Involvement Of Serotonergic System Research Articles

Involvement of serotonergic neurotransmission in the antidepressant-like effect elicited by cholecalciferol in the chronic unpredictable stress model in mice.

Cholecalciferol deficiency has been associated with stress-related psychiatric disorders, particularly depression. Therefore, the present study investigated the antidepressant-like effect of cholecalciferol in female mice and the possible role of the serotonergic system in this response. The ability of cholecalciferol to elicit an antidepressant-like effect and to modulate serotonin levels in the hippocampus and prefrontal cortex of mice subjected to chronic unpredictable stress (CUS) was also investigated. The administration of cholecalciferol (2.5, 7.5, and 25µg/kg, p.o.) for 7days, similar to fluoxetine (10mg/kg, p.o., serotonin reuptake inhibitor), reduced the immobility time in the tail suspension test, without altering the locomotor performance in the open-field test. Moreover, the administration of p-chlorophenylalanine methyl ester (PCPA - 100mg/kg, i.p., for 4days, a selective inhibitor of tryptophan hydroxylase, involved in the serotonin synthesis) abolished the antidepressant-like effect of cholecalciferol and fluoxetine in the tail suspension test, demonstrating the involvement of serotonergic system. Additionally, CUS protocol (21days) induced depressive-like behavior in the tail suspension test and decreased serotonin levels in the prefrontal cortex and hippocampus of mice. Conversely, the administration of cholecalciferol and fluoxetine in the last 7days of CUS protocol completely abolished the stress-induced depressive-like phenotype. Cholecalciferol was also effective to abrogate CUS-induced reduction on serotonin levels in the prefrontal cortex, but not in the hippocampus. Our results indicate that cholecalciferol has an antidepressant-like effect in mice by modulating the serotonergic system and support the assumption that cholecalciferol may have beneficial effects for the management of depression.

Possible role of serotonin in the gastrokinetic activity of Amorphophallus paeoniifolius tuber

Background: Amorphophallus paeoniifolius (Dennst.) Nicolson (Araceae) tuber is consumed by various tribes for the treatment of constipation, hemorrhoids, functional dyspepsia and abdominal pain as ethnomedicinal practices. In our previous study, the tuber extract showed alteration of gastric emptying in healthy rats and ameliorated the gastrointestinal motor disorders, constipation and piles. Aim of the study: Hence, the present study evaluated the effect of Amorphophallus paeoniifolius tuber on experimentally-induced delayed gastric emptying in rats as well as investigated the plausible mechanism involved therein. Methods: Methanolic extract of Amorphophallus paeoniifolius (APME) was orally administered at the doses of 125, 250 and 500 mg/kg for 7 days. Delayed gastric emptying was induced in rats by cisplatin (10 mg/kg, i.p.) on the last day of extract treatment and gastric emptying was studied. To study the involvement of serotonergic system, the effect of APME (500 mg/kg) was investigated on gastric emptying in p-chlorophenylalanine (PCPA, a serotonergic neurotoxin) treated rats. Ex-vivo studies in isolated tissue preparation were also conducted to test the effect of APME on fundus contractility. Results: APME significantly reversed the delayed gastric emptying caused by cisplatin comparable to standard prokinetic drug, metoclopramide. Interestingly, the co-administration of sub-maximal doses of APME and metoclopramide showed synergistic effect on delayed gastric emptying. Further, in PCPA treated rats, APME (500 mg/kg) did not show any significant influence on delayed gastric emptying similar to metoclopramide. In Ex-vivo studies, the contractile response of APME remained unaltered in presence of atropine while it was potentiated significantly (P < 0.001) in presence of 5-HT as compared to the individual responses of 5-HT or APME. Phytochemical studies revealed the presence of betulinic acid in APME which is partial serotonergic agonist. Conclusion: The tuber of Amorphophallus paeoniifolius exhibited gastrokinetic activity and may be beneficial on functional dyspepsia. The effect may be ascribed to modulation of serotonergic neurotransmission in GIT.

