Kava decreases the stereotyped behavior induced by amphetamine in mice

https://doi.org/10.1016/j.jep.2020.113293Get rights and content

Abstract

Ethnopharmacological relevance

Kava extract (Piper methysticum) is a phytotherapic mainly used for the treatment of anxiety. Although the reported effects of Kava drinking improving psychotic symptoms of patients when it was introduced to relieve anxiety in aboriginal communities, its effects on models of psychosis-like symptoms are not investigated.

Aim of the study

To investigate the effects of Kava extract on behavioral changes induced by amphetamine (AMPH) and its possible relation with alterations in monoamine oxidase (MAO) activity.

Materials and methods

Mice received vehicle or Kava extract by gavage and, 2 h after vehicle or AMPH intraperitoneally. Twenty-five minutes after AMPH administration, behavioral (elevated plus maze, open field, stereotyped behavior, social interaction and Y maze) and biochemical tests (MAO-A and MAO-B activity in cortex, hippocampus and striatum) were sequentially evaluated.

Results

Kava extract exhibited anxiolytic effects in plus maze test, increased the locomotor activity of mice in open field test and decreased MAO-A (in cortex) and MAO-B (in hippocampus) activity of mice. Kava extract prevented the effects of AMPH on stereotyped behavior and, the association between Kava/AMPH increased the number of entries into arms in Y maze test as well as MAO-B activity in striatum. However, Kava extract did not prevent hyperlocomotion induced by AMPH in open field test. The social interaction was not modified by Kava extract and/or AMPH.

Conclusion

The results showed that Kava extract decreased the stereotyped behavior induced by AMPH at the same dose that promotes anxiolytic effects, which could be useful to minimize the psychotic symptoms in patients.

Introduction

Schizophrenia is a chronic psychiatric illness that affects approximately 1% of the population around the world (Millier et al., 2014; Mueser and McGurk, 2004; Saha et al., 2005). It is characterized by positive (hallucinations, delusions), negative (apathy, social withdrawal) and cognitive (cognitive impairment) symptoms (Brennan et al., 2013; Insel, 2010; Mueser and McGurk, 2004; Nagai et al., 2011). Although the etiology of schizophrenia remains not completely elucidated, it is considered a multifactorial neurodevelopmental disorder associated with genetic and environmental factors (Broome et al., 2005; Van Os et al., 2010). Dopamine (DA), glutamate, serotonin (5-HT) and γ-aminobutyric acid (GABA) are some of the neurotransmitters involved in schizophrenia (Brennan et al., 2013). The alterations in these neurotransmitter circuits have been associated with hyperactivation of the mesolimbic dopaminergic pathway and a decrease in the mesocortical dopaminergic pathway with consequent appearance of schizophrenia symptoms (Abi-Dargham et al., 2000; Kucinski et al., 2011; Janowsky and Risch, 1979; Lieberman et al., 1990).

Amphetamine (AMPH) is a psychostimulant drug that acts by increasing the synaptic levels of DA, 5-HT and noradrenaline (NE) in the central nervous system (CNS) (Tonge, 1974; Vogel et al., 1985). In rodents, AMPH is a pharmacological agent used as a tool to mimic psychosis-like symptoms, allowing a better understanding of its mechanisms as well as finding agents with therapeutic potential for schizophrenia (Ceretta et al., 2018; Featherstone et al., 2007; Jones et al., 2011). AMPH may act either by increasing the processes of release or decreasing the re-uptake and metabolism of monoamines (DA, 5-HT and NE) (Faraone, 2018; Heal et al., 2013). The monoamine oxidase (MAO) enzyme catalyzes the oxidative deamination of the monoamines in their corresponding aldehydes with formation of hydrogen peroxide (H2O2) and ammonia (Cohen et al., 2002; Vindis et al., 2001). Alterations in the levels and the consequent metabolism of monoamines are related to the appearance of various neurological diseases including schizophrenia (Meltzer and Stahl, 1976).

