Antidepressant effects of the water extract from Taraxacum officinale leaves and roots in mice

Context: The leaves and roots of the Taraxacum officinale F. (Asteraceae) is widely used as traditional medicinal herb in Eastern Asian countries.

Objective: In the present study, the antidepressant-like effects of the water extract of T. officinale (WETO) leaves and roots were investigated in mice using forced swimming test (FST), tail suspension test (TST) and open field test (OFT).

Materials and methods: Effects of acute (1-day) and chronic treatments (14-days) with WETO (50, 100 and 200?mg/kg) on the behavioral changes in FST, TST and OFT, and the serum corticotrophin releasing factor (CRF), adrenocorticotropic hormone (ACTH) and corticosterone concentration were assessed in mice.

Results: Chronic treatment (14-days) with WETO at the doses of 50, 100 and 200?mg/kg significantly decreased the immobility time in both FST (92.6, 85.1 and 77.4?s) and TST (84.8, 72.1 and 56.9?s). Acute treatment (1-day) with WETO at a dose of 200?mg/kg also markedly decreased the immobility time in both FST (81.7?s) and TST (73.2?s). However, all treatments did not affect the locomotor activity in the OFT. Moreover, FST induced a significant increase in serum CRF (5.8?ng/ml), ACTH (104.7?pg/ml) and corticosterone levels (37.3?ng/ml). Chronic treatment (14-days) with WETO decreased the serum CRF (200?mg/kg: 3.9?ng/ml) and corticosterone (50?mg/kg: 29.9?ng/ml; 100?mg/kg: 22.5?ng/ml; 200?mg/kg: 19.8?ng/ml) levels.

Discussion and conclusion: These results clearly demonstrated the antidepressant effects of WETO in animal models of behavioral despair and suggested the mechanism involved in the neuroendocrine system.     

Antidepressant-like effect of extract from Polygala paniculata: Involvement of the monoaminergic systems

Context: Polygala paniculata Linnaeus (Polygalaceae) has shown neuroprotective effects, but there is no report about its antidepressant potential.

Objective: The antidepressant-like effect of the hydroalcoholic extract from P. paniculata and some of the possible mechanisms involved in this effect were investigated in forced swimming test (FST).

Materials and methods: Mice received extract by oral route and were submitted to FST and open-field test. Animals were forced to swim and the total immobility time was registered (6-min period). A reduction in the immobility time is considered an antidepressant-like effect. In order to investigate the involvement of the monoaminergic systems, mice were treated with pharmacological antagonists before administration of the extract.

Results: The acute administration of the hydroalcoholic extract from P. paniculata produced an antidepressant-like effect, since it significantly reduced the immobility time in FST (0.01–30?mg/kg) as compared to control group, without changing locomotor activity. Pretreatment of mice with yohimbine (1?mg/kg, i.p., α₂-adrenoceptor antagonist), propranolol (1?mg/kg, i.p., β-adrenoceptor antagonist), SCH23390 (0.05?mg/kg, s.c., dopamine D₁ receptor antagonist) or sulpiride (50?mg/kg, i.p., dopamine D₂ receptor antagonist) prevented the antidepressant-like effect of the extract in FST (30?mg/kg). Moreover, ketanserin (5?mg/kg, i.p., preferential 5-HT_2A receptor antagonist) enhanced the effect of the extract in FST.

Discussion and conclusion: The results of the present study indicate that the extract from P. paniculata has an antidepressant-like action that is likely mediated by an interaction with the serotonergic (5-HT_2A receptors), noradrenergic (α₂ and β-receptor) and dopaminergic (D₁ and D₂ receptors) systems.     

Possible involvement of nitric oxide in antidepressant-like effect of silymarin in male mice

Abstract

Context: Silymarin (SM) is extracted from milk thistle Silybum marianum L. [Asteraceae (Compositae)] and known for antioxidative and anti-inflammatory effects.

Objective: The potential antidepressant-like effect of acute SM and possible involvement of nitric oxide (NO) were determined in male mice.

