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.     

Evidence for the involvement of the noradrenergic system, dopaminergic and imidazoline receptors in the antidepressant-like effect of tramadol in mice

The involvement of the noradrenergic system, imidazoline, dopaminergic and adenosinergic receptors in the antidepressant-like action of tramadol in the mouse forced swimming test (FST) was evaluated in this study. The antidepressant-like effect of tramadol (40 mg/kg, per oral, p.o.) in the FST was blocked with yohimbine (1 mg/kg, i.p., an α₂-adrenoceptor antagonist), α-methyl-para-tyrosine methyl ester (AMPT, 100 mg/kg, i.p., an inhibitor of tyrosine hydroxylase), efaroxan (1 mg/kg, i.p., an imidazoline I₁/α₂-adrenoceptor antagonist), idazoxan (0.06 mg/kg, i.p., an imidazoline I₂/α₂-adrenoceptor antagonist), antazoline (5 mg/kg, i.p., a ligand with high affinity for the I₂ receptor), haloperidol (0.2 mg/kg, i.p., a non selective dopamine receptor antagonist), SCH23390 (0.05 mg/kg, subcutaneously, s.c., a dopamine D₁ receptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D₂ and D₃ receptor antagonist) but was not reversed by prazosin (1 mg/kg, intraperitoneally, i.p., an α₁-adrenoceptor antagonist) and caffeine (3 mg/kg, i.p., a nonselective adenosine receptor antagonist). Monoamine oxidase-A and -B (MAO-A and MAO-B) activities were neither inhibited in the whole brain nor in specific brain regions of mice treated with tramadol. These data demonstrated that the antidepressant-like effect caused by oral administration of tramadol in the mouse FST is mediated by the noradrenergic system, dopaminergic and imidazoline receptors.     

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.     

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     

Antidepressant-like effect of ursolic acid isolated from Rosmarinus officinalis L. in mice: Evidence for the involvement of the dopaminergic system

Ursolic acid, a constituent from Rosmarinus officinalis, is a triterpenoid compound which has been extensively known for its anticancer and antioxidant properties. In the present study, we investigated the antidepressant-like effect of ursolic acid isolated from this plant in two predictive tests of antidepressant property, the tail suspension test (TST) and the forced swimming test (FST) in mice. Furthermore, the involvement of dopaminergic system in its antidepressant-like effect was investigated in the TST. Ursolic acid reduced the immobility time in the TST (0.01 and 0.1 mg/kg, p.o.) and in the FST (10 mg/kg, p.o.), similar to fluoxetine (10 mg/kg, p.o.), imipramine (1 mg/kg, p.o.) and bupropion (10 mg/kg, p.o.). The effect of ursolic acid (0.1 mg/kg, p.o.) in the TST was prevented by the pretreatment of mice with SCH23390 (0.05 mg/kg, s.c., a dopamine D₁ receptor antagonist) and sulpiride (50 mg/kg, i.p., a dopamine D₂ receptor antagonist). The administration of a sub-effective dose of ursolic acid (0.001 mg/kg, p.o.) in combination with sub-effective doses of SKF38393 (0.1 mg/kg, s.c., a dopamine D₁ receptor agonist), apomorphine (0.5 μg/kg, i.p., a preferential dopamine D₂ receptor agonist) or bupropion (1 mg/kg, i.p., a dual dopamine/noradrenaline reuptake inhibitor) reduced the immobility time in the TST as compared with either drug alone. Ursolic acid and dopaminergic agents alone or in combination did not cause significant alterations in the locomotor and exploratory activities. These results indicate that the antidepressant-like effect of ursolic acid in the TST is likely mediated by an interaction with the dopaminergic system, through the activation of dopamine D₁ and D₂ receptors.     