Involvement of Serotonergic System in Oxaliplatin-Induced Neuropathic Pain.

Oxaliplatin is a chemotherapeutic agent widely used against colorectal and breast cancers; however, it can also induce peripheral neuropathy that can rapidly occur even after a single infusion in up to 80–90% of treated patients. Numerous efforts have been made to understand the underlying mechanism and find an effective therapeutic agent that could diminish pain without damaging its anti-tumor effect. However, its mechanism is not yet clearly understood. The serotonergic system, as part of the descending pain inhibitory system, has been reported to be involved in different types of pain. The malfunction of serotonin (5-hydroxytryptamine; 5-HT) or its receptors has been associated with the development and maintenance of pain. However, its role in oxaliplatin-induced neuropathy has not been clearly elucidated. In this review, 16 in vivo studies focused on the role of the serotonergic system in oxaliplatin-induced neuropathic pain were analyzed. Five studies analyzed the involvement of 5-HT, while fourteen studies observed the role of its receptors in oxaliplatin-induced allodynia. The results show that 5-HT is not involved in the development of oxaliplatin-induced allodynia, but increasing the activity of the 5-HT1A, 5-HT2A, and 5-HT3 receptors and decreasing the action of 5-HT2C and 5-HT6 receptors may help inhibit pain.

Chemical Composition of Essential Oil from Flower of 'Shanzhizi' (Gardenia jasminoides Ellis) and Involvement of Serotonergic System in Its Anxiolytic Effect.

Gardenia jasminoides Ellis is a famous fragrant flower in China. Previous pharmacological research mainly focuses on its fruit. In this study, the essential oil of the flower of ‘Shanzhizi’, which was a major variety for traditional Chinese medicine use, was extracted by hydro distillation and analyzed by GC-MS. Mouse anxiety models included open field, elevated plus maze (EPM), and light and dark box (LDB), which were used to evaluate its anxiolytic effect via inhalation. The involvement of monoamine system was studied by pretreatment with neurotransmitter receptor antagonists WAY100635, flumazenil and sulpiride. The monoamine neurotransmitters contents in the prefrontal cortex (PFC) and hippocampus after aroma inhalation were also analyzed. The results showed that inhalation of G. jasminoides essential oil could significantly elevated the time and entries into open arms in EPM tests and the time explored in the light chamber in LDB tests with no sedative effect. WAY100635 and sulpiride, but not flumazenil, blocked its anxiolytic effect. Inhalation of G. jasminoides essential oil significantly down-regulated the 5-HIAA/5-HT in the PFC and reduced the 5-HIAA content in hippocampus compared to the control treatment. In conclusion, inhalation of gardenia essential oil showed an anxiolytic effect in mice. Monoamine, especially the serotonergic system, was involved in its anxiolytic effect.

Modulatory Effect of Serotonergic System in Pentylenetetrazole-Induced Seizures and Associated Memory Deficit: Role of 5-HT&lt;sub&gt;1A&lt;/sub&gt; and 5-HT&lt;sub&gt;2A/2C&lt;/sub&gt;

Background and PurposeRecent studies have recognised the memory deficit as one of the most common psychiatric issues in the patients with epilepsy, which severely affects the quality of life. Our previous studies have demonstrated the possible involvement of serotonergic system in the pathogenesis of epilepsy and associated memory deficit. The possible involvement of 5-HT1A and 5-HT2A/2C receptor has not been explored yet. Therefore, this study has been envisaged to explore the effect of 5-HT1A and 5-HT2A/2C receptor modulation on epilepsy and memory deficit in pentylenetetrazole-kindled mice.MethodsIn the present experimental approach, we examined the efficacy of modulation of 5-HT1A and 5-HT2A/2C receptor in pentylenetetrazole-induced kindling in male Swiss mice (n=75). Mice were kindled by sub-convulsive dose of pentylenetetrazole (35 mg/kg, intraperitoneal injection), at the interval of 48±2 hours). Successfully kindled animals were treated with 5-HT1A and 5-HT2A/2C receptor modulators. The effect of different treatments on seizure severity score and memory impairment was analysed.Results5-HT1A receptor agonist improved the memory functions while seizure severity was not improved, and the opposite effect was observed with 5-HT1A receptor antagonist. On the other hand, 5-HT2A/2C receptor agonist significantly improved memory deficit as well as seizure severity in the kindled animals.ConclusionsThe outcome of the study indicates the possible involvement of 5-HT2A/2C receptor in the pathogenesis of epilepsy and associated memory deficit, which can be further explored for its management.

