p.) also caused an antidepressant-like effect in the FST. These results indicate that inosine possesses an antidepressant-like effect in the FST and TST probably through the activation of adenosine A₁ and A_2A receptors, further reinforcing the potential of targeting the purinergic system to the management of mood disorders.     

Effect of a Selective Cyclooxygenase Type 2 Inhibitor Celecoxib on Depression Associated with Obesity in Mice: An Approach Using Behavioral Tests

The biological mechanisms that link the development of depression to metabolic disorders such as obesity and diabetes remain ambiguous. In the present study the potential of a selective cyclooxygenase inhibitor celecoxib (15 mg/kg p.o.) was investigated in depression associated with obesity in mice. Behavioral tests used to assess depressive-like behavior were sucrose preference test, forced swim test (FST), tail suspension test (TST) and elevated plus maze (EPM). The basal locomotor score in obese mice was not altered. Furthermore, estimation of biochemical parameters was performed for plasma glucose, total cholesterol, triglycerides and total proteins. Escitalopram (10 mg/kg p.o.) served as reference standard drug. In the results, chronic treatment with celecoxib for 28 days significantly attenuated the behavioral alterations as indicated by increased the sucrose consumption, reduced the immobility time in FST and TST, increased the percent open arm time and entries in EPM in obese mice. In the biochemical parameters celecoxib significantly reversed the increased plasma glucose, total cholesterol, triglycerides and total proteins in obese mice. In conclusion, celecoxib exhibited potential antidepressant-like effect in depression associated with obesity, which to some extent is mediated by reversing the altered plasma glucose in obese mice.     

Antidepressant-like effect of onion (Allium cepa L.) powder in a rat behavioral model of depression

The present study evaluated the antidepressant-like effect of the quercetin-rich vegetable, onion, by using the rat behavioral model of depression, the forced swimming test (FST). Daily administration of onion powder at a dosage of 50 mg/kg of body weight/day for 14 days significantly reduced the immobility time in FST without changing the motor dysfunction, indicating that the daily consumption of onion exerted antidepressant-like activity. The plasma corticosterone level was elevated after an FST trial, and pretreatment with onion powder did not modulate this elevation. Although the FST trial tended to increase the dopaminergic activity in the rat hypothalamus, the administration of onion powder (50 mg/kg) suppressed the increase in the turnover of this neurotransmitter. However, the same prevention was also observed with a higher dosage of onion, in which no significant antidepressant effect was apparent. The results of the present study suggest that onion exerted antidepressant-like activity in a behavioral model that acted independently of the hypothalamic-pituitary-adrenal axis.     

Antidepressant-like responses to lithium in genetically diverse mouse strains

A mood stabilizing and antidepressant response to lithium is only found in a subgroup of patients with bipolar disorder and depression. Identifying strains of mice that manifest differential behavioral responses to lithium may assist in the identification of genomic and other biologic factors that play a role in lithium responsiveness. Mouse strains were tested in the forced swim test (FST), tail suspension test (TST) and open-field test after acute and chronic systemic and intracerebroventricular (ICV) lithium treatments. Serum and brain lithium levels were measured. Three (129S6/SvEvTac, C3H/HeNHsd and C57BL/6J) of the eight inbred strains tested, and one (CD-1) of the three outbred strains, showed an antidepressant-like response in the FST following acute systemic administration of lithium. The three responsive inbred strains, as well as the DBA/2J strain, displayed antidepressant-like responses to lithium in the FST after chronic administration of lithium. However, in the TST, acute lithium resulted in an antidepressant-like effect only in C3H/HeNHsd mice. Only C57BL/6J and DBA/2J showed an antidepressant-like response to lithium in the TST after chronic administration. ICV lithium administration resulted in a similar response profile in BALB/cJ (non-responsive) and C57BL/6J (responsive) strains. Serum and brain lithium concentrations showed that behavioral results were not because of differential pharmacokinetics of lithium in individual strains, suggesting that genetic factors likely regulate these behavioral responses to lithium. Our results indicate that antidepressant-like responses to lithium in tests of antidepressant efficacy varies among genetically diverse mouse strains. These results will assist in identifying genomic factors associated with lithium responsiveness and the mechanisms of lithium action.     