Antidepressant-like effect of the organoselenium compound ebselen in mice: Evidence for the involvement of the monoaminergic system

Ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one] is a seleno-organic compound which possesses a potent antioxidant activity and has been shown to exert neuroprotective effects in vitro and in vivo in a variety of pro-oxidative insults. The present study investigates a possible antidepressant activity of ebselen using two predictive tests for antidepressant activity in rodents: the forced swimming test and tail suspension test. Additionally, the mechanisms involved in the antidepressant-like effect of ebselen in mice were also assessed. Ebselen (10 mg/kg, s.c.) decreased the immobility time in the forced swimming test without accompanying changes in ambulation in the open-field test. In contrast, the administration of ebselen (10-30 mg/kg) did not produce any effect in the tail suspension test. The anti-immobility effect of ebselen (10 mg/kg, s.c.) was not prevented by pre-treatment of mice with p-chlorophenylalanine (PCPA, 100 mg/kg, i.p., an inhibitor of serotonin synthesis, 4 consecutive days), NAN-190 (0.5 mg/kg, i.p., a serotonin 5-HT_1A receptor antagonist) or ketanserin (5 mg/kg, i.p., a serotonin 5-HT_2A/2C receptor antagonist). On the other hand, the pre-treatment of mice with prazosin (1 mg/kg, i.p., an α₁-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an α₂-adrenoceptor antagonist), SCH23390 (0.05 mg/kg, s.c., a dopamine D₁ receptor antagonist) or sulpiride (50 mg/kg, i.p., a dopamine D₂ receptor antagonist) completely blocked the antidepressant-like effect of ebselen (10 mg/kg, s.c.) in the forced swimming test. It may be concluded that ebselen produces an antidepressant-like effect in the forced swimming test that seems to be dependent on its interaction with the noradrenergic and dopaminergic systems, but not with the serotonergic system.     

Potentiation of the antidepressant-like effect of desipramine or reboxetine by metyrapone in the forced swimming test in rats

The obtained results revealed that joint administration of desipramine or reboxetine and metyrapone (a glucocorticoid synthesis inhibitor) had more potent antidepressant-like activity in the forced swimming test (FST) in rats compared to treatment with either drug alone. WAY 100636 (a 5-HT_1A antagonist), and prazosin (an α₁-adrenergic antagonist), used in doses ineffective in the FST, inhibited the antidepressant-like effect induced by co-administration of desipramine (10 mg/kg) or reboxetine (10 mg/kg) and metyrapone (50 mg/kg). The above-mentioned findings suggest that, among other mechanisms, the 5-HT_1A and α₁-adrenergic receptors may play a role in this effect. Furthermore, they may be of particular importance to the pharmacotherapy of drug-resistant depression.     

Melatonin affects the immobility time of rats in the forced swim test: The role of serotonin neurotransmission

The efficacy of melatonin or its derivatives in depressive patients has been recently considered for clinical application. However, the evidence for its effect on experimental models of depression is not consolidated. Here, the effects of melatonin on the model of forced swim test (FST) paradigm were studied in male rats of the Wistar strain after acute intraperitoneal (i.p.) administration of 0.1, 0.5 or 1 mg/kg of the hormone. Melatonin at doses of 0.5 and 1 mg/kg, but not of 0.1 mg/kg, decreased the immobility of rats in the FST paradigm suggesting a possible antidepressant-like activity. The dose of 0.5 mg/kg appeared to be as potent as clomipramine 50 mg/kg in reducing the immobility time of rats in the FST paradigm. The effect of melatonin on immobility time of rats in the FST paradigm was abolished by the simultaneous injection of the non-selective melatonin antagonist, luzindole (0.25 mg/kg, subcutaneously). Similarly, administration of small quantities of serotonin (5-HT, 5 ng/1 μl) or of the 5-HT_2A/5-HT_2C receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (2 ng/1 μl) injected into the amygdale totally suppressed the reduction of immobility time in the FST paradigm induced by melatonin 0.5 mg/kg. These results may suggest that effects of melatonin on the behavioral reaction of rats in the FST paradigm are due to an interaction of the hormone with central 5-HT neurotransmission.     