The Contribution of Serotonergic Receptors and Nitric Oxide Systems in the Analgesic Effect of Acetaminophen: An Overview of the Last Decade.

Acetaminophen is a widely used analgesic and antipyretic agent. It is also available in over the counter formulations, which has increased its wide use. There have been many studies to date that have aimed to evaluate the mechanism of the analgesic action of acetaminophen. Additional to the inhibition of the cyclooxygenase pathway in the central nervous system, the involvement of opioidergic, cannabinoidergic, dopaminergic, cholinergic, and nitrergic systems as well as the contribution of descending pain inhibitory systems like the bulbospinal serotonergic pathway has been proposed as possible mechanisms of the analgesic action of acetaminophen. In this review, we aimed to collect the data from studies revealing the contribution of the central serotonergic system and the role of central nervous system-located serotonergic receptor subtypes in the analgesic effect of acetaminophen. While doing this, we mainly focused on the research that has been performed in the last ten years and tried to link the previous data with the lately added results. In addition to serotonergic system involvement, we also reviewed the role of nitric oxide in the analgesic action of acetaminophen, especially with the new findings reported over the last decade.

Involvement of serotonergic system in the antidepressant-like effect of a novel curcumin derivative CUD003 in mice

Involvement of serotonergic system in the antidepressant-like effect of a novel curcumin derivative CUD003 in mice

New arylpiperazine derivatives with antidepressant-like activity containing isonicotinic and picolinic nuclei: evidence for serotonergic system involvement

Therapy of depression is difficult and still insufficient despite the presence of many antidepressants on the market. Therefore, there is a constant need to search for new, safer, and more effective drugs that could be used in the treatment of depression. Among many methods, chemical modification is an important strategy for new drug development. This study evaluates antidepressant-like effects and possible mechanism of action of two new arylpiperazine derivatives with isonicotinic and picolinic nuclei, compounds 4pN-(3-(4-(piperonyl)piperazin-1-yl)propyl) isonicotinamide and 3oN-(2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl) picolinamide. The forced swim test (FST) and tail suspension test (TST), as two predictive tests for antidepressant effect in mice, were used. The possible involvement of serotonergic system in the effects of the new compounds in the FST through pharmacological antagonists/modulators of serotonergic transmission was also investigated. Compounds 4p and 3o were shown to possess antidepressant activity in both tests, FST and TST. The antidepressant-like effects of the new compounds in the FST were prevented by pretreatment of mice with pCPA (serotonin depletor), (−)pindolol (mixed 5-HT1A/1B and β-adrenergic antagonist), and WAY 100635 (selective 5-HT1A antagonist). Additionally, in drug interaction studies, the 5-HT2A/2C antagonist, ketanserin, and the classic antidepressant, imipramine, potentiated antidepressant-like effect of both new compounds. The obtained results demonstrate that the new compounds 4p and 3o produce an antidepressant-like effect in mice which seems to be mediated by interaction with the serotonin 5-HT1A receptors and in the case of 4p, also with the 5-HT2C receptors.

Synthesis of Novel Benzazole Derivatives and Evaluation of Their Antidepressant-Like Activities with Possible Underlying Mechanisms.