Material and methods: SM was administered orally (5, 10, 20, 50, 100, and 200?mg/kg; p.o.) 60?min before the tests. After assessment of locomotor activity, the immobility time was measured in forced swimming test (FST) and tail suspension test (TST). To assess the possible involvement of NO, a non-specific NO synthase inhibitor, l-NAME (10?mg/kg, i.p.), and a specific iNOS inhibitor, aminoguanidine (AG) (50?mg/kg, i.p.), were administered separately 30?min before SM (20 and 100?mg/kg).

Results: SM at its effective doses 10, 20, 50, and 100?mg/kg decreased the immobility time in a dose-dependent manner (p?<?0.01, p?<?0.05, p?<?0.05, and p?<?0.001, respectively) in FST. SM (10, 20, 50, and 100?mg/kg) also lowered the immobility measure dose dependently in TST (p?<?0.01, p?<?0.05, p?<?0.01, and p?<?0.001, respectively). In addition, 50% of maximum response (ED₅₀) of SM was around 10?mg/kg. The dose 100?mg/kg proved the most effective dose in both the tests. Further, this effect was not related to changes in locomotor activity. Moreover, l-NAME reversed the effect of SM (20 and 100?mg/kg) in FST and SM (100?mg/kg) in TST. However, AG did not influence this impact.

Conclusion: The antidepressant-like effect of SM is probably mediated at least in part through NO and SM may increase NO tune.     

Evidence for involvement of the monoaminergic system in antidepressant-like activity of an ethanol extract of Boerhaavia diffusa and its isolated constituent,punarnavine, in mice

Context: Boerhaavia diffusa Linn. (Nyctaginaceae) roots possess potent antioxidant, antistress, and anticonvulsant activities. It is used as a medicinal plant in Ayurvedic and natural herbal medicines.

Objective: To evaluate the effect of Boerhaavia diffusa root ethanol extract and its active constituent, punarnavine, on depression in Swiss albino mice.

Materials and methods: Ethanol extract (50, 100, and 200?mg/kg, p.o.) and punarnavine (20 and 40?mg/kg, p.o.) were separately administered to 22 and 17 groups of mice, respectively, for 14 successive days followed by testing in the tail suspension and forced swim tests (FST). About 2% w/v gum acacia and double distilled water were used as controls for the extract and punarnavine, respectively.

Results: Antidepressant-like effect of the lowest dose (50?mg/kg) of the extract and lower dose (20?mg/kg) of punarnavine were found to be comparable to fluoxetine. The ED₅₀ value of the ethanol extract was 26.30?mg/kg (FST) and 33.11?mg/kg (tail suspension test); and of punarnavine was 15.14?mg/kg (FST) and 17.38?mg/kg (tail suspension test). The drugs did not show any significant effect on locomotor activities of mice. Prazosin (α₁-adrenoceptor antagonist), sulpiride (selective D₂-receptor antagonist), para-chlorophenylalanine) (p-CPA) (tryptophan hydroxylase inhibitor), and baclofen (GABA_B agonist) significantly attenuated the extract and punarnavine induced-antidepressant-like effect in the tail suspension test. The extract and punarnavine also significantly reduced mouse brain monoamine oxidase (MAO)-A levels, but there was no significant effect on plasma corticosterone levels.

Conclusion: Ethanol extract of Boerhaavia diffusa and punarnavine produced an antidepressant-like effect in mice probably through interaction with monoaminergic and GABAergic systems.     

NMDA receptor involvement in antidepressant-like effect of pioglitazone in the forced swimming test in mice

Rationale

Previously, we showed that pioglitazone exerts its antidepressant-like effect through peroxisome proliferator-activated receptor gamma receptors and demonstrated the possible involvement of calcium-dependent nitric oxide synthase inhibitors. Based upon the in vitro results, pioglitazone reduces N-methyl-d-aspartate (NMDA)-mediated calcium currents in hippocampal neurons.

Objective

In this study, we evaluated the involvement of the NMDA receptor (NMDAR) on the antidepressant-like effect of pioglitazone in the forced swimming test (FST) in mice.