Antidepressant and anxiolytic effects of amentoflavone isolated from Cnestis ferruginea in mice

The root decoction of Cnestis ferruginea (CF) Vahl DC (Connaraceae) is used in traditional African medicine in the management of psychiatric disorders. This study presents the antidepressant and anxiolytic effects of amentoflavone (CF-2) isolated from the root extract of C. ferruginea.The antidepressant effect was studied using the forced swimming (FST) and tail suspension tests (TST) while the hole-board, elevated plus maze (EPM) and light/dark tests were used to evaluate the anxiolytic effect. Acute treatment with CF extract and amentoflavone significantly (p < 0.001) reduced the duration of immobility in FST and TST with peak effects observed at 100 and 50 mg/kg respectively in comparison to control treated. Antidepressant effects of CF and amentoflavone were significantly higher (p < 0.05) when compared to imipramine in FST but comparable to the fluoxetine treated group in TST.The pretreatment of mice with metergoline (4 mg/kg, i.p., a 5-HT2 receptor antagonist), prazosin (62.5 μg/kg, i.p., an α1-adrenoceptor antagonist), and yohimbine (1 mg/kg, i.p., an α2-adrenoceptor antagonist), but not sulpiride (50 mg/kg, i.p., a dopamine D2 receptor antagonist), cyproheptadine (3 mg/kg, i.p., a 5-HT2 receptor antagonist), atropine (1 mg/kg, i.p., a muscarinic receptor antagonist) 15 mins before the administration of amentoflavone (50 mg/kg; p.o.) significantly prevented its antiimmobility effect in the FST.CF extract and CF-2 significantly (p < 0.05) attenuated anxiety by increasing the number of head-dips in the hole-board test, the time spent on the open arms in the EPM, and the exploration of the light chamber in the light/dark test. Pretreatment with flumazenil (3 mg/kg, i.p., ionotropic GABA receptor antagonist) 15 min before oral administration of amentoflavone (25 mg/kg) significantly reduced the time spent in the open arms in EPM. It is concluded from the results obtained that amentoflavone produces its antidepressant effect through interaction with 5-HT2 receptor and α1-, and α2-adrenoceptors while the anxiolytic effect involved the ionotropic GABA receptor.     

Diltiazem potentiates pentobarbital-induced hypnosis via 5-HT1A and 5-HT2A/2C receptors: role for dorsal raphe nucleus

It has been reported that the sedative component of pentobarbital is mediated by GABA receptors in an endogenous sleep pathway and the ventrolateral preoptic area (VLPO)-tuberomammillary nucleus (TMN) or VLPO-dorsal raphe nucleus (DRN) neural circuit is important in the sedative response to pentobarbital. Our previous findings indicated that the VLPO-TMN neuronal circuit may play crucial part in the augmentative effect of diltiazem on pentobarbital sleep and the serotonergic system may be involved. This study was designed to investigate the role of DRN and the serotonergic receptors 5-HT_1A and 5-HT_2A/2C in the augmentative effect of diltiazem on pentobarbital-induced hypnosis in rats. The results showed that diltiazem (5 mg/kg, i.g.) significantly reversed pentobarbital-induced (35 mg/kg, i.p.) reduction of c-Fos expression in 5-HT neurons of DRNV (at − 7.5 mm Bregma), DRND, DRNVL and MRN (at − 8.0 mm Bregma). However it did not influence this reducing effect of pentobarbital on non-5-HT neurons either in DRN or in MRN. Moreover, the effect of diltiazem (1 or 2 mg/kg, i.g.) on pentobarbital-induced (35 mg/kg, i.p.) hypnosis was significantly inhibited by 5-HT_1A agonist 8-OH-DPAT (0.5 mg/kg, i.p.) and 5-HT_2A/2C agonist DOI (0.5 mg/kg, i.p.), and potentiated by 5-HT_1A antagonist p-MPPI (2 mg/kg, i.p.) and 5-HT_2A/2C antagonist ritanserin (2 mg/kg, i.p.), respectively. From these results, it should be presumed that the augmentative effect of diltiazem on pentobarbital-induced sleep may be related to 5-HT_1A and 5-HT_2A/2C receptors, and DRN may be involved. In addition, it also suggested that the DRN may play a multi-modulating role in sleep-wake regulation rather than being recognized simply as arousal nuclei.     