Novel benzazole derivative compounds 4a–4h were obtained by the reaction of corresponding 2-(benzazol-2-ylthio)acetohydrazide and appropriate 4-substituted benzaldehydes. The chemical structures of the synthesized compounds were elucidated by FT-IR, 1H-NMR, 13C-NMR and LCMS spectroscopic methods. Antidepressant-like effects of the compounds were evaluated by tail suspension test (TST) and modified forced swimming tests (MFST). Moreover, locomotor activities of the animals were assessed by an activity cage apparatus. In the series, compounds 4a, 4b, 4e and 4f (at 50 mg/kg) significantly decreased the immobility time of mice in both of the TST and MFST. The same compounds prolonged the swimming time of animals in MFST without any change in the climbing duration. These data indicated that compounds 4a, 4b, 4e and 4f possess significant antidepressant-like activities. Moreover, pre-treatments with p-chloro-phenylalanine methyl ester (an inhibitor of serotonin synthesis), NAN-190 (a 5-HT1A antagonist), ketanserin (a 5-HT2A/2C antagonist), and ondansetron (a 5-HT3 antagonist) reversed the exhibited pharmacological effects. Results of the mechanistic studies suggested the involvement of serotonergic system and contributions of 5-HT1A, 5-HT2A/2C and 5-HT3 receptors to the antidepressant-like effects of compounds 4a, 4b, 4e and 4f. Furthermore, unchanged locomotor activity of mice following the administrations of these four derivatives confirmed that the presented antidepressant-like effects are specific.

Genistein, a dietary soy isoflavone, exerts antidepressant-like effects in mice: Involvement of serotonergic system

Genistein, a principal isoflavone property of soybeans, possesses multiple pharmacological activities such as neuroprotection. Recently, it was reported that genistein exerted antidepressant-like effects in animal models, but the mechanism of action remains ambiguous. The purpose of this study was to investigate the antidepressant-like effect of genistein in mice and explore the underlying mechanism(s), using two mouse models of depression, i.e. forced swim test (FST) and tail suspension test (TST). Chronic, but not acute (single dose), genistein treatment (5, 15 or 45 mg/kg, p.o., once per day for three weeks) exerted dose-dependently antidepressant-like effect in mice, concomitant with escalated levels of brain monoamines and suppressed monoamine oxidase (MAO) activity. Chemical depletion of brain serotonin by PCPA abrogated the antidepressant-like action of genistein, but it was not the case for ablation of NA by DSP-4. Moreover, the anti-depression by genistein was preferentially counteracted by co-administration of 5-HT1A receptor antagonist WAY-100635, suggesting a pivotal role for 5-HT system coupled with 5-HT1A receptors in mediating such genistein anti-depression. This point was further validated by the fact that genistein action was potentiated by co-treatment with 8-OH-DPAT, a selective 5-HT1A receptor agonist. Collectively, these findings confirm that chronic genistein administration to mice engenders antidepressant-like efficacy evidenced by lessened behavioral despair. Serotonergic system that preferentially couples with 5-HT1A receptors may be critically responsible for the present genistein anti-depression.

Comparative study of granisetron versus pethidine for the prevention of perioperative shivering under spinal Anesthesia

