Kava decreases the stereotyped behavior induced by amphetamine in mice
Graphical abstract
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)
- et al.
Gabapentin reduces haloperidol-induced vacuous chewing movements in mice
Pharmacol. Biochem. Behav.
(2018) - et al.
Valeriana officinalis does not alter the orofacial dyskinesia induced by haloperidol in rats: role of dopamine transporter
Prog. Neuro-Psychopharmacol. Biol. Psychiatry
(2007) - et al.
An improved fluorimetric assay for brain monoamine oxidase
Journal of pharmacological methods
(1985) - et al.
Schizophrenia
Lancet
(2004) - et al.
Enduring changes in brain and behavior produced psychosis by chronic of amphetamine Administration : a review and evaluation Anima1 models of amphetamine
Brain Res. Rev.
(1986) - et al.
Biochemical and behavioral changes in rats during and after chronic d-amphetamine exposure
Drug Alcohol Depend.
(1985) - et al.
Increased baseline occupancy of D2 receptors by dopamine in schizophrenia
Proc. Natl. Acad. Sci. U.S.A.
(2000) - et al.
GPR30 activation decreases anxiety in the open field test but not in the elevated plus maze test in female mice
Brain Behav
(2014) Tests for emotionality in rats and mice: a review
Anim. Behav.
(1973)- et al.
Liver toxicity and carcinogenicity in F344/N rats and B6C3F1 mice exposed to Kava Kava
Food Chem. Toxicol.
(2011)
Functional dysconnectivity in schizophrenia and its relationship to neural synchrony
Expert Rev. Neurother.
What causes the onset of psychosis?
Resveratrol protects against vacuous chewing movements induced by chronic treatment with fluphenazine
Neurochem. Res.
The neurobehavioural effects of kava
Aust. N. Z. J. Psychiatr.
Effects of antipsychotics and amphetamine on social behaviors in spontaneously hypertensive rats
Behav. Brain Res.
Parameters of kava used as a challenge to alcohol
Aust. N. Z. J. Psychiatr.
Gabapentin prevents behavioral changes on the amphetamine-induced animal model of schizophrenia
Schizophr. Res.
Kavain, the major constituent of the anxiolytic kava extract, potentiates gabaa receptors: functional characteristics and molecular mechanism
PloS One
Parkinson disease: a new link between monoamine oxidase and mitochondrial electron flow
Proc. Natl. Acad. Sci. Unit. States Am.
Caffeine and adenosine A2a receptor antagonists prevent β-amyloid (25-35)-induced cognitive deficits in mice
Exp. Neurol.
Silymarin recovers 6-hydroxydopamine-induced motor deficits in mice
Food Chem. Toxicol.
Interaction of various Piper methysticum cultivars with CNS receptors in vitro
Planta Med.
Interaction of various Piper methysticum cultivars with CNS receptors in vitro
Planta Med.
Animal models with construct validity for schizophrenia
Behav. Pharmacol.
The pharmacology of amphetamine and methylphenidate: relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities
Neurosci. Biobehav. Rev.
The amphetamine-induced sensitized state as a model of schizophrenia
Prog. Neuro-Psychopharmacol. Biol. Psychiatry
Effects of diphenyl diselenide on behavioral and biochemical changes induced by amphetamine in mice
J. Neural. Transm.
Inhibitors of MAO-A and MAO-B in psychiatry and neurology
Front. Pharmacol.
Striatal dopamine metabolism in monoamine oxidase B-deficient mice: a brain dialysis study
J. Neurochem.
Amphetamine, past and present - a pharmacological and clinical perspective
J. Psychopharmacol.
Rethinking schizophrenia
Nature
Amphetamine psychosis and psychotic symptoms
Psychopharmacology (Berlin)
Animal models of schizophrenia
Br. J. Pharmacol.
Opposite effects of neonatal hypoxia on acute amphetamine-induced hyperlocomotion in adult and adolescent mice
Psychiatr. Res.
Tardive Dyskinesia: Prevalence, Incidence, and Risk Factors
The open field test for measuring locomotor activity and anxiety-like behavior
Alpha7 neuronal nicotinic receptors as targets for novel therapies to treat multiple domains of schizophrenia
Curr. Pharmaceut. Biotechnol.
Cited by (6)
Influence of the dose of ketamine used on schizophrenia-like symptoms in mice: A correlation study with TH, GAD<inf>67</inf>, and PPAR-γ
2023, Pharmacology Biochemistry and BehaviorPaliperidone alleviates MK-801-induced damage to prefrontal cortical neurons via the PP2A/PTEN pathway
2022, Journal of Affective DisordersEx vivo and in vitro inhibitory potential of Kava extract on monoamine oxidase B activity in mice
2022, Journal of Traditional and Complementary MedicineCitation 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 PreventionHawaiian Plants with Beneficial Effects on Sleep, Anxiety, and Mood, etc.
2023, PharmaceuticalsAn Updated Review on the Psychoactive, Toxic and Anticancer Properties of Kava
2022, Journal of Clinical Medicine