Method

After the assessment of locomotor activity in the open-field test, mice were forced to swim individually and the immobility time of the last 4?min was evaluated. Pioglitazone was administered orally with doses of 5, 10, and 20?mg/kg 4?h before FST. To assess the involvement of NMDARs in the possible antidepressant-like effect of pioglitazone, a selective glutamate receptor agonist, NMDA (75?mg/kg, intraperitoneally [i.p.] or 20?ng/mouse, intracerebroventricularly [i.c.v.]), was administered before pioglitazone (20?mg/kg). To further determine a possible role of NMDARs in this effect, a noncompetitive antagonist of the NMDA, MK-801 (0.05?mg/kg, i.p. or 100?ng/mouse, i.c.v.), was coadministered with pioglitazone (10?mg/kg) 4?h prior to FST.

Results

Pioglitazone (20?mg/kg) administered 4?h prior to FST significantly reduced the immobility time. Coadministration of the noneffective doses of pioglitazone and MK-801 revealed an antidepressant-like effect in FST. Moreover, NMDA significantly reversed the antidepressant-like effect of pioglitazone administered 4?h prior to FST.

Conclusion

The antidepressant-like effect of pioglitazone in the FST is mediated partly through NMDAR signaling. This study provides a new approach for the treatment of depression.     

Study of antidepressant-like activity of an enriched phloroglucinol fraction obtained from Hypericum caprifoliatum

Context: Hypericum caprifoliatum Cham &; Schlecht (Guttiferae) extracts have a potential antidepressant-like effect in rodents. However, the molecular mechanisms by which these extracts exert this effect remain unclear.

Objective: This study evaluated the effect of HC1, a fraction obtained from H. caprifoliatum enriched in phloroglucinol derivatives, on the Na⁺, K⁺ ATPase activity in mouse brain and verified the influence of veratrine on the effect of HC1 in the forced swimming test (FST).

Materials and methods: Veratrine (0.06?mg/kg) and HC1 (360?mg/kg) were given alone or combined i.p. 60 and p.o. 30?min, respectively, before FST. The effect of single and repeated administration (once a day for 3 consecutive days) of HC1 (360?mg/kg) on Na⁺, K⁺ ATPase activity was evaluated ex vivo in the cerebral cortex and hippocampus of mice subjected or not to FST.

Results: HC1 reduced the immobility time (103.15?±?18.67?s), when compared to the control group (183.6?±?9.51?s). This effect was prevented by veratrine (151.75?±?22.19?s). Mice repeatedly treated with HC1 presented a significant increase in Na⁺, K⁺ ATPase activity, both in cerebral cortex (46?±?2.41?nmol Pi/min?mg protein) and hippocampus (49.83?±?2.31?nmol Pi/min?mg protein), in relation to the respective controls (30?±?2.66 and 29.83?±?2.31?nmol Pi/min?mg protein respectively).

Discussion and conclusion: The HC1 antidepressant-like effect on FST might be related to its capacity to inhibit Na⁺?influx. HC1 increases hippocampal and cortical Na⁺, K⁺ ATPase activities possibly through long-term regulatory mechanisms.     

Involvement of serotonin receptor subtypes in the antidepressant-like effect of trim in the rat forced swimming test

Depression is a common illness with severe morbidity and mortality. Nitric oxide synthase (NOS) inhibitors are shown to elicit antidepressant-like effect in various animals models. It is widely known that serotonin plays an important role in the antidepressant-like effect of drugs. The aim of this study is to investigate the involvement of 5-HT₁ and 5-HT₂ receptor subtypes in the antidepressant-like effect of TRIM, a nNOS inhibitor, in the rat forced swimming test (FST). TRIM displays an antidepressant-like activity in FST which is blocked by pretreatment with the NOS substrate l-arginine. Depletion of endogenous serotonin using para-chlorophenylalanine (pCPA; 3 × 150 mg/kg, i.p.) partially attenuated TRIM (50 mg/kg)-induced reductions in immobility time in FST. Pretreatment with methiothepin (0.1 mg/kg, i.p, a non-selective 5-HT receptor antagonist), cyproheptadine (3 mg/kg i.p, a 5-HT₂ receptor antagonist) or ketanserin (5 mg/kg i.p, a 5HT_2A/2C receptor antagonist) prevented the effect of TRIM (50 mg/kg) in the FST. WAY 100635 (0.1 mg/kg i.p, a selective 5-HT_1A receptor antagonist) and GR 127935 (3 mg/kg i.p, a selective 5-HT_1B/1D receptor antagonist) slightly reversed the immobility-reducing effect of TRIM in the FST, but this failed to reach a statistically significant level. The results of this study demonstrate that antidepressant-like effect of TRIM in the FST seems to be mediated, at least in part, by an interaction with 5-HT₂ receptors while non-significant effects were obtained with 5-HT₁ receptors.     