Aims: Shivering, the big little problem, has an incidence of 19-33% following spinal anesthesia. Recently, studies showed the involvement of serotonergic system in the control of postanesthetic shivering. Pharmacological management includes opioids (pethidine) and nonopioids like 5-HT3 receptor antagonists (ondansetron and granisetron). Pethidine which is considered as a time-tested drug for control of shivering can have adverse effects such as respiratory depression, nausea, and vomiting. This study was performed to compare the effect of prophylactic granisetron versus pethidine in prevention of perioperative shivering in patients under spinal anesthesia. Settings and Design: A prospective randomized, double blinded study was conducted on 60 patients of ASA I and II physical status aged between 20-50 years scheduled for elective lower abdominal surgeries under spinal anesthesia. Subjects and Methods: After obtaining ethical committee clearance and patient consent, sixty American Statistical Association Grade I and II patients, aged 20-50 years scheduled for elective lower abdominal surgeries under spinal anesthesia were recruited for a randomized double-blinded study divided into Group G and Group P and received intravenous (IV) granisetron 40 mcg/kg and pethidine 0.4 mg/kg, respectively. Perioperatively, vitals and core temperature were monitored and shivering was assessed using 5-item scale once in every 15 min up to 6 h. Statistical Analysis: The results were analysed using Statistical Package for Social Science software. Results: Of the sixty patients we studied, the demographic profile between the two groups was comparable. Six patients had shivering in each group. The mean temperature at which patient developed shivering was 36.31°C in Group G and 35.85°C in Group P. The mean time of onset for shivering to occur in Group G was 95 min and in Group P was 65 min. None of the patients received rescue drug. Patients in both the groups were hemodynamically stable. Conclusions: Prophylactic granisetron 40 μg/kg IV is as effective as pethidine 0.4 mg/kg IV in preventing perioperative shivering following spinal anesthesia and also reduces the need of antiemetics.

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-HT1A 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-HT1A receptor, in the antidepressant- and anxiolytic-like actions of investigated compounds.

Involvement of serotonergic system in the effect of a metabotropic glutamate 5 receptor antagonist in the novelty-suppressed feeding test

The blockade of metabotropic glutamate 5 (mGlu5) receptor has been reported to exert antidepressant effects in several animal models. We previously reported that both ketamine and an mGlu5 receptor antagonist exerted an effect in a novelty-suppressed feeding (NSF) test, and that the effect of ketamine may be mediated through an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-dependent increase in serotonergic transmission. However, the involvement of the serotonergic system in the effect of mGlu5 receptor antagonists in the NSF test is not well understood. Therefore, we examined the roles of the serotonergic system in the effect of an mGlu5 receptor antagonist, 6-methyl-2-(phenylethynyl)pyridine hydrochloride (MPEP), in the NSF test in mice. The administration of MPEP significantly shortened the latency to feed, which was not attenuated by the AMPA receptor antagonist, 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX). The effect of MPEP was abolished by the tryptophan hydroxylase inhibitor, para-chlorophenylalanine (PCPA). Moreover, the effect of MPEP was blocked by a serotonin (5-HT)2A/2C receptor antagonist, ritanserin, but not by a 5-HT1A receptor antagonist, N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridynyl) cyclohexane-carboxamide (WAY100635). These results suggest that the effect of an mGlu5 receptor antagonist may be mediated by the serotonergic system, including the stimulation of the 5-HT2A/2C receptor, in an AMPA receptor-independent manner in the NSF test.

Antidepressant-like activity of a new piperazine derivative of xanthone in the forced swim test in mice: The involvement of serotonergic system

BackgroundThe studied compound: 3-chloro-5-{[4-(2-hydroxyethyl)piperazin-1-yl]methyl}-9H-xanthen-9-one dihydrochloride (HBK-6) is a new xanthone derivative. In this study we investigated its antidepressant-like properties and possible mechanism of action. MethodsAntidepressant-like activity was evaluated in the forced swim test (FST) in mice. The influence on locomotor activity in mice was analyzed to determine whether the observed in FST effect is specific. Rotarod test was used to determine neurotoxic properties. ResultsHBK-6 reduced immobility time in mice in FST at the doses 5 and 10mg/kg, whereas fluoxetine (FX) at 15mg/kg, reboxetine (RX) at 10mg/kg and bupropion (BPR) at 5mg/kg. Joint administration of sub-effective doses of HBK-6 and FX, but not RX or BPR, reduced immobility in mice in FST. HBK-6 at the dose 5mg/kg did not show activity in FST after pretreatment with p-chlorophenylalanine. The studied xanthone derivative at the doses 5 and 10mg/kg did not impair motor coordination in mice. ConclusionsWe demonstrated that HBK-6 has a potent antidepressant-like activity in FST, stronger than that of FX and RX, and seems to mediate its effect through serotonergic system. Moreover, at antidepressant-like doses it does not show neurotoxic properties. Given the promising results, HBK-6 may have potential in the treatment of depression, but this needs extended studies.