A novel 5-HT2A receptor antagonist exhibits antidepressant-like effects in a battery of rodent behavioural assays: Approaching early-onset antidepressants

Collective evidence suggests that inhibition of neuronal 5-hydroxytryptamine type 2A (5-HT_2A) receptors contributes to the assuagement of depression-like behaviour in rodents. The present study evaluated the antidepressant-like effect of the 5-((4-benzo [α] isothiazol-3-yl) piperazin-1-yl) methyl)-6-chloroindolin-2-one (BIP-1), a compound having affinity to 5-HT_2A receptors, using a rodent behavioural test battery. Acute BIP-1 (0.25-4 mg/kg) pretreatment reduced the quipazine-induced head twitches in mice and produced antidepressant-like effects in mouse forced swim and tail suspension tests. BIP-1 reversed the depressogenic-like effects of meta-chlorophenyl piperazine and augmented the antidepressant-like effects of amitryptiline and harmane. Chronic (14 days) treatment with BIP-1 (1 and 2 mg/kg) or amitriptyline (10 mg/kg) alleviated the behavioural anomalies of olfactory bulbectomised rats in modified open field exploration, social interaction, hyperemotionality and sucrose preference paradigms. When BIP-1 treatment was combined with amitryptyline, a short duration regimen (7 days) was sufficient to reverse the bulbectomy induced anomalies. This investigation revealed that 5-HT_2A receptor antagonism is the principal mechanism behind the antidepressant-like effects of BIP-1. Finally, we propound the combination of 5-HT_2A receptor antagonists and tricyclic antidepressants as a likely strategy to achieve an early-onset of antidepressant action.     

Antidepressant-like effect of novel 5-HT3 receptor antagonist N-n-butyl-3-ethoxyquinoxalin-2-carboxamide (6p): An approach using rodent behavioral antidepressant tests

Objective:

The present study was designed to investigate the antidepressant potential of N-n-butyl-3-ethoxyquinoxalin-2-carboxamide (6p), a novel 5-HT₃ receptor antagonist in rodent behavioral models of depression.

Materials and Methods:

The compound 6p was examined in various behavioral models like forced swim test (FST), tail suspension test (TST), mechanistic models [5-hydroxytryptophan (5-HTP)-induced head twitch and reserpine-induced hypothermia (RIH)], and in chronic surgery model-olfactory bulbectomy in rats.

Results:

Compound 6p (1, 2, and 4 mg/kg, i.p.) exhibited antidepressant-like effect in FST and TST after acute treatment without having an effect on baseline locomotor activity. Moreover, 6p (2 mg/kg, i.p.), potentiated the 5-HTP–induced head twitch responses in mice and inhibited the RIH in rats. Chronic treatment (14 days) with 6p (1 and 2 mg/kg, p.o.) and paroxetine (10 mg/kg, p.o.) in rats significantly reversed the behavioral anomalies induced by bilateral olfactory bulbectomy using open field exploration.

Conclusion:

The preliminary studies reveal that compound 6p exhibits antidepressant-like effect in behavioral rodent models of depression.KEY WORDS: 5-HT₃ receptor antagonists, antidepressant, forced swim test, quinoxaline, serotonin     

In vitro antioxidant activity and in vivo antidepressant-like effect of α-(phenylselanyl) acetophenone in mice

In this study, the antioxidant and antidepressant-like effects of α-(phenylselanyl) acetophenone (PSAP), an organoselenium compound, were investigated. To assess the in vitro antioxidant properties, PSAP was evaluated in four test systems (DPPH, ABTS, FRAP and inhibition of lipid peroxidation). PSAP (100-500 μM) showed potent antioxidant activity and protected against lipid peroxidation. Additionally, we investigated whether PSAP, when administered in mice (100, 200 and 400 mg/kg, per oral, p.o.), could cause acute toxicity. Our results demonstrated that PSAP did not cause the death of any animal, significantly reduce body weight or cause any oxidative tissue stress following treatment. This study also evaluated the effect of PSAP (0.1-10 mg/kg, p.o) on mice in a forced swim test (FST) and tail suspension test (TST), assays that are predictive of depressant activity and motor activity in the open-field. PSAP (5-10 mg/kg) significantly reduced immobility time in the FST and TST without affecting motor activity. In addition, the antidepressant-like effect caused by PSAP (5 m/kg, p.o) in mice during the TST was dependent on an interaction with the serotonergic system (5-HT_1A receptors), but not with the noradrenergic, dopaminergic or adenosinergic system. Together, these results suggest that PSAP possesses antioxidant and antidepressant-like properties and may be of interest as a therapeutic agent for the treatment of depressive disorders.     

