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Published in: BMC Complementary Medicine and Therapies 1/2016

Open Access 01-12-2016 | Research article

Subchronic oral administration of crude khat extract (Catha edulis forsk) induces schizophernic-like symptoms in mice

Authors: Tegegne Bogale, Epherm Engidawork, Engida Yisma

Published in: BMC Complementary Medicine and Therapies | Issue 1/2016

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Abstract

Background

Chewing fresh leaves of the khat plant (Catha edulis forsk) is a deep rooted and widespread habit in East Africa and the Middle East. Although a body of knowledge exists about the adverse effects of khat on health, data are sparse with regard to the consequences of long-term khat chewing in resulting schizophrenic like symptoms.

Methods

A crude extract of khat at different doses (100 mg/kg (K (khat)100), 200 mg/kg (K200) and 400 mg/kg (K400)) were administered for experimental group of mice whereas standard (ketamine (KT) 10 mg/kg- positive controls (KT10)) and vehicle (2 % v/v Tween-80 in distilled water – negative control groups (CON)) were administered for control groups of mice daily for two months to evaluate subchronic oral administration of crude khat extract to induce schizophrenic-like symptoms in mice. Mice were subjected to a battery of behavioural tests and parameters like locomotor activity, total time spent in social interaction and level of cognition among different groups of mice were measured and analyzed.

Results

Khat at all doses significantly increased (p < 0.001) the mean locomotor activity score of mice compared to CON. However, the mean locomotor activity score of mice treated with khat was significantly lower (p < 0.001) compared to the mean locomotor activity score of KT10 mice (p < 0.001).
The mean total time score (in seconds) spent in social interaction, mean total time score (in seconds) spent in sniffing and following the partner was significantly higher (p < 0.001) in CON groups of mice compared to khat and ketamine treated groups. Moreover, in spatial memory task, the mean latency score (in seconds) to find the platform of khat and ketamine treated mice was significantly higher (p < 0.05) when compared to CON.