Chronic resveratrol treatment exerts antihyperalgesic effect and corrects co-morbid depressive like behaviors in mice with mononeuropathy: Involvement of serotonergic system

Patients suffering from chronic neuropathic pain are at high risk of co-morbid depression, which burdens healthcare. This work aimed to investigate the effects of resveratrol, a phenolic monomer enriched in red wine and grapes, on pain-related and depressive-like behaviors in mice with mononeuropathy, and explored the mechanism(s). Mice received chronic constriction injury (CCI) of sciatic nerves, and sequentially developed pain-related and depressive-like behaviors, as evidenced by sensory hypersensitivity (thermal hyperalgesia in Hargreaves test and mechanical allodynia in von Frey test) and behavioral despair (prolonged immobility time in forced swim test). Chronic treatment of neuropathic mice with resveratrol (30 mg/kg, p.o., twice per day for three weeks) normalized their thermal hyperalgesia (but not mechanical allodynia) and depressive-like behaviors, and these actions were abolished by chemical depletion of central serotonin (5-HT) but potentiated by co-treatment with 5-HTP, a precursor of 5-HT. The anti-hyperalgesia and anti-depression exerted by resveratrol may be pharmacologically segregated, since intrathecal (i.t.) and intracerebroventricular (i.c.v.) injection of methysergide, a non-selective 5-HT receptor antagonist, separately abrogated the two actions. Furthermore, the antihyperalgesic action of resveratrol was preferentially counteracted by co-administration of the 5-HT7 receptor antagonist SB-258719, while the anti-depression was abrogated by 5-HT1A receptor antagonist WAY-100635. These results confirm that chronic resveratrol administration exerts curative-like effects on thermal hyperalgesia and co-morbid depressive-like behaviors in mice with mononeuropathy. Spinal and supraspinal serotonergic systems (coupled with 5-HT7 and 5-HT1A receptors, respectively) are differentially responsible for the antihyperalgesic and antidepressant-like properties of resveratrol.

Antidepressant and anti-anxiety like effects of 4i (N-(3-chloro-2-methylphenyl) quinoxalin-2-carboxamide), a novel 5-HT3 receptor antagonist in acute and chronic neurobehavioral rodent models

Depression and anxiety are the most debilitating mood disorders with poor therapeutic recovery rates. In the last decades, 5-HT3 receptor antagonists have been identified as potential agents for mood disorders. The current investigation focuses on evaluating the, antidepressant and anti-anxiety like effects of a novel 5-HT3 antagonist, 4i (N-(3-chloro-2-methylphenyl) quinoxalin-2-carboxamide). Preliminary, in vitro 5-HT3 receptor binding affinity was performed in isolated longitudinal muscle-myenteric plexus from the guinea pig ileum. Consequently, neurobehavioral effects of 4i in acute and chronic rodent models were evaluated. In addition, involvement of serotonergic system in the postulated effects of the compound was analyzed by in vivo assay. in vitro, 4i demonstrated high 5-HT3 receptor antagonistic activity (pA2, 7.6). in vivo acute study, 4i exhibited decreased duration of immobility in forced swim and tail suspension tests, and increased exploratory parameters as number and duration of nose-poking in hole board test and latency and time spent in aversive brightly illuminated light chamber in light–dark model. Moreover, in chronic model of depression, i.e., olfactory bulbectomy with behavioral deficits, 4i reversed depressive anhedonia in sucrose preference test and anxious hyperactive behavior in open field test in rats. Furthermore, synergistic effect of 4i with fluoxetine (a selective serotonin reuptake inhibitor) and inhibitory effect of 1-(m-chlorophenyl)-biguanide (a 5-HT3 receptor agonist) revealed serotonergic modulation by 4i mediated 5-HT3 receptor antagonism, which was further confirmed by potentiation of 5-hydroxytryptophan (a serotonin synthesis precursor) induced head twitch response. These findings suggest the potential antidepressant and anti-anxiety like effects of 4i, which may be related to the modulation of serotonergic system.