Berberine produces antidepressant-like effects in the forced swim test and in the tail suspension test in mice

This study investigated the effect of berberine (BER) in the mouse forced swim test (FST) and in the tail suspension test (TST), two models predictive of antidepressant activity. We also investigated the antidepressant-like mechanism of BER by the combination of the desipramine [DES, an inhibitor of reuptake of noradrenaline (NA) and serotonin (5-HT)], maprotiline (MAP, selective NA reuptake inhibitor), fluoxetine (FLU, selective 5-HT reuptake inhibitor) and moclobemide [MOC, monoamine oxidase (MAO) A inhibitor). Then we further measured the levels of monoamines [NA, dopamine (DA) and 5-HT) in mice striatum, hippocampus and frontal cortex. The results show that BER (10, 20 mg/kg, p.o.), significantly reduced the immobility time during the FST and the TST. The immobility time after treatment with BER (20 mg/kg, p.o.) in FST was augmented by DES, FLU and MOC, and not affected by MAP. Furthermore, BER (20 mg/kg, p.o.) increased NA and 5-HT levels in the hippocampus and frontal cortex. Our findings support the view that BER exerts antidepressant-like effect. The antidepressant-like mechanism of BER may be related to the increase in NA and 5-HT levels in the hippocampus and frontal cortex.     

Evaluation of antidepressant-like activity of aqueous and ethanolic extracts of Terminalia bellirica Roxb. fruits in mice

The present study was undertaken to investigate the effect of aqueous and ethanolic extracts of T. bellirica on depression in mice using forced swim test (FST) and tail suspension test (TST). The extracts were administered orally for 10 successive days in separate groups of Swiss young male albino mice. Aqueous extract (50, 100 and 200 mg/kg) in a dose-dependent manner and ethanolic extract (100 mg/kg) significantly reduced the immobility time of mice in both FST and TST. The extracts were without any significant effect on locomotor activity of mice. The efficacies of aqueous extract (200 mg/kg) and ethanolic extract (100 mg/kg) were found to be similar to that of imipramine (15 mg/kg, po) and fluoxetine (20 mg/kg, po) administered for 10 successive days. Both extracts reversed reserpine-induced extension of immobility period of mice in FST and TST. Prazosin (62.5 microg/kg, ip; an alpha1-adrenoceptor antagonist), sulpiride (50 mg/kg, ip; a selective D2 receptor antagonist) and p-chlorophenylalanine (100 mg/kg, ip; an inhibitor of serotonin synthesis) significantly attenuated the aqueous and ethanolic extract-induced antidepressant-like effect in TST. Thus, both the aqueous and ethanolic extracts of T. bellirica elicited a significant antidepressant-like effect in mice by interaction with adrenergic, dopaminergic and serotonergic systems.     

Antidepressant- and Anxiolytic-Like Effects of New Dual 5-HT1A and 5-HT7 Antagonists in Animal Models