5-HT7 receptor activation attenuates thermal hyperalgesia in streptozocin-induced diabetic mice

The role of 5-HT7 receptors in the nociceptive processing received most attention during the last few years. The involvement of 5-HT₇ receptors in nerve injury-induced neuropathic pain states have been reported only recently; however, there are no reports on its contribution in diabetic neuropathic pain. We therefore planned to investigate the effect of 5-HT₇ receptor activation on the changes of nociceptive threshold in diabetic mice. Diabetes was induced by a single intraperitoneal injection of streptozocin (150 mg/kg, i.p.). The nociceptive responses in normal and diabetic animals were tested in the hot-plate and tail-flick assays. Both hot-plate and tail-flick latencies significantly shortened at 1-3/4 weeks (thermal hyperalgesia) and prolonged at 6-7 weeks (thermal hypoalgesia) after streptozocin administration. At the dose of 10 mg/kg, systemic injections of AS-19, a selective 5-HT₇ receptor agonist, reduced thermal hyperalgesia at early stage of diabetes, but did not influence thermal hypoalgesia at late stage. Co-administration of SB-258719, a selective 5-HT₇ receptor antagonist, at a dose that had no effect on its own (10 mg/kg), reversed the anti-hyperalgesic effect of AS-19. Our results indicate that systemic administration of 5-HT₇ receptor agonists may have clinical utility in treating diabetic neuropathic pain.     

Antidepressant-like pharmacological profile of 3-(4-fluorophenylselenyl)-2,5-diphenylselenophene: Involvement of serotonergic system

This study evaluated the effect of 3-(4-fluorophenylselenyl)-2,5-diphenylselenophene (DPS) in the mouse forced swim test (FST) and tail suspension test (TST), two assays predictive of depressant activity. The involvement of serotonergic system in the effect caused by DPS was studied. The antidepressant-like effect of combined treatment with subeffetive doses of DPS and paroxetine, a selective serotonin reuptake inhibitor (SSRI) was investigated. Further, we verified the possible mechanism responsible for antidepressive-like effect of DPS. The results show that DPS (50 and 100 mg/kg, p.o.) significantly reduced the immobility time during the FST and TST, without accompanying changes in ambulation when assessed in the open-field test. The anti-immobility effect of DPS (50 mg/kg, p.o.) in the FST was prevented by pretreatment of mice with pCPA (100 mg/kg, i.p., once a day for 4 consecutive days, an inhibitor of 5-HT synthesis), WAY 100635 (0.1 mg/kg, s.c., a selective 5-HT1A receptor antagonist), ritanserin (1 mg/kg, i.p., a 5-HT2 receptor antagonist) or ondansetron (1 mg/kg, i.p., a 5-HT3 receptor antagonist). Combined treatment with paroxetine and DPS reduced the immobility time in the FST. DPS at the doses of 10-100 mg/kg did not produce any change in the cerebral activity of MAO-A or MAO-B. DPS at the dose of 50 mg/kg inhibited significantly 5-HT uptake in synaptosomes. These results suggest that DPS produced an antidepressant-like effect in the mouse FST and TST and this effect seems most likely to be mediated through an interaction with serotonergic system, particularly by 5-HT reuptake inhibition.     

Role of endocannabinoid and glutamatergic systems in DOI-induced head-twitch response in mice

We previously reported that systemic administration of the endocannabinoid anandamide inhibited the head-twitches induced by the hallucinogenic drug 2,5-dimethoxy-4-iodoamphetamine (DOI) in mice, which is mediated via the activation of 5-HT_2A receptors. Endocannabinoid and glutamatergic systems have been suggested to modulate the function of 5-HT_2A receptors. In the present study, we further investigated the role of endocannabinoid and glutamatergic systems in DOI-induced head-twitch response in mice. An anandamide transport inhibitor AM404 (0.3-3 mg/kg, i.p.), a fatty acid amide hydrolase inhibitor URB597 (0.1-10 mg/kg, i.p.), a glutamate release inhibitor riluzole (0.3 and 1 mg/kg, i.p.), a natural glutamate analog l-glutamylethylamide (theanine, 1 and 3 mg/kg, p.o.) and an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist NBQX (0.01-0.3 mg/kg, i.p.) significantly inhibited DOI-induced head-twitch response. The AMPA receptor positive modulator aniracetam (30 or 100 mg/kg, p.o.) reversed inhibition of head-twitch response by NBQX and URB597. These findings indicated that endocannabinoid and glutamatergic systems participate in the mechanism of action of DOI to induce head-twitch response.     