Conclusions

Subchronic oral administration of khat showed an enhanced locomotor activity, reduced social interaction and impaired cognitive function, which demonstrated that long-term use of khat is associated with schizophernic-like symptoms.
Literature
2.
go back to reference Szymanski S, Kane JM, Lieberman JA. A selective review of biological markers in schizophrenia. Schizophr Bull. 1991;17(1):99–111.CrossRefPubMed Szymanski S, Kane JM, Lieberman JA. A selective review of biological markers in schizophrenia. Schizophr Bull. 1991;17(1):99–111.CrossRefPubMed
3.
go back to reference Widmann M, Warsame AH, Mikulica J, et al. Khat use, PTSD and psychotic symptoms among Somali refugees in Nairobi – a pilot study. Front Public Health. 2014;2:71.CrossRefPubMedPubMedCentral Widmann M, Warsame AH, Mikulica J, et al. Khat use, PTSD and psychotic symptoms among Somali refugees in Nairobi – a pilot study. Front Public Health. 2014;2:71.CrossRefPubMedPubMedCentral
4.
go back to reference Odenwald M, Neuner F, Schauer M, et al. Khat use as risk factor for psychotic disorders: a cross-sectional and case–control study in Somalia. BMC Med. 2005;3:5.CrossRefPubMedPubMedCentral Odenwald M, Neuner F, Schauer M, et al. Khat use as risk factor for psychotic disorders: a cross-sectional and case–control study in Somalia. BMC Med. 2005;3:5.CrossRefPubMedPubMedCentral
5.
go back to reference Odenwald M, Klein A, Warfa N. In: Miller PM, editor. Khat addiction. Principles of Addiction: Comprehensive Addictive Behaviors and Disorders. USA: Elsevier; 2013. Odenwald M, Klein A, Warfa N. In: Miller PM, editor. Khat addiction. Principles of Addiction: Comprehensive Addictive Behaviors and Disorders. USA: Elsevier; 2013.
7.
go back to reference Al-Motarreb A, Al-Habori M, Broadley KJ. Khat chewing, cardiovascular diseases and other internal medical problems: The current situation and directions for future research. J Ethnopharmacol. 2010;132(3):540–8.CrossRefPubMed Al-Motarreb A, Al-Habori M, Broadley KJ. Khat chewing, cardiovascular diseases and other internal medical problems: The current situation and directions for future research. J Ethnopharmacol. 2010;132(3):540–8.CrossRefPubMed
8.
go back to reference Cox G, Rampes H. Adverse effects of khat: a review. Adv Psychiatr Treat. 2003;9(6):456–63.CrossRef Cox G, Rampes H. Adverse effects of khat: a review. Adv Psychiatr Treat. 2003;9(6):456–63.CrossRef
9.
go back to reference Kassim S, Islam S, Croucher R. Validity and reliability of a Severity of Dependence Scale for khat (SDS-khat). J Ethnopharmacol. 2010;132(3):570–7.CrossRefPubMed Kassim S, Islam S, Croucher R. Validity and reliability of a Severity of Dependence Scale for khat (SDS-khat). J Ethnopharmacol. 2010;132(3):570–7.CrossRefPubMed
10.
go back to reference Griffiths P, Gossop M, Wickenden S, Dunworth J, Harris K, Lloyd C. A transcultural pattern of drug use: qat (khat) in the UK. Br J Psychiatry. 1997;170:281–4.CrossRefPubMed Griffiths P, Gossop M, Wickenden S, Dunworth J, Harris K, Lloyd C. A transcultural pattern of drug use: qat (khat) in the UK. Br J Psychiatry. 1997;170:281–4.CrossRefPubMed
11.
12.
go back to reference Al-Motarreb A, Baker K, Broadley KJ. Khat: Pharmacological and medical aspects and its social use in Yemen. Phytother Res. 2002;16(5):403–13.CrossRefPubMed Al-Motarreb A, Baker K, Broadley KJ. Khat: Pharmacological and medical aspects and its social use in Yemen. Phytother Res. 2002;16(5):403–13.CrossRefPubMed
13.
go back to reference Giannini A, Castellani S. A manic-like psychosis due to khat. J Toxicol Clin Toxicol. 1982;19(5):455–9.CrossRefPubMed Giannini A, Castellani S. A manic-like psychosis due to khat. J Toxicol Clin Toxicol. 1982;19(5):455–9.CrossRefPubMed
14.
go back to reference Yousef G, Huq Z, Lambert T. Khat chewing as a cause of psychosis. Bri J Hosp Med (Lond). 1995;54(7):322–6. Yousef G, Huq Z, Lambert T. Khat chewing as a cause of psychosis. Bri J Hosp Med (Lond). 1995;54(7):322–6.
15.
go back to reference Alem A, Shibre T. Khat induced psychosis and its medico-legal implication: a case report. Ethiop Med J. 1997;35:137–9.PubMed Alem A, Shibre T. Khat induced psychosis and its medico-legal implication: a case report. Ethiop Med J. 1997;35:137–9.PubMed
16.
go back to reference Brenneisen R, Geisshusler S, Schorno X. Metabolism of cathinone to (−) - norephedrine and (−)-norpseudoephedrine. J Pharm Pharmacol. 1986;38(4):298–300.CrossRefPubMed Brenneisen R, Geisshusler S, Schorno X. Metabolism of cathinone to (−) - norephedrine and (−)-norpseudoephedrine. J Pharm Pharmacol. 1986;38(4):298–300.CrossRefPubMed
17.