The aim of this study was to further characterize pharmacological properties of two phenylpiperazine derivatives: 1-{2-[2-(2,6-dimethlphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazynine hydrochloride (HBK-14) and 2-[2-(2-chloro-6-methylphenoxy)ethoxy]ethyl-4-(2- methoxyphenyl)piperazynine dihydrochloride (HBK-15) in radioligand binding and functional in vitro assays as well as in vivo models. Antidepressant-like properties were investigated in the forced swim test (FST) in mice and rats. Anxiolytic-like activity was evaluated in the four-plate test in mice and elevated plus maze test (EPM) in rats. Imipramine and escitalopram were used as reference drugs in the FST, and diazepam was used as a standard anxiolytic drug in animal models of anxiety. Our results indicate that HBK-14 and HBK-15 possess high or moderate affinity for serotonergic 5-HT₂, adrenergic α₁, and dopaminergic D₂ receptors as well as being full 5-HT_1A and 5-HT₇ receptor antagonists. We also present their potent antidepressant-like activity (HBK-14—FST mice: 2.5 and 5 mg/kg; FST rats: 5 mg/kg) and (HBK-15—FST mice: 1.25, 2.5 and 5 mg/kg; FST rats: 1.25 and 2.5 mg/kg). We show that HBK-14 (four-plate test: 2.5 and 5 mg/kg; EPM: 2.5 mg/kg) and HBK-15 (four-plate test: 2.5 and 5 mg/kg; EPM: 5 mg/kg) possess anxiolytic-like properties. Among the two, HBK-15 has stronger antidepressant-like properties, and HBK-14 displays greater anxiolytic-like activity. Lastly, we demonstrate the involvement of serotonergic system, particularly 5-HT_1A receptor, in the antidepressant- and anxiolytic-like actions of investigated compounds.     

Neuronal NOS Inhibitor and Conventional Antidepressant Drugs Attenuate Stress-induced Fos Expression in Overlapping Brain Regions

Recent evidence indicates that the administration of inhibitors of neuronal nitric oxide synthase (nNOS) induces antidepressant-like effects in animal models such as the forced swimming test (FST). However, the neural circuits involved in these effects are not yet known. Therefore, this study investigated the expression of Fos protein, a marker of neuronal activity, in the brain of rats submitted to FST and treated with the preferential nNOS inhibitor, 7-nitroindazole (7-NI), or with classical antidepressant drugs (Venlafaxine and Fluoxetine). Male Wistar rats were submitted to a forced swimming pretest (PT) and, immediately after, started receiving a sequence of three ip injections (0, 5, and 23 h after PT) of Fluoxetine (10 mg/kg), Venlafaxine (10 mg/kg), 7-NI (30 mg/kg) or respective vehicles. One hour after the last drug injection the animals were submitted to the test session, when immobility time was recorded. After the FST they were sacrificed and had their brains removed and processed for Fos immunohistochemistry. Independent group of non-stressed animals received the same drug treatments, or no treatment (naïve). 7-NI, Venlafaxine or Fluoxetine reduced immobility time in the FST, an antidepressant-like effect. None of the treatments induce significant changes in Fos expression per se. However, swimming stress induced significant increases in Fos expression in the following brain regions: medial prefrontal cortex, nucleus accumbens, locus coeruleus, raphe nuclei, striatum, hypothalamic nucleus, periaqueductal grey, amygdala, habenula, paraventricular nucleus of hypothalamus, and bed nucleus of stria terminalis. This effect was attenuated by 7-NI, Venlafaxine or Fluoxetine. These results show that 7-NI produces similar behavioral and neuronal activation effects to those of typical antidepressants, suggesting that these drugs share common neurobiological substrates.     