Serotonergic mediation of the antidepressant-like effects of nitric oxide synthase inhibitors

Recent studies indicate that nitric oxide (NO) synthase inhibitors have antidepressant-like potential in various animal models. In the present study the behavioural activity of the NO synthase inhibitors, N(G)-nitro-L-arginine (L-NA) and 7-nitroindazole (7-NI), were assessed in a modified rat forced swimming test (FST). Both L-NA and 7-NI, dose dependently reduced immobility and increased swimming behaviour in the rat FST. This behavioural profile parallels the one previously shown with selective serotonin re-uptake inhibitors and serotonergic agonists. Thus, we examined the role of serotonin mediating the behavioural effects of L-NA and 7-NI in the rat FST. Depletion of endogenous serotonin using para-chlorophenylalanine (pCPA; 3 x 150 mg/kg, i.p.) completely blocked L-NA (20 mg/kg, i.p.) and 7-NI (20 mg/kg, i.p.)-induced reductions in immobility and increases in swimming behaviour during the FST. In conclusion these observations suggest that NO synthase inhibitors elicit their antidepressant-like activity in the modified swimming test through a serotonin dependent mechanism.     

On the mechanism of antidepressant-like action of berberine chloride

Berberine, an alkaloid isolated from Berberis aristata Linn. has been used in the Indian system of medicines as a stomachic, bitter tonic, antiamoebic and also in the treatment of oriental sores. Evidences have demonstrated that berberine possesses central nervous system activities, particularly the ability to inhibit monoamine oxidase-A, an enzyme involved in the degradation of norepinephrine and serotonin (5-HT). With this background, the present study was carried out to elucidate the antidepressant-like effect of berberine chloride in different behavioural paradigms of despair. Berberine (5, 10, 20 mg/kg, i.p.) inhibited the immobility period in mice in both forced swim and tail-suspension test, however, the effect was not dose-dependent. Berberine (5 and 10 mg/kg, i.p.) also reversed the reserpine-induced behavioral despair. Berberine (5 mg/kg, i.p.) enhanced the anti-immobility effect of subeffective doses of various typical but not atypical antidepressant drugs in forced swim test. Berberine (5 mg/kg, i.p.) following its acute administration in mice resulted in increased levels of norepinephrine (31%), serotonin (47%) and dopamine (31%) in the whole brain. Chronic administration of berberine (5 mg/kg, i.p.) for 15 days significantly increased the levels of norepinephrine (29%), serotonin (19%) as well as dopamine (52%) but at higher dose (10 mg/kg, i.p.), there was no change in the norepinephrine (12%) levels but a significant increase in the serotonin (53%) and dopamine (31%) levels was found. The antidepressant-like effect of berberine (5 mg/kg, i.p.) in forced swim test was prevented by pretreatment with l-arginine (750 mg/kg, i.p.) or sildenafil (5 mg/kg, i.p.). On the contrary, pretreatment of mice with 7-nitroindazole (7-NI) (25 mg/kg, i.p.) or methylene blue (10 mg/kg, i.p.) potentiated the effect of berberine (2 mg/kg, i.p.) in the forced swim test. Pretreatment of mice with (+)-pentazocine (2.5 mg/kg, i.p.), a high-affinity sigma1 receptor agonist, produced synergism with subeffective dose of berberine (2 mg/kg, i.p.). Pretreatment with various sigma receptor antagonists viz. progesterone (10 mg/kg, s.c.), rimcazole (5 mg/kg, i.p.) and N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD1047; 1 mg/kg, i.p.) reversed the anti-immobility effects of berberine (5 mg/kg, i.p.). Berberine at lower dose did not affect the locomotor activity and barbiturate-induced sleep time. It produced mild hypothermic action in rats and displayed analgesic effect in mice. Taken together, theses findings demonstrate that berberine exerted antidepressant-like effect in various behavioural paradigms of despair possibly by modulating brain biogenic amines (norepinephrine, serotonin and dopamine). Further, nitric oxide pathway and/or sigma receptors are involved in mediating its antidepressant-like activity in mouse forced swim test.     