go back to reference Schechter MD. Dopaminergic nature of acute cathine tolerance. Pharmacol Biochem Behav. 1990;36(4):817–20.CrossRefPubMed Schechter MD. Dopaminergic nature of acute cathine tolerance. Pharmacol Biochem Behav. 1990;36(4):817–20.CrossRefPubMed
18.
go back to reference Warfa N, Klein A, Bhui K, Leavey G, Craig T, Stansfield SA. Khat use and mental illness. A critical review. Soc Sci Med. 2007;65(2):309–18.CrossRefPubMed Warfa N, Klein A, Bhui K, Leavey G, Craig T, Stansfield SA. Khat use and mental illness. A critical review. Soc Sci Med. 2007;65(2):309–18.CrossRefPubMed
19.
go back to reference Powell KJ, Hori SE, Leslie R. Cognitive impairments in the STOP null mouse model of schizophrenia. Behav Neurosci. 2007;121(5):826–35.CrossRefPubMed Powell KJ, Hori SE, Leslie R. Cognitive impairments in the STOP null mouse model of schizophrenia. Behav Neurosci. 2007;121(5):826–35.CrossRefPubMed
20.
go back to reference Vogel HG. Drug discovery and evaluation: pharmacological assays. 2nd ed. Verlag Berlin Heidelberg New York: Springer; 2008.CrossRef Vogel HG. Drug discovery and evaluation: pharmacological assays. 2nd ed. Verlag Berlin Heidelberg New York: Springer; 2008.CrossRef
21.
go back to reference Dawe GS, Hwang EHJ, Tan CH. Pathophysiology and animal models of schizophrenia. Ann Acad Med Singapore. 2009;38:425–30.PubMed Dawe GS, Hwang EHJ, Tan CH. Pathophysiology and animal models of schizophrenia. Ann Acad Med Singapore. 2009;38:425–30.PubMed
22.
go back to reference Connor JD, Rostom A, Makonnen E. Comparison of the effects of khat extracts and amphetamine on motor behaviors in mice. J Ethnopharmacol. 2002;81:65–71.CrossRefPubMed Connor JD, Rostom A, Makonnen E. Comparison of the effects of khat extracts and amphetamine on motor behaviors in mice. J Ethnopharmacol. 2002;81:65–71.CrossRefPubMed
23.
go back to reference Widler P, Mathys K, Brenneisen R, Kalix P, Fisch HU. Pharmacodynamics and pharmacokinetics of khat: a controlled study. Clin Pharmacol Ther. 1994;55(5):556–62.CrossRefPubMed Widler P, Mathys K, Brenneisen R, Kalix P, Fisch HU. Pharmacodynamics and pharmacokinetics of khat: a controlled study. Clin Pharmacol Ther. 1994;55(5):556–62.CrossRefPubMed
24.
go back to reference Toennes SW, Harder S, Schramm M, Niess C, Kauert GF. Pharmacokinetics of cathinone, cathine and norephedrine after the chewing of khat leaves. Br J Clin Pharmacol. 2003;56:125–30.CrossRefPubMedPubMedCentral Toennes SW, Harder S, Schramm M, Niess C, Kauert GF. Pharmacokinetics of cathinone, cathine and norephedrine after the chewing of khat leaves. Br J Clin Pharmacol. 2003;56:125–30.CrossRefPubMedPubMedCentral
25.
go back to reference Admassie E, Engidawork E. Subchronic administration of Catha edulis F. (khat) extract is marked by elevation of cardiac biomarkers and subendocardial necrosis besides blood pressure alteration in rats. J Ethnopharmacol. 2011;136:246–53.CrossRefPubMed Admassie E, Engidawork E. Subchronic administration of Catha edulis F. (khat) extract is marked by elevation of cardiac biomarkers and subendocardial necrosis besides blood pressure alteration in rats. J Ethnopharmacol. 2011;136:246–53.CrossRefPubMed
26.
go back to reference Morris RG. Learning and motivation. J Biosci Tech. 1981;12:239–60. Morris RG. Learning and motivation. J Biosci Tech. 1981;12:239–60.
27.
28.
go back to reference Wabe NT. Chemistry, pharmacology, and toxicology of khat (Catha Edulis Forsk): a review. Addict Health. 2011;3(3–4):137–49.PubMedPubMedCentral Wabe NT. Chemistry, pharmacology, and toxicology of khat (Catha Edulis Forsk): a review. Addict Health. 2011;3(3–4):137–49.PubMedPubMedCentral
29.
go back to reference Lopez-Arnau R, Martinez-Clemente J, Pubill D, Escubedo E, Camarasa J. Comparative neuropharmacology of three psychostimulant cathinone derivatives: butylone, mephedrone and methylone. Br J Pharmacol. 2012;167(2):407–20.CrossRefPubMedPubMedCentral Lopez-Arnau R, Martinez-Clemente J, Pubill D, Escubedo E, Camarasa J. Comparative neuropharmacology of three psychostimulant cathinone derivatives: butylone, mephedrone and methylone. Br J Pharmacol. 2012;167(2):407–20.CrossRefPubMedPubMedCentral
30.
go back to reference Banjaw MY, Mayerhofer A, Schmidt WJ. Anticataleptic activity of cathinone and MDMA (Ecstasy) upon acute and subchronic administration in rat. Synapse. 2003;49:232–8.CrossRefPubMed Banjaw MY, Mayerhofer A, Schmidt WJ. Anticataleptic activity of cathinone and MDMA (Ecstasy) upon acute and subchronic administration in rat. Synapse. 2003;49:232–8.CrossRefPubMed
31.
go back to reference Petrinovich L, Peeke HV. Habituation to territorial song in the White-crowned sparrow (Zonotrichia leucophrys). Behav Biol. 1973;8:743–8.CrossRefPubMed Petrinovich L, Peeke HV. Habituation to territorial song in the White-crowned sparrow (Zonotrichia leucophrys). Behav Biol. 1973;8:743–8.CrossRefPubMed