人参总皂苷和远志总苷配伍对小鼠抗抑郁作用

目的确定人参总皂苷（GTS）和远志总苷（PTG）抗抑郁配伍剂量比例,形成参远苷（SGY）制剂,为研制开发抗抑郁新药提供实验数据。方法采用析因设计方法,GTS和PTG均选取25、50、100 mg/kg三个剂量,按照完全随机的两因素3×3实验设计,得到参远苷的9个不同配比组。C57BL/6J小鼠（用于悬尾实验）和ICR小鼠（用于强迫游泳实验）随机分为对照组、阳性药组（10 mg/kg,帕罗西汀用于悬尾实验;阿米替林用于强迫游泳实验）及参远苷的9个不同配比组,共11组。灌胃给药7 d,观察各组对悬尾或强迫游泳实验小鼠不动时间的影响,并通过空场实验观察参远苷各配比对小鼠自主活动的影响。参远苷与单味GTS、PTG的抗抑郁作用比较实验中,C57BL/6J小鼠（用于悬尾实验）和ICR小鼠（用于强迫游泳实验）随机分为对照组、阳性药组（10 mg/kg,帕罗西汀用于悬尾实验;阿米替林用于强迫游泳实验）、参远苷低中高剂量组（37.5、75、150 mg/kg）、GTS和PTG各四个剂量组（均为18.75、37.5、75、150 mg/kg）,共13组。灌胃给药7 d,观察各组对悬尾或强迫游泳实验小鼠不动时间的影响。结果析因设计结果表明,GTS和PTG之间无交互效应。参远苷配比组75 mg/kg（GTS∶PTG为50∶25）及150mg.kg-1（GTS∶PTG为100∶50）显著并稳定缩短悬尾或强迫游泳不动时间（P〈0.05）,得出GTS和PTG的剂量配伍比例为2：1。空场实验结果显示,参远苷各配比对小鼠运动总路程无影响。参远苷与单味GTS、PTG抗抑郁作用比较实验结果显示,GTS 75、150 mg/kg缩短悬尾实验小鼠不动时间（P〈0.01,P〈0.05）,对强迫游泳实验小鼠不动时间无影响。PTG 18.75、37.5 mg/kg缩短强迫游泳实验小鼠不动时间（P〈0.01,P〈0.05）,对悬尾实验小鼠不动时间无影响。参远苷75、150 mg/kg缩短悬尾实验小鼠不动时间（P〈0.05）。同时,参远苷37.5、75 mg/kg缩短强迫游泳实验小鼠不动时间（P〈0.01,P〈0.05）。结论 GTS和PTG以2：1的比例形成的参远苷（SYG）制剂,质量容易控制,作用机制多样,符合抑郁症复杂多样的发病机制,优于单味GTS和PTG,进一步研究之后,有可能成为新型的抗抑郁药物。     

Testosterone has antidepressant-like efficacy and facilitates imipramine-induced neuroplasticity in male rats exposed to chronic unpredictable stress

Hypogonadal men are more likely to develop depression, while testosterone supplementation shows antidepressant-like effects in hypogonadal men and facilitates antidepressant efficacy. Depression is associated with hypothalamic–pituitary–adrenal (HPA) axis hyperactivity and testosterone exerts suppressive effects on the HPA axis. The hippocampus also plays a role in the feedback regulation of the HPA axis, and depressed patients show reduced hippocampal neuroplasticity. We assessed the antidepressant-like effects of testosterone with, or without, imipramine on behavioral and neural endophenotypes of depression in a chronic unpredictable stress (CUS) model of depression. A 21-day CUS protocol was used on gonadectomized male Sprague–Dawley rats treated with vehicle, 1 mg of testosterone propionate, 10 mg/kg of imipramine, or testosterone and imipramine in tandem. Testosterone treatment reduced novelty-induced hypophagia following CUS exposure, but not under non-stress conditions, representing state-dependent effects. Further, testosterone increased the latency to immobility in the forced swim test (FST), reduced basal corticosterone, and reduced adrenal mass in CUS-exposed rats. Testosterone also facilitated the effects of imipramine by reducing the latency to immobility in the FST and increasing sucrose preference. Testosterone treatment had no significant effect on neurogenesis, though the combination of testosterone and imipramine increased PSA-NCAM expression in the ventral dentate gyrus. These findings demonstrate the antidepressant- and anxiolytic-like effects of testosterone within a CUS model of depression, and provide insight into the mechanism of action, which appears to be independent of enhanced hippocampal neurogenesis.     