Ketamine elicits sustained antidepressant-like activity via a serotonin-dependent mechanism

Rationale

Behavioural antidepressant-like effects of ketamine have been reported in the forced swimming test (FST). The mechanisms mediating such effects are unknown.

Objectives

As serotonin (5-HT) is an important transmitter mediating antidepressant responsiveness in the FST, the influence of 5-HT depletion on the antidepressant-like effect of ketamine was assessed.

Methods

The effect of ketamine (25 mg/kg, i.p., 1 or 24 h prior to test) was assessed in the FST in naive rats or animals subjected to 5-HT depletion, repeated stress or following a combination of 5-HT depletion and stress. Endogenous 5-HT was depleted using the tryptophan hydroxylase inhibitor para-chlorophenylalanine (3?×?150 mg/kg, i.p.). Stress was induced by physical restraint (2 h/day for 10 days).

Results

In naive rats, ketamine administered 24 or 1 h prior to test produced a characteristic antidepressant-like reduction in immobility time in the FST. Depletion of 5-HT blocked this reduction in immobility when ketamine was administered 24 h prior FST, indicative of 5-HT dependency. The increase in immobility provoked by repeated restraint stress (2 h/day for 10 days) was blocked by ketamine when administered 24 h prior to FST, but this effect dissipated when animals were subjected to 5-HT depletion.

Conclusions

These observations are consistent with a role for 5-HT in mediating sustained antidepressant activity of ketamine in the FST. Molecular and cellular changes induced by ketamine may produce a rapid adaptation of 5-HT transmission which underlies the antidepressant response.     

Involvement of NMDA receptors and l-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effects of escitalopram in the forced swimming test

Escitalopram is a serotonin reuptake inhibitor used in the treatment of depression and anxiety disorders. This study investigated the effect of escitalopram in forced swimming test (FST) and in the tail suspension test (TST) in mice, and tested the hypothesis that the inhibition of NMDA receptors and NO-cGMP synthesis is implicated in its mechanism of action in the FST. Escitalopram administered by i.p. route reduced the immobility time both in the FST (0.3–10 mg/kg) and in the TST (0.1–10 mg/kg). Administration of escitalopram by p.o route (0.3–10 mg/kg) also reduced the immobility time in the FST. The antidepressant-like effect of escitalopram (3 mg/kg, p.o.) in the FST was prevented by the pretreatment of mice with NMDA (0.1 pmol/site, i.c.v.), l-arginine (750 mg/kg, i.p., a substrate for nitric oxide synthase) or sildenafil (5 mg/kg, i.p., a phosphodiesterase 5 inhibitor). The administration of 7-nitroindazole (50 mg/kg, i.p., a neuronal nitric oxide synthase inhibitor), methylene blue (20 mg/kg, i.p., an inhibitor of both nitric oxide synthase and soluble guanylate cyclase) or ODQ (30 pmol/site i.c.v., a soluble guanylate cyclase inhibitor) in combination with a subeffective dose of escitalopram (0.1 mg/kg, p.o.) reduced the immobility time in the FST as compared with either drug alone. None of the drugs produced significant effects on the locomotor activity in the open-field test. Altogether, our data suggest that the antidepressant-like effect of escitalopram is dependent on inhibition of either NMDA receptors or NO-cGMP synthesis. The results contribute to the understanding of the mechanisms underlying the antidepressant-like effect of escitalopram and reinforce the role of NMDA receptors and l-arginine-NO-GMP pathway in the mechanism of action of antidepressant agents.     

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

Objectives:

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

Materials and Methods:

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

Results:

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

Conclusion:

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

Indorenate produces antidepressant-like actions in the rat forced swimming test via 5-HT1A receptors