Involvement of Serotonergic System and Magnesium on Anxiolytic Effects of Pomegranate in Male Mice

The anxiolytic activities of Punica granatum L. fruit juice (PGFJ) in various validated animal models of anxiety and amnesia have been recently reported in mice. Similarly, anxiolytic-like activity of magnesium chloride has been exhibited in the elevated plus-maze test in mice, in some studies. Buspirone is an anxiolytic psychoactive drug with known effects on 5-HT1A receptors that its action is not related to benzodiazepines. The purpose of the present study was to examine interactions between PGFJ, magnesium (Mg) and buspirone as a partial agonist of 5-HT1A receptors in producing anxiolytic-like activity in the elevated plus maze in mice. The anxiolytic-like effect of PGFJ (5, 10 and 20 ml/kg, orally), buspirone (5 mg/kg, i.p), Mg (50 mg/kg, orally) and their interactions were evaluated after ten days’ treatment. PGFJ given at all doses induced an anxiolyticlike effect significantly increasing the percentage of the time spent in the open arms, and the percentage of the open arm entries, in a dose-dependent manner. Buspirone showed anxiolytic effect after ten days; however, its effect was roughly comparable to the effect of PGFJ 5 ml/kg. Buspirone in combination with PGFJ (5 ml/kg), did produce more effect compared to buspirone alone and nearly in the range of PGFJ 5 ml/kg response. Also, Mg induced an anxiolytic-like effect that was more than effects observed by buspirone 5 mg/kg. However, binary application of buspirone and Mg showed anxiolytic effects more than buspirone, alone. In another group, Mg in combination with PGFJ (5 ml/kg), produced more anxyolitic effects compared to either Mg or PEF alone. It can be concluded that Pomegranate anxyolitic-like effect is dependent on interactions with both GABAergic (related to Mg) and serotonergic (5-HT1A) systems.

Piperine potentiates the antidepressant-like effect of trans-resveratrol: involvement of monoaminergic system

Major depression is characterized by dysfunction of neuroendocrine and immune networks. Trans-resveratrol, a phenolic compound presented in polygonum cuspidatum, was demonstrated previously to exert antidepressant-like effects through regulating monoaminergic system, oxidative/antioxidant defense and inflammatory response. The present study investigated the synergistic antidepressant-like effect of trans-resveratrol and piperine, a bioavailability enhancer, in mice and explored the possible mechanism. Trans-resveratrol was shown to reduce the immobility time both in the tail suspension and forced swimming tests (TST and FST). But the maximal inhibition was nearly 60% even if the doses were increased by 160 mg/kg; while piperine produced weak antidepressant-like effects in these two models. The interaction between trans-resveratrol and piperine was shown a clear-cut synergistic effect as evidenced by an isobolographic analysis. The further study suggested that the anti-immobility response from the subthreshold dose of piperine (2.5 mg/kg) and low doses of trans-resveratrol (10 and 20 mg/kg) was abolished by pretreatment with para-chlorophenylalanine (PCPA, 300 mg/kg, i.p.) in TST and FST, indicating the involvement of serotonergic system. Moreover, treatment with the subthreshold dose of piperine and low doses of trans-resveratrol attenuated reserpine-induced hypothermia and ptosis arguing for the relevance of noradrenaline. Additional evidence from neurochemical (monoamines in the frontal cortex, hippocampus, and hypothalamus) and biochemical (monoamine oxidase, MAO activity) assays corroborated the synergistically elevated monoaminergic system after co-treatment with trans-resveratrol and piperine. The present results indicate the effect of trans-resveratrol combined with piperine on depressive-like behaviors may be partly due to the potentiated activation of monoaminergic system in the brain. Further studies are necessary to elucidate the involvement of the oxidative/nitrosative stress, inflammatory and neuroprotective pathway in the antidepressant-like effect of this combination. The synergistic effect obtained from the combination may provide innovative clues for designing novel antidepressants with high efficacy and low side effects.