Antidepressant effect of Chaihu-Shugan-San extract and its constituents in rat models of depression

Herbal preparations may be effective alternatives in the treatment of depression, which remains difficult to manage. Chaihu-Shugan-San (CSS), an oriental traditional medicine, has been used as a remedy for Hwa-Byung, a Korean culture-bound syndrome resembling depression. We examined whether aqueous extracts of CSS and its constituent herbs exert antidepressant-like effects in two experimental animal models: the forced swimming test (FST) and the chronic mild stress (CMS) model. The herbal extracts were administered orally for 7 days in the FST and for 21 days during the CMS model; imipramine at 20 mg/kg/day was injected intraperitoneally as a positive control. CSS, Radix Bupleuri (one of the most important constituent plants in CSS), and imipramine had significant anti-immobility effects in the FST and reversed the CMS-induced reduction in sucrose consumption. Rhizoma Cyperi, another constituent of CSS, had antidepressant activity in the FST, while it failed in the CMS model. In conclusion, our results suggest that CSS and its constituent herbs exert antidepressant-like effects comparable to those of imipramine in experimental animal models.     

Genistein regulated serotonergic activity in the hippocampus of ovariectomized rats under forced swimming stress

The mortality of individuals suffering from depression has been increasing, especially post-menopausal women; therefore, their care and treatment are important to maintain a high quality of life. In the present study, we evaluated the antidepressant-like effects of a major isoflavonoid, genistein (4',5,7-trihydroxyisoflavone), using a behavioral model of depression, the forced swimming test (FST), in ovariectomized rats. Daily administration of genistein to ovariectomized rats at a dosage of 10 mg/kg of body weight/d for 14 d significantly reduced the immobility time during the FST without changing motor dysfunction. On the other hand, a higher dosage, 100 mg/kg/d, did not have any effects on the immobility time compared with the vehicle control. Repeated administration of genistein at 10 mg/kg of body weight did not affect serotonergic activities in the hippocampus compared to the vehicle control in ovariectomized rats. A 5-min FST trial stimulated these activities. On the other hand, repeated pretreatment with genistein protected against changes in activity during the FST trial. These results suggest that daily consumption of genistein 10 mg/kg/d might have antidepressant-like effect on ovariectomized rats by regulating changes in serotonergic metabolism in the hippocampus under stressful conditions.     

Evaluation of Potential Antidepressant-Like Activity of Chalcone-1203 in Various Murine Experimental Depressant Models

Two classic animal behavior despair tests-the forced swimming test (FST) and the tail suspension test (TST) were used to evaluate antidepressant-like activity of a new chalcone compound, chalcone-1203 in mice. It was observed that chalcone-1203 at dose of 1, 5, and 10 mg/kg significantly reduced the immobility time in the FST and TST in mice 30 min after treatment. In addition, chalcone-1203 was found to exhibit significant oral activity in the FST in mice. It also produced a reduction in the ambulation in the open-field test in mice not previously habituated to the arena, but no effect in the locomotor activity in mice previously habituated to the open-field. The main monoamine neurotransmitters and their metabolites in mouse brain regions were also simultaneously determined by HPLC–ECD. It was found that chalcone-1203 significantly increased the concentrations of the main neurotransmitters 5-HT and NE in the hippocampus, hypothalamus and cortex. Chalcone-1203 also significantly reduced the ratio of 5-HIAA/5-HT in the hippocampus and cortex, shown down 5-HT metabolism compared with mice treated with stress vehicle. In conclusion, chalcone-1203 produced significant antidepressant-like activity, and the mechanism of action may be due to increased 5-HT and NE in the mouse hippocampus and cortex.     

