Methanolic extract of Mitragyna speciosa Korth leaf inhibits ethanol seeking behaviour in mice: involvement of antidopaminergic mechanism.

In the current study, the effect of methanolic extract of Mitragyna speciosa leaf (MMS) against the rewarding and reinforcing properties of ethanol using a mouse model of conditioned place preference (CPP) and runway model of drug self-administration was studied. Subsequently, the effect of MMS on dopamine level in the nucleus accumbens (NAc) of the mouse brain was further investigated. From the data obtained, MMS (50 and 75 mg/kg, p.o.) significantly reversed the ethanol-place preference in mice, which is similar to the effect observed in the reference drugs acamprosate (300 mg/kg, p.o.) and clozapine (1 mg/kg, p.o.) treatment groups in CPP test. Likewise, the escalating doses of ethanol-conditioned mice reduced the runtime to reach goal box, infers the positive reinforcing effects of alcohol. Interestingly, MMS (50, 75 and 100 mg/kg, p.o.) significantly prolonged the runtime in ethanol-conditioned mice. Besides, MMS (50 and 75 mg/kg, p.o.) and reference drugs; acamprosate (300 mg/kg, p.o.) and clozapine (1 mg/kg, p.o.) treated mice significantly decreased the alcohol-induced elevated dopamine level in the NAc region of the brain. Overall, this study provides first evidence that MMS inhibits ethanol seeking behaviour in mice. Based on these findings, we suggest that Mitragyna speciosa may well be utilized for novel drug development to combat alcohol dependence.

Methanolic extract of Morinda citrifolia Linn. unripe fruit attenuates methamphetamine-induced conditioned place preferences in mice.

The first objective of the present study was to determine the appropriate dose of methamphetamine (Meth) to induce a successful conditioned place preference (CPP) in mice. The next objective was to examine the effect of a methanolic extract of M. citrifolia unripe fruit (MMC) against Meth-induced CPP in mice. In answering to the first objective, following the preconditioning test, an intraperitoneal injection of a fixed dose of Meth (0.5 or 1 or 2 mg/kg, i.p.) or saline (10 ml/kg, i.p.) was given on alternate days during the 10 days conditioning period followed by a postconditioning test conducted in Meth-free state. The first experiment revealed that 0.5 mg/kg of Meth could be an appropriate fixed low dose to induce CPP in mice. Meanwhile, in other experiments, the effect of MMC and bupropion (BUPR) against the expression, extinction, and reinstatement of Meth (0.5 mg/kg)-induced CPP in mice, respectively, was investigated. In a separate set of studies on each phase, an oral administration of MMC (1, 3 and 5 g/kg, p.o.) or BUPR (20 mg/kg, p.o.) was given 60 min prior to CPP postconditioning testing or extinction testing or reinstatement testing in mice. Extinction trials were conducted in Meth-free state to weaken CPP over the next 5 days. Reinstatement test was conducted by a single low dose priming injection of Meth (0.1 mg/kg, i.p.). The present study, however, failed to establish a successful extinction and reinstatement of Meth-CPP in mice. Further studies using other doses of Meth are warranted for a successful establishment of all phases of Meth CPP in mice. This study also demonstrates that MMC (3 and 5 g/kg, p.o.) and BUPR (20 mg/kg, p.o.) could attenuate the expression of Meth-induced CPP in mice.

Anxiolytic- and antidepressant-like activities of a methanolic extract of Morinda citrifolia Linn. (noni) fruit in mice: Involvement of benzodiazepine-GABAAergic, serotonergic and adrenergic systems.

This study presents anxiolytic- and antidepressant-like effects of a methanolic extract of Morinda citrifolia Linn. (noni) fruit (MMC) in well-established mouse models of anxiety and depression. The administration of MMC (1 g/kg, p.o.) and diazepam (1 mg/kg, i.p.) significantly attenuated anxiety-like behaviour in mice by increasing the percentage of time spent and number of entries in the open arms in the elevated plus maze (EPM), and significantly enhanced the exploration in the light box in the light/dark test (LDT). The pre-treatment with flumazenil (6 mg/kg, i.p.) or bicuculline (3 mg/kg, i.p.) or WAY 100635 (1 mg/kg, i.p.) antagonized the anxiolytic-like effect elicited by MMC (1 g/kg, p.o.). These results suggest the possible involvement of benzodiazepine-GABAAergic and serotonergic mechanisms in the anxiolytic-like effect of noni fruit. Meanwhile, in the antidepressant study, the administration of MMC (0.5 and 0.75 g/kg, p.o.) and desipramine (30 mg/kg, i.p.) significantly reduced the duration of immobility in the tail suspension test (TST). Furthermore, pre-treatment of mice with 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA; 100 mg/kg, i.p., an inhibitor of serotonin synthesis) for four consecutive days or a single dose of WAY 100635 (1 mg/kg, i.p., 5HT1A receptor antagonist) or α-methyl-DL-tyrosine (AMPT; 100 mg/kg, i.p., an inhibitor of noradrenaline synthesis) significantly reversed the anti-immobility effect of MMC (0.5 g/kg, p.o.) in TST by indicating the specific involvement of the serotonergic and noradrenergic systems in the antidepressant-like effect of noni fruit. Taken together, these findings suggest that MMC has both anxiolytic- and antidepressant-like activities to be resorted as a valuable alternative therapy for comorbid anxiety and depressive conditions.