Piper methysticum is a perennial shrub from Piperaceae (pepper) family, also called Kava due to the presence of kavalactones, which are the main constituents of its extract (Rex et al., 2002; Sarris et al., 2012). The crude extract of Kava has been used as ceremonial and social drink in the Pacific islands and, in the phytotherapy, as an effective short-term treatment of anxiety (Sarris et al., 2011; Singh and Singh, 2002). Furthermore, it has other medicinal uses which include actions anti-stress and sedative (Singh and Singh, 2002). The main mechanism associated to the anxiolytic effects of Kava on CNS of mammals is through the GABAA modulation (Chua et al., 2016; Sarris et al., 2011). However, other targets to Kava extract were also demonstrated as binding DA type-2 receptor, blockage of voltage-gated sodium and calcium ion channels, reduction of the neuronal reuptake of DA and NE, as well as an MAO-B inhibitor (Cairney et al., 2002; Dinh et al., 2001a; Laporte et al., 2011; Ligresti et al., 2012; Uebelhack et al., 1998). Of particular importance to the present study, evidences in the literature showed the possible antipsychotic effects of Kava extract improving the psychotic symptoms of patients from aboriginal communities in north Australia from Oceania when the Kava drinking was introduced to relieve anxiety (Cawte, 1986). Corroborating, Kava reduced psychotic symptoms in patients (Cairney et al., 2002; Cawte, 1986) and caused motor alterations as dyskinesia which are clinical signs of central DA antagonism (Cairney et al., 2002; Schelosky et al., 1995). Experimental data demonstrated that Kava extract could alters the DA levels in the nucleus accumbens of rats (Sällström Baum et al., 1998b) and bind to DA type-2 receptor (Dinh et al., 2001a) suggesting the action of Kava components on dopaminergic system. Despite of case-related reporting the effects of Kava on psychotic symptoms in patients, its effects were not investigated in a model of psychosis-like symptoms induced by AMPH in rodents. Based on the above-mentioned evidence, the research for new therapeutic agents as well as possible pharmacological adjuvants to use in the treatment of schizophrenia is relevant. Thus, the present study aimed to investigate the effects of the crude extract of Kava on behavioral changes induced by AMPH in mice and whether these effects are associated with alterations in MAO activity.

Section snippets

Drugs

The crude extract of Kava rhizome (P. methysticum) was obtained from Huakang Biotechnology Development (China-manufacturer's lot HK20160415) with approximately 30% of kavalactones (according to the supplier's report). High-performance liquid chromatography (HPLC) was used to characterize the compounds of the extract. All reagents were purchased from Sigma (Sigma-Aldrich, St. Louis, MO, USA) or other with high quality and purity.

Quantification of phenolics and flavonoids compounds by HPLC-DAD

The quantification of phenolic and flavonoid compounds was carried

HPLC analysis

HPLC fingerprinting of the Kava extract showed an elution diagram when the peaks were grouped into three regions based on the UV absorption profile. These regions showed typical patterns of UV absorption, supporting the presence of gallic acid (14.35min; peak 1), chlorogenic acid (23.98 min; peak 2), caffeic acid (27.15 min; peak 3), rosmarinic acid (32.54 min; peak 4), rutin (39.08min; peak 5), isoquercitrin (44.26; peak 6), quercitrin (46.35min; peak 7), quercetin (49.13min; peak 8) and

Discussion

The present study aimed to investigate whether the crude extract of Kava could protect against behavioral alterations induced by AMPH in mice and, whether changes in MAO activity could be involved in its effects. The present results showed that AMPH produced an increase in behavioral responses as locomotor activity and stereotyped behavior without altering social interaction and spatial working memory. The pre-treatment with Kava extract avoided the increase of stereotyped behavior but did not

Conclusion

Taken together, the present study demonstrated that the Kava extract prevented the appearance of stereotyped behavior induced by AMPH in mice, suggesting a potential therapeutic in psychotic symptoms. Furthermore, Kava extract decreases the stereotyped behavior at the same dose which could help to alleviate anxiety symptoms found in patients.

Co-authors contribution

De Freitas, C. M.; Ceretta, A. P. C.; Barbosa, C. P.; Reis, E. de M.: Behavioral and biochemical analysis. Scussel, R.; Corneo, E. S.; Machado-de-Avila, R. A.: Biochemical analysis. Boligon, A: carried out HPLC analysis. Krum, B.: Fachinetto, R.: investigation and writing–original draft preparation.

Declaration of competing interest

The authors declare that there are no conflicts of interest associated with this study.

Acknowledgments

This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001, Fundação de Amparo à Pesquisa do Estado do RS (FAPERGS) (PqG - 2080-2551/13-5-1 and PRONEM – 16/2551-0000248-7) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (Universal - 475210/2013-1). We also acknowledge fellowships from CNPq (R.A.M. and R.F.) and CAPES (B.N.K., C.M.F, A.P.C.C., C.P.B., E.M.R., R.S.). We specially acknowledge the

References (74)

  • A.M. Brennan et al.

    Functional dysconnectivity in schizophrenia and its relationship to neural synchrony

    Expert Rev. Neurother.

    (2013)
  • M.R. Broome et al.

    What causes the onset of psychosis?

  • A. Busanello et al.

    Resveratrol protects against vacuous chewing movements induced by chronic treatment with fluphenazine

    Neurochem. Res.