Antidepressant-like activity of 2-(4-phenylpiperazin-1-yl)-1, 8-naphthyridine-3-carboxylic acid (7a), a 5-HT3 receptor antagonist in behaviour based rodent models: Evidence for the involvement of serotonergic system

The present study was designed to investigate the putative antidepressant-like activity of 7a, a 5-HT3 receptor antagonist, (although indirect evidence of 5-HT3 antagonism) with an optimal log P (3.35) and pA2 value (7.6) greater than ondansetron (pA2 — 6.6) using behavioural tests battery of depression. Acute treatment of 7a (0.5-2mg/kg, i.p.) in mice produced antidepressant-like effects in forced swim test (FST) and tail suspension test (TST) without affecting the baseline locomotion in actophotometer test in mice. Moreover, the combination of a sub-effective dose of 7a (0.25mg/kg, i.p.) and fluoxetine (5mg/kg, i.p.) produced an anti-immobility effect in mouse FST. Pretreatment of mice with p-chlorophenylalanine methyl ester (PCPA; 100mg/kg, i.p., an inhibitor of serotonin (5-HT) synthesis, for 4 consecutive days) and 1-(m-Chlorophenyl)-biguanide (mCPBG, 10mg/kg, i.p., a 5-HT3 receptor agonist) prevented the anti-immobility effects of 7a (2mg/kg, i.p.) in the mouse FST. In addition, 7a (0.5–2mg/kg, i.p.) treatment also potentiated the 5-hydroxytryptophan (5-HTP) and pargyline induced head twitch response in mice. Furthermore, sub-chronic treatment (14days) with 7a (0.5–2mg/kg, i.p.) and paroxetine (10mg/kg, i.p.) significantly attenuated the behavioural anomalies induced by bilateral olfactory bulbectomy in rats in a modified open field paradigm. These results suggest that the antidepressant-like action of 7a may be mediated by an interaction with the serotonergic system and this molecule should be further investigated as an alternative therapeutic approach for the treatment of depression.

5‐HT1 and 5‐HT2 Receptors Are Involved in the Anxiolytic‐Like Effects of the Neuronal NOS Inhibitor TRIM in the Rat

Abstract Preclinical Research TRIM, a selective neuronal NOS inhibitor, had anxiolytic effects in the elevated plus‐maze (EPM) test. The aim of the present study was to evaluate the involvement of serotonergic system in the anxiolytic‐like effect of TRIM in the EPM test, a widely used animal model of anxiety. The anxiolytic‐like effect of TRIM (50 mg/kg, i.p.) in adult Wistar albino male rats in the EPM test was antagonized by pretreatment with the 5‐HT depleting agent; parachlorophenylalanine methyl ester (3 × 150 mg/kg i.p.) that inhibits 5‐HT synthesis; methiothepin (0.1 mg/kg, i.p.), a nonselective 5‐HT receptor antagonist; WAY 100635 (0.1 mg/kg i.p.), a selective 5‐HT1A receptor antagonist; GR 127935 (3 mg/kg i.p.), a selective 5‐HT1B/1D receptor antagonist; cyproheptadine (3 mg/kg i.p.), a 5‐HT2 receptor antagonist; or ketanserin (5 mg/kg i.p.), a 5‐HT2A/2C receptor antagonist. The anxiolytic‐like effects of TRIM thus appear to be mediated in part by 5‐HT1 and 5‐HT2 receptors.