32.
go back to reference Izawa J, Yamanashi K, Asakura T, Misu Y, Goshima Y. Differential effects of methamphetamine and cocaine on behavior and extracellular levels of dopamine and 3,4-dihydroxyphenylalanine in the nucleus accumbens of conscious rats. Eur J Pharmacol. 2006;549(1–3):84–90.CrossRefPubMed Izawa J, Yamanashi K, Asakura T, Misu Y, Goshima Y. Differential effects of methamphetamine and cocaine on behavior and extracellular levels of dopamine and 3,4-dihydroxyphenylalanine in the nucleus accumbens of conscious rats. Eur J Pharmacol. 2006;549(1–3):84–90.CrossRefPubMed
33.
go back to reference Banjaw MY, Schmidt WJ. Behavioral sensitization following repeated intermittent oral administration of Catha edulis in rats. Behav Brain Res. 2005;156:181–9.CrossRefPubMed Banjaw MY, Schmidt WJ. Behavioral sensitization following repeated intermittent oral administration of Catha edulis in rats. Behav Brain Res. 2005;156:181–9.CrossRefPubMed
34.
go back to reference Robinson TE, Becker JB. Enduring changes in brain and behaviour produced by chronic amphetamine administration : a review and evaluation of animal models of amphetamine psychosis. Brain Res. 1986;11:157–98.CrossRef Robinson TE, Becker JB. Enduring changes in brain and behaviour produced by chronic amphetamine administration : a review and evaluation of animal models of amphetamine psychosis. Brain Res. 1986;11:157–98.CrossRef
35.
go back to reference Pantelis C, Hindler CG, Taylor JC. Use and abuse of khat (Catha edulis): a review of the distribution, pharmacology, side effects and a description of psychosis attributed to khat chewing. Psychol Med. 1989;19(3):657–68.CrossRefPubMed Pantelis C, Hindler CG, Taylor JC. Use and abuse of khat (Catha edulis): a review of the distribution, pharmacology, side effects and a description of psychosis attributed to khat chewing. Psychol Med. 1989;19(3):657–68.CrossRefPubMed
36.
go back to reference Chen CK, Lin SK, Sham PC, Ball D, Loh EW, Hsiao CC, Chiang YL, Ree SC, Lee CH, Murray RM. Pre-morbid characteristics and co-morbidity of methamphetamine users with and without psychosis. Psychol Med. 2003;33:1407–14.CrossRefPubMed Chen CK, Lin SK, Sham PC, Ball D, Loh EW, Hsiao CC, Chiang YL, Ree SC, Lee CH, Murray RM. Pre-morbid characteristics and co-morbidity of methamphetamine users with and without psychosis. Psychol Med. 2003;33:1407–14.CrossRefPubMed
37.
go back to reference Srisurapanont M, Ali R, Marsden J, Sunga A, Wada K, Monteiro M. Psychotic symptoms in methamphetamine psychotic in-patients. Int J Neuropsychopharmacol. 2003;6:347–52.CrossRefPubMed Srisurapanont M, Ali R, Marsden J, Sunga A, Wada K, Monteiro M. Psychotic symptoms in methamphetamine psychotic in-patients. Int J Neuropsychopharmacol. 2003;6:347–52.CrossRefPubMed
38.
go back to reference Awas M, Kebede D, Alem A. Major mental disorders in Butajira, Southern Ethiopia. Acta Psychiatr Scand Suppl. 1999;397:56–64.CrossRefPubMed Awas M, Kebede D, Alem A. Major mental disorders in Butajira, Southern Ethiopia. Acta Psychiatr Scand Suppl. 1999;397:56–64.CrossRefPubMed
39.
go back to reference Aleryani SL, Aleryani RA, Al-Akwa AA. Khat a drug of abuse: roles of free radicals and antioxidants. Drug Test Anal. 2011;3(9):548–51.CrossRefPubMed Aleryani SL, Aleryani RA, Al-Akwa AA. Khat a drug of abuse: roles of free radicals and antioxidants. Drug Test Anal. 2011;3(9):548–51.CrossRefPubMed
40.
go back to reference Abi-Dargham A, Moore H. Prefrontal DA transmission at D1 receptors and the pathology of schizophrenia. Neuroscientist. 2003;9:404–16.CrossRefPubMed Abi-Dargham A, Moore H. Prefrontal DA transmission at D1 receptors and the pathology of schizophrenia. Neuroscientist. 2003;9:404–16.CrossRefPubMed
41.
go back to reference Pycock CJ, Kerwin RW, Carter CJ. Effect of lesion of cortical dopamine terminals on subcortical dopamine receptors in rats. Nature. 1980;286:74–7.CrossRefPubMed Pycock CJ, Kerwin RW, Carter CJ. Effect of lesion of cortical dopamine terminals on subcortical dopamine receptors in rats. Nature. 1980;286:74–7.CrossRefPubMed
42.
go back to reference Kwon CH, Luikart BW, Powell CM, Zhou J, Matheny SA, Zhang W, et al. Pten regulates neuronal arborization and social interaction in mice. Neuron. 2006;50(3):377–88. Kwon CH, Luikart BW, Powell CM, Zhou J, Matheny SA, Zhang W, et al. Pten regulates neuronal arborization and social interaction in mice. Neuron. 2006;50(3):377–88.
43.
go back to reference Moghaddam B, Jackson ME. Glutamatergic animal models of schizophrenia. Ann N Y Acad Sci. 2003;1003:131–7.CrossRefPubMed Moghaddam B, Jackson ME. Glutamatergic animal models of