Antipsychotic-like activity of scopoletin and rutin against the positive symptoms of schizophrenia in mouse models.

In an earlier report, we demonstrated an antipsychotic-like activity of a methanolic extract of Morinda citrifolia Linn fruit in mouse models and postulated the contribution of its bioactive principles, scopoletin and rutin. Moreover, the antidopaminergic activities of scopoletin and rutin were reported in isolated vas deferens preparations. In the present study, scopoletin and rutin were assessed for antipsychotic-like activity using apomorphine-induced climbing behavior and methamphetamine-induced stereotypy in mice. The results of this study revealed that scopoletin and rutin (0.05, 0.1, 0.5, and 1 mg/kg, p.o.) had a "U-shaped" dose-dependent effect on climbing and stereotyped behaviors induced by apomorphine and methamphetamine, respectively, in mice. A significant reduction in climbing and stereotyped behaviors caused by scopoletin and rutin was observed only at a dose 0.1 mg/kg. This study suggests that scopoletin and rutin can alleviate positive symptoms of schizophrenia only at a specific dose. Further studies evaluating the effects of scopoletin and rutin on animal models for negative symptoms of schizophrenia are required for a novel drug discovery in the treatment of neuropsychiatric diseases.

PHYTOCHEMICAL, PHARMACOLOGICAL AND BIOLOGICAL PROFILES OF TRAGIA SPECIES (FAMILY: EUPHORBIACEAE).

BACKGROUND: Tragia belongs to the family Euphorbiaceae which contains about 152 species. Interestingly, most of the earlier investigations have been done using only five Tragia species, namely, Tragia involucrata, Tragia cannabina, Tragia spathulata, Tragia plukenetii, and Tragia benthamii. The objective of the present review is to compile the phytochemical, pharmacological and biological studies of the selected five Tragia species reported in the literature. METHODS: The reported data/information was retrieved mainly from the online databases of PubMed (MEDLINE), EMBASE and Botanical Survey of India. RESULTS: The present review elaborated the phytochemical, pharmacological and biological properties of the selected five Tragia species obtained from recent literature. CONCLUSION: This review provides a basis for future investigation of Tragia species and, especially for those species that have not been explored for biological and pharmacological activities.

The ethyl acetate fraction of a methanolic extract of unripe noni (Morinda citrifolia Linn.) fruit exhibits a biphasic effect on the dopaminergic system in mice.

In earlier ex vivo studies, we reported the biphasic effect of a methanolic extract of unripe Morinda citrifolia fruit (MMC) on dopamine-induced contractility in isolated rat vas deferens preparations. The present in vivo study was designed and undertaken to further explore our earlier ex vivo findings. This study examined the effect of the ethyl acetate fraction of a methanolic extract of unripe Morinda citrifolia Linn. fruit (EA-MMC; 5-100 mg/kg, p.o.) on the dopaminergic system using mouse models of apomorphine-induced climbing time and climbing behavior, methamphetamine-induced stereotypy (sniffing, biting, gnawing, and licking) and haloperidol-induced catalepsy using the bar test. Acute treatment with EA-MMC at a low dose (25 mg/kg, p.o.) significantly attenuated the apomorphine-induced climbing time and climbing behavior in mice. Similarly, EA-MMC (5 and 10 mg/kg, p.o.) significantly inhibited methamphetamine-induced stereotyped behavior in mice. These results demonstrated that the antidopaminergic effect of EA-MMC was observed at relatively lower doses (<25 mg/kg, p.o.). On the other hand, EA-MMC showed dopaminergic agonistic activity at a high dose (3,000 mg/kg, p.o.), which was evident from alleviation of haloperidol (a dopamine D2 blocker)-induced catalepsy in mice. Therefore, it is concluded that EA-MMC might possess a biphasic effect on the dopaminergic system, i.e., an antagonistic effect at lower doses (<25 mg/kg, p.o.) and an agonistic effect at higher doses (>1,000 mg/kg, p.o.). However, further receptor-ligand binding assays are necessary to confirm the biphasic effects of M. citrifolia fruit on the dopaminergic system.