Abstract Rationale. Indorenate has been proposed to possess antihypertensive, anorectic, stimulus control and anxiolytic-like actions. This compound has affinity mainly for the serotonergic_1A/1B receptors, hence it could possess antidepressant-like activity. Objectives. The general purpose of this study was to explore the possible antidepressant-like effects of the serotonergic compound indorenate in the forced swimming test (FST). Methods. In a first approach, a comparison of the actions of several doses of indorenate (2.5, 5.0, 10 mg/kg) with those of other 5-HT_1A agonists, buspirone (5.0, 10.0 mg/kg) and 8-OH-DPAT (0.25, 0.50, 1.0 mg/kg), was performed in the FST. Secondly, in order to determine the serotonergic receptors that are participating in indorenate's action, different doses of serotonergic antagonists were administered. The compounds used were the 5-HT_1A/1B and β-adrenergic antagonist pindolol (2.5, 5.0 mg/kg), the 5-HT_1B receptor antagonist GR 55562 (0.75, 1.5, 3.0 mg/kg), the 5-HT_1A antagonist WAY 100635 (0.25, 0.5, 1.0 mg/kg) and the 5-HT₂ antagonist ketanserin (1.0, 2.0, 4.0 mg/kg). Results. Indorenate (10 mg/kg), 8-OH-DPAT (1.0 mg/kg) and buspirone (5.0 and 10.0 mg/kg) reduced immobility behaviour in the FST, considered as an antidepressant-like effect. Both doses of pindolol (2.5 and 5.0 mg/kg) and WAY 100635 (0.5 and 1.0 mg/kg) antagonised the antidepressant-like effect of indorenate. Neither 5-HT_1B (GR55562) nor 5-HT₂ (ketanserin) antagonists produced changes in the effect of indorenate in the FST. Conclusions. Indorenate produces antidepressant-like actions in the FST that are mediated by the stimulation of 5-HT_1A receptors. Electronic Publication     

Serotonergic mediation of the effects of fluoxetine, but not desipramine, in the rat forced swimming test

Rationale: The forced swimming test (FST) is a behavioral test in rodents that predicts the clinical efficacy of many types of antidepressant treatments. Recently, a behavior sampling technique was developed that scores individual response categories, including swimming, climbing and immobility. Although all antidepressant drugs reduce immobility in the FST, at least two distinct active behavioral patterns are produced by pharmacologically selective antidepressant drugs. Serotonin-selective reuptake inhibitors increase swimming behavior, while drugs acting primarily to increase extracellular levels of norepinephrine or dopamine increase climbing behavior. Distinct patterns of active behaviors in the FST may be mediated by distinct neurotransmitters, but this has not been shown directly. Objectives: The present study examined the role of serotonin in mediating active behaviors in the forced swimming test after treatment with two antidepressant drugs, the selective serotonin reuptake inhibitor, fluoxetine and the selective norepinephrine reuptake inhibitor, desipramine. Methods: Endogenous serotonin was depleted by administering para-cholorophenylalanine (PCPA, 150 mg/kg, IP.) to rats 72 h and 48 h prior to the swim test. Fluoxetine (10 mg/kg, SC) or desipramine (10 mg/kg, SC) was given three times over a 24-h period prior to the FST. Behavioral responses, including immobility, swimming and climbing, were counted during the 5-min test. Results: Pretreatment with PCPA blocked fluoxetine-induced reduction in immobility and increase in swimming behavior during the FST. In contrast, PCPA pretreatment did not interfere with the ability of desipramine to reduce immobility and increase climbing behavior. Conclusions: Depletion of serotonin prevented the behavioral effects of the selective serotonin reuptake inhibitor fluoxetine in the rat FST. Furthermore, depletion of serotonin had no impact on the behavioral effects induced by the selective norepinephrine reuptake inhibitor, desipramine. The effects of antidepressant drugs on FST-induced immobility may be exerted by distinguishable contributions from different neurotransmitter systems. Received: 4 February 1999 / Final version: 2 June 1999     

Antidepressant-like effect of Δ-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L.