The involvement of NMDA and AMPA receptors in the mechanism of antidepressant-like action of zinc in the forced swim test

Antidepressant-like activity of zinc in the forced swim test (FST) was demonstrated previously. Enhancement of such activity by joint administration of zinc and antidepressants was also shown. However, mechanisms involved in this activity have not yet been established. The present study examined the involvement of the NMDA and AMPA receptors in zinc activity in the FST in mice and rats. Additionally, the influence of zinc on both glutamate and aspartate release in the rat brain was also determined. Zinc-induced antidepressant-like activity in the FST in both mice and rats was antagonized by N-methyl-d-aspartic acid (NMDA, 75 mg/kg, i.p.) administration. Moreover, low and ineffective doses of NMDA antagonists (CGP 37849, L-701,324, d-cycloserine, and MK-801) administered together with ineffective doses of zinc exhibit a significant reduction of immobility time in the FST. Additionally, we have demonstrated the reduction of immobility time by AMPA receptor potentiator, CX 614. The antidepressant-like activity of both CX 614 and zinc in the FST was abolished by NBQX (an antagonist of AMPA receptor, 10 mg/kg, i.p.), while the combined treatment of sub-effective doses of zinc and CX 614 significantly reduces the immobility time in the FST. The present study also demonstrated that zinc administration potentiated a veratridine-evoked glutamate and aspartate release in the rat’s prefrontal cortex and hippocampus. The present study further suggests the antidepressant properties of zinc and indicates the involvement of the NMDA and AMPA glutamatergic receptors in this activity.     

Antidepressant-like deliverables from the sea: evidence on the efficacy of three different brown seaweeds via involvement of monoaminergic system

Brown seaweeds exhibit several health benefits in treating and managing wide array of ailments. In this study, the antidepressant-like effect of methaolic extracts from Sargassum swartzii (SS), Stoechospermum marginatum (SM), and Nizamuddinia zanardinii (NZ) was examined in forced swimming test (FST), in rats. Oral administration of SS, SM, and NZ extract (30–60 mg/kg) exhibited antidepressant-like activity in FST by reducing immobility time as compared to control group, without inducing significant change in ambulatory behavior in open field test. In order to evaluate the involvement of monoaminergic system, rats were pretreated with the inhibitor of brain serotonin stores p-chlorophenylalanin (PCPA), dopamine (SCH23390 and sulpiride), and adrenoceptor (prazosin and propranolol) antagonists. Rats receiving treatment for 28 days were decapitated and brains were analyzed for monoamine levels. It may be concluded that the extracts of SS, SM, and NZ produces antidepressant-like activity via modulation of brain monoaminergic system in a rat model.     

Piperine Reverses Chronic Unpredictable Mild Stress-Induced Behavioral and Biochemical Alterations in Rats

Previous studies in our laboratory have demonstrated that piperine produced antidepressant-like action in various mouse models of behavioral despair, which was related to the serotonergic system. The present study aimed to examine the behavioral and biochemical effects of piperine in rats exposed to chronic unpredictable mild stress (CUMS). The results showed that CUMS caused depression-like behavior in rats, as indicated by the significant decrease in sucrose consumption and increase in immobility time in the forced swim test. In addition, it was found that serotonin (5-HT) and brain-derived neurotrophic factor (BDNF) contents in the hippocampus and frontal cortex were significantly decreased in CUMS-treated rats. Treating the animals with piperine significantly suppressed behavioral and biochemical changes induced by CUMS. The results suggest that piperine produces an antidepressant-like effect in CUMS-treated rats, which is possibly mediated by increasing 5-HT and BDNF contents in selective brain tissues.     

Antidepressant-like effect of 17beta-estradiol: involvement of dopaminergic, serotonergic, and (or) sigma-1 receptor systems