    (2017)
  • S. Cairney et al.

    The neurobehavioural effects of kava

    Aust. N. Z. J. Psychiatr.

    (2002)
  • M.B. Calzavara et al.

    Effects of antipsychotics and amphetamine on social behaviors in spontaneously hypertensive rats

    Behav. Brain Res.

    (2011)
  • J. Cawte

    Parameters of kava used as a challenge to alcohol

    Aust. N. Z. J. Psychiatr.

    (1986)
  • A.P.C. Ceretta et al.

    Gabapentin prevents behavioral changes on the amphetamine-induced animal model of schizophrenia

    Schizophr. Res.

    (2016)
  • H.C. Chua et al.

    Kavain, the major constituent of the anxiolytic kava extract, potentiates gabaa receptors: functional characteristics and molecular mechanism

    PloS One

    (2016)
  • G. Cohen et al.

    Parkinson disease: a new link between monoamine oxidase and mitochondrial electron flow

    Proc. Natl. Acad. Sci. Unit. States Am.

    (2002)
  • O.P. Dall'Igna et al.

    Caffeine and adenosine A2a receptor antagonists prevent β-amyloid (25-35)-induced cognitive deficits in mice

    Exp. Neurol.

    (2007)
  • C.M. de Freitas et al.

    Silymarin recovers 6-hydroxydopamine-induced motor deficits in mice

    Food Chem. Toxicol.

    (2018)
  • L.D. Dinh et al.

    Interaction of various Piper methysticum cultivars with CNS receptors in vitro

    Planta Med.

    (2001)
  • L.D. Dinh et al.

    Interaction of various Piper methysticum cultivars with CNS receptors in vitro

    Planta Med.

    (2001)
  • B.A. Ellenbroek et al.

    Animal models with construct validity for schizophrenia

    Behav. Pharmacol.

    (2006)
  • S.V. Faraone

    The pharmacology of amphetamine and methylphenidate: relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities

    Neurosci. Biobehav. Rev.

    (2018)
  • R.E. Featherstone et al.

    The amphetamine-induced sensitized state as a model of schizophrenia

    Prog. Neuro-Psychopharmacol. Biol. Psychiatry

    (2007)
  • F.H. Figueira et al.

    Effects of diphenyl diselenide on behavioral and biochemical changes induced by amphetamine in mice

    J. Neural. Transm.

    (2015)
  • J.P.M. Finberg et al.

    Inhibitors of MAO-A and MAO-B in psychiatry and neurology

    Front. Pharmacol.

    (2016)
  • F. Fornai et al.

    Striatal dopamine metabolism in monoamine oxidase B-deficient mice: a brain dialysis study

    J. Neurochem.

    (1999)
  • D.J. Heal et al.

    Amphetamine, past and present - a pharmacological and clinical perspective

    J. Psychopharmacol.

    (2013)
  • T.R. Insel

    Rethinking schizophrenia

    Nature

    (2010)
  • D.S. Janowsky et al.

    Amphetamine psychosis and psychotic symptoms

    Psychopharmacology (Berlin)

    (1979)
  • C. Jones et al.

    Animal models of schizophrenia

    Br. J. Pharmacol.

    (2011)
  • S.R. Kameda et al.

    Opposite effects of neonatal hypoxia on acute amphetamine-induced hyperlocomotion in adult and adolescent mice

    Psychiatr. Res.

    (2013)
  • J.M. Kane et al.

    Tardive Dyskinesia: Prevalence, Incidence, and Risk Factors

    (2011)
  • A.K. Kraeuter et al.

    The open field test for measuring locomotor activity and anxiety-like behavior

  • J. Kucinski et al.

    Alpha7 neuronal nicotinic receptors as targets for novel therapies to treat multiple domains of schizophrenia

    Curr. Pharmaceut. Biotechnol.

    (2011)
  • Cited by (6)

    • Ex vivo and in vitro inhibitory potential of Kava extract on monoamine oxidase B activity in mice

      2022, Journal of Traditional and Complementary Medicine
      Citation Excerpt :

      In this sense, MAO inhibitors have a long-standing use as anti-parkinsonian and anti-depressant drugs that improve quality of life for patients.20 Recently, Krum et al. demonstrated that Kava extract avoided the increase of stereotyped behavior in a model of psychosis-like symptoms induced by amphetamine (AMPH) in mice.8 Furthermore, the acute administration of Kava extract inhibited MAO isoforms in cortex and hippocampus of mice.8

    • ROLE OF FUNCTIONAL FOODS IN PSYCHOTIC DISORDERS

      2024, Applications of Functional Foods in Disease Prevention
    View full text