The antidepressant action of cannabis as well as the interaction between antidepressants and the endocannabinoid system has been reported. This study was conducted to assess the antidepressant-like activity of ?⁹-THC and other cannabinoids. Cannabinoids were initially evaluated in the mouse tetrad assay to determine doses that do not induce hypothermia or catalepsy. The automated mouse forced swim (FST) and tail suspension (TST) tests were used to determine antidepressant action. At doses lacking hypothermic and cataleptic effects (1.25, 2.5, and 5 mg/kg, i.p.), both ?⁹-THC and ?⁸-THC showed a U-shaped dose response with only ?⁹-THC showing significant antidepressant-like effects at 2.5 mg/kg (p < 0.05) in the FST. The cannabinoids cannabigerol (CBG) and cannabinol (CBN) did not produce antidepressant-like actions up to 80 mg/kg in the mouse FST, while cannabichromene (CBC) and cannabidiol (CBD) exhibited significant effect at 20 and 200 mg/kg, respectively (p < 0.01). The antidepressant-like action of ?⁹-THC and CBC was further confirmed in the TST. ?⁹-THC exhibited the same U-shaped dose response with significant antidepressant-like action at 2.5 mg/kg (p < 0.05) while CBC resulted in a significant dose-dependent decrease in immobility at 40 and 80 mg/kg doses (p < 0.01). Results of this study show that ?⁹-THC and other cannabinoids exert antidepressant-like actions, and thus may contribute to the overall mood-elevating properties of cannabis.     

The association effect of insulin and clonazepam on oxidative stress in liver of an experimental animal model of diabetes and depression

Abstract

Context: It is known that oxidative stress occurs in peripheral blood in an experimental animal model of diabetes and depression, and acute treatment with insulin and clonazepam (CNZ) has a protective effect on oxidative stress in this model.

Objective: This study evaluated the effect of insulin plus CNZ on oxidative stress parameters in the liver of diabetic male rats induced with streptozotocin (STZ) and subjected to forced swimming test (FST).

Materials and methods: Diabetes was induced by a single intraperitoneal (i.p.) dose of STZ 60?mg/kg in male Wistar rats. Insulin (4?IU/kg) plus CNZ acute i.p. treatment (0.25?mg/kg) was administered 24, 5 and 1?h before the FST. Nondiabetic control rats received i.p. injections of saline (1?mL/kg). Protein oxidative damage was evaluated by carbonyl formation and the antioxidant redox parameters were analyzed by the measurements of enzymatic activities of the superoxide dismutase (SOD), catalase and glyoxalase I (GLO). Glycemia levels also were determined.

Results: Our present study has shown an increase in carbonyl content from diabetic rats subjected to FST (2.04?±?0.55), while the activity of catalase (51.83?±?19.02) and SOD (2.30?±?1.23) were significantly decreased in liver from these animals, which were reverted by the treatment. Also, the activity of GLO (0.15?±?0.02) in the liver of the animals was decreased.

Discussion and conclusion: Our findings showed that insulin plus CNZ acute treatment ameliorate the antioxidant redox parameters and protect against protein oxidative damage in the liver of diabetic rats subjected to FST.     

A role for serotonin in the antidepressant activity of N-Nitro-L-arginine, in the rat forced swimming test

The present study determined regional serotonin (5-HT) synthesis and metabolism changes associated with the nitric oxide synthase (NOS) inhibitor N^G-nitro-L-arginine (L-NA) and the influence of 5-HT receptor blockade in the antidepressant-like actions of L-NA in the forced swimming test (FST). Regional effects of L-NA (5,10 and 20 mg/kg i.p.) on tryptophan hydroxylase (TPH) activity, the rate limiting enzyme for 5-HT synthesis, were determined by measuring accumulation of the transient intermediate 5-hydoxytryptophan (5-HTP) following in vivo administration of the amino acid decarboxylase inhibitor, NSD 1015 (100 mg/kg). L-NA (5-20 mg/kg) dose dependently increased 5-HTP accumulation, particularly in the amygdaloid cortex, following exposure to the FST. L-NA also provoked an increase in regional brain 5-HIAA concentrations and in the 5-HIAA:5-HT metabolism ratio. Co-treatment with NSD-1015 failed to consistently modify the antidepressant-like effects of L-NA in the FST. Sub-active doses of L-NA (1 mg/kg) and the 5-HT re-uptake inhibitor fluoxetine (2.5 mg/kg) acted synergistically to increase swimming in the test. Co-treatment with the non-selective 5-HT receptor antagonist metergoline (1, 2 and 4 mg/kg), attenuated the L-NA (20 mg/kg)-induced reduction in immobility and increase in swimming behaviours. Metergoline alone however provoked an increase in immobility and reduction in swimming behaviours in the test. A similar response was obtained following co-treatment with the preferential 5-HT_2A receptor antagonist ketanserin (5 mg/kg) and the 5-HT_2C receptor antagonist RO-430440 (5 mg/kg). Co-treatment with the 5-HT_1A receptor antagonist WAY 100635 (0.3 mg/kg) or the 5-HT_1B receptor antagonist GR 127935 (4 mg/kg) failed to influence the antidepressant-like activity of L-NA. Taken together these data provide further support for a role for 5-HT in the antidepressant-like properties of NOS inhibitors.     

Antidepressant-like and antinociceptive-like actions of 4-(4'-chlorophenyl)-6-(4''-methylphenyl)-2-hydrazinepyrimidine Mannich base in mice

This study investigated the possible antidepressant and antinociceptive action of CPMPH Mannich base, as well as the involvement of serotonergic, dopaminergic, noradrenergic and opioid systems and the L-arginine-nitric oxide pathway in the antidepressant-like effect of CPMPH in the forced swimming test (FST) in mice. The immobility time in the FST was significantly reduced by CPMPH (0.1-10 mg/kg, i.p.), without accompanying changes in the ambulation in an open-field. CPMPH at high doses (i.p. or s.c. routes) produced a significant inhibition of acetic acid-induced writhing. The antidepressant-like effect of CPMPH (1 mg/kg, i.p.) in the FST was prevented by pre-treatment of mice with methysergide (2 mg/kg, i.p., a non-selective serotonin receptor antagonist), sulpiride (32 mg/kg, i.p., a D2 receptor antagonist) or yohimbine (1 mg/kg, i.p., an alpha2-adrenoceptor antagonist). In contrast, the antidepressant-like effect of CPMPH was not affected by pre-treatment (i.p.) with naloxone (1 mg/kg, a non-selective opioid receptor antagonist) or L-arginine (750 mg/kg, a nitric oxide precursor). The results demonstrate that CPMPH had an antidepressant-like action that appears to be mediated through its interaction with serotonergic, dopaminergic and noradrenergic systems.     

藏药佐太的抗抑郁抗焦虑作用研究

目的 观察藏药佐太的抗抑郁和抗焦虑作用,并探讨其可能作用机制。方法 1）初步评价实验：在小鼠ig给予6.07、60.70、303.49、606.97 mg/kg佐太14 d后,通过强迫游泳实验和开场实验初步评价佐太对抑郁和焦虑的影响,同时通过检测小鼠血清中5-羟色胺（5-HT）和去甲肾上腺素（NE）水平来探讨佐太产生影响的可能作用机制。2）不可预测性慢性温和应激模型（CUMS）实验：建立CUMS模型,ig给予6.07、60.70、606.97 mg/kg佐太后,通过小鼠体质量变化、糖水偏爱实验、小鼠悬尾实验、开场实验和埋珠实验评价佐太对CUMS模型小鼠的抗抑郁和抗焦虑作用,同时检测小鼠血清中皮质酮（CORT）、促肾上腺皮质激素（ACTH）和下丘脑中促肾上腺皮质激素释放激素（CRH）水平,测定佐太对CUMS模型小鼠下丘脑-垂体-肾上腺（HPA）轴的影响。结果 1）佐太能够显著减少小鼠强迫游泳实验中不动时间（6.07、60.70、303.49、606.97 mg/kg）;增加小鼠在开场实验中中央区停留时间百分率（606.97 mg/kg）和中央区运动百分比（303.49、606.97 mg/kg）;增加小鼠血清中5-HT（6.07、606.97 mg/kg）和NE（6.07、303.49、606.97 mg/kg）水平。2）CUMS实验中,与对照组比较,经过42 d CUMS慢性应激小鼠表现出明显的抑郁和焦虑样行为,包括糖水偏爱率的降低、悬尾不动时间显著增加、开场实验中运动时间、中央区域停留时间及运动距离的减少和周边区域运动距离的增加、埋珠实验中埋珠个数的增加。而ig给予佐太（6.07、60.70、606.97 mg/kg）能够显著改善CUMS模型引起的上述症状,并且佐太（6.07、60.70 mg/kg）能够显著降低CORT、ACTH和CRH水平,抑制CUMS模型引起的HPA轴亢进。结论 佐太具有一定的抗抑郁和抗焦虑作用,并且其作用机制可能与升高5-HT、NE水平和抑制HPA轴亢进有关。