17beta-estradiol has been reported to possess antidepressant-like activity in animal models of depression, although the mechanism for its effect is not well understood. The present study is an effort in this direction to explore the mechanism of the antidepressant-like effect of 17beta-estradiol in a mouse model(s) of behavioral depression (despair behavior). Despair behavior, expressed as helplessness to escape from a situation (immobility period), as in a forced swim test in which the animals are forced to swim for a total of 6 min, was recorded. The antiimmobility effects (antidepressant-like) of 17beta-estradiol were compared with those of standard drugs like venlafaxine (16 mg/kg, i.p.). 17beta-estradiol produced a U-shaped effect in decreasing the immobility period. It had no effect on locomotor activity of the animal. The antidepressant-like effect was comparable to that of venlafaxine (16 mg/kg, i.p.). 17beta-estradiol also exhibited a similar profile of antidepressant action in the tail suspension test. When coadministered with other antidepressant drugs, 17beta-estradiol (5 microg/kg, i.p.) potentiated the antiimmobility effect of subeffective doses of fluoxetine (5 mg/kg, i.p.), venlafaxine (2 mg/kg, i.p.), or bupropion (10 mg/kg, i.p.), but not of desipramine (5 mg/kg, i.p.) or tranylcypromine (2 mg/kg, i.p.), in the forced swim test. The reduction in the immobility period elicited by 17beta-estradiol (20 microg/kg, i.p.) was reversed by haloperidol (0.5 mg/kg, i.p.; a D(2) dopamine receptor antagonist), SCH 23390 (0.5 mg/kg, i.p.; a D(1) dopamine receptor antagonist), and sulpiride (5 mg/kg, i.p.; a specific dopamine D(2) receptor antagonist). In mice pretreated with (+)-pentazocine (2.5 mg/kg, i.p.; a high-affinity sigma-1 receptor agonist), 17beta-estradiol (5 microg/kg, i.p.) produced a synergistic effect. In contrast, pretreatment with progesterone (10 mg/kg, s.c.; a sigma-1 receptor antagonist neurosteroid), rimcazole (5 mg/kg, i.p.; another sigma-1 receptor antagonist), or BD 1047 (1 mg/kg, i.p.; a novel sigma-1 receptor antagonist) reversed the antiimmobility effects of 17beta-estradiol (20 microg/kg, i.p.). Similarly, in mice pretreated with a subthreshold dose of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, a 5-HT1A serotonin receptor agonist), 17beta-estradiol (5 microg/kg, i.p.) produced an antidepressant-like effect. These findings demonstrate that 17beta-estradiol exerted an antidepressant-like effect preferentially through the modulation of dopaminergic and serotonergic receptors. This action may also involve the participation of sigma-1 receptors.     

Role of serotonin (5-HT) in the antidepressant-like properties of neuropeptide Y (NPY) in the mouse forced swim test

Neuropeptide Y (NPY) is thought to be implicated in depressive disorders. The mouse forced swim test (FST) is an animal model widely used as a predictor of the efficacy of antidepressant drugs. The present study was undertaken to explore the possible contribution of endogenous serotonin (5-HT) systems in the behavioral effects elicited by NPY in this model. The selective serotonin re-uptake inhibitor (SSRI), fluoxetine, was also tested for comparison. 5-HT was depleted prior to testing by the administration of the tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA; 300 mg/kg, i.p., each day for 3 days; control mice received saline-vehicle over the same period). On the fourth day, mice received NPY (3 nmol, I.C.V.), fluoxetine (16 mg/kg, i.p.) or saline injections before testing in the FST. Both NPY and fluoxetine significantly reduced immobility time in saline-treated control animals. Pre-treatment with PCPA significantly blocked the effects of fluoxetine in the FST, confirming the role of endogenous 5-HT. Similarly, pre-treatment with PCPA also significantly attenuated the anti-immobility effects of NPY, thus suggesting a role for 5-HT in the effects of NPY in the FST. Quantitative receptor autoradiography revealed increases in specific [125I][Leu31, Pro34]PYY sites that were sensitive to BIBP3226 (Y1-like sites) in various brain regions. Specific [125I]GR231118 and [125I]PYY(3-36) binding levels were not changed following PCPA treatment, suggesting that depletion of endogenous 5-HT resulted in an apparent increase in the level of Y1 sites in their high-affinity state. Taken together, these results suggest a role for 5-HT-related systems in the antidepressant-like properties of NPY.