Further analysis of the antinociceptive action caused by p-methoxyl-diphenyl diselenide in mice

The objective of this study was to extend our previous findings by investigating in greater detail the mechanisms that might be involved in the antinociceptive action of p-methoxyl-diphenyl diselenide, (MeOPhSe)₂, in mice. The pretreatment with nitric oxide precursor, l-arginine (600 mg/kg, intraperitoneal, i.p.), reversed antinociception caused by (MeOPhSe)₂ (10 mg/kg, p.o.) or N^G-nitro-l-arginine (l-NOARG, 75 mg/kg, i.p.) in the glutamate test. Ondansetron (0.5 mg/kg, i.p., a 5-HT₃ receptor antagonist) and SCH23390 (0.05 mg/kg, i.p.., a D₁ receptor antagonist) blocked the antinociceptive effect caused by (MeOPhSe)₂. Conversely, pindolol (1 mg/kg, i.p., a 5-HT_1A/_1B receptor/β adrenoceptor antagonist), WAY 100635 (0.7 mg/kg, i.p., a selective 5-HT_1A receptor antagonist), ketanserin (0.3 mg/kg, i.p., a selective 5-HT_2A receptor antagonist), prazosin (0.15 mg/kg, i.p., an α₁-adrenoreceptor antagonist), yohimbine (1.0 mg/kg, i.p., an α₂-adrenoreceptor antagonist), sulpiride (5 mg/kg, i.p., a D₂ receptor antagonist), naloxone (1 mg/kg, i.p., a non-selective opioid receptor antagonist) and caffeine (3 mg/kg, i.p., a non-selective adenosine receptor antagonist) did not change the antinociceptive effect of (MeOPhSe)₂. (MeOPhSe)₂ significantly inhibited nociception induced by intraplantar (i.pl.) injection of bradykinin (10 nmol/paw) and Des-Arg⁹-bradykinin (10 nmol/paw, a B₁ receptor agonist). (MeOPhSe)₂ significantly inhibited phorbol myristate acetate (PMA, 0.03 μg/paw, a protein kinase C (PKC) activator)-induced licking response. These results indicate that (MeOPhSe)₂ produced antinociception in mice through mechanisms that involve an interaction with nitrergic system, 5-HT₃ and D₁ receptors. The antinociceptive effect is related to (MeOPhSe)₂ ability to interact with kinin B₁ and B₂ receptors and PKC pathway mediated mechanisms.     

Effects of LPS and serotonergic drugs on hygienic behavior in mice

Hygienic self-grooming is a behavioral adaptation for removing litter particles and pathogenic agents from animal fur and skin. We studied contribution of brain serotonin system into mechanisms regulating hygienic behavior in intact mice and mice with LPS(lipopolysaccharide)-induced sickness. A spot of fluorescent dye was applied on the back of a mouse, and the decrease in its fluorescence served as an index of fur cleaning efficiency estimated using original classifier algorithm. Agonist of 5-HT_1A receptor (8-OH-DPAT) or 5-HT_2A/2C receptor (DOI) attenuated fur cleaning at a dose of 1 mg/kg but not of 0.2 mg/kg. MAO-A inhibitor clorgyline decreased hygienic self-grooming at a dose of 10 but not of 5 mg/kg. SSRI paroxetine had no effect while fluoxetine diminished hygienic behavior at the higher dose used (20 mg/kg). Inhibitory effect of LPS treatment (50 μg/kg) on fur cleaning was not altered by administration of p-MPPI (5-HT_1A receptor antagonist, 1 mg/kg) or DOI (1 mg/kg) while 8-OH-DPAT (1 mg/kg) produced additive effect. The results suggest the involvement of 5-HT_1A and 5-HT_2A/2C brain serotonin receptors and MAO-A in the inhibition of hygienic behavior in mice. However, LPS-induced depression of fur cleaning appeared to be mediated via different mechanisms and enhanced by 5-HT_1A receptor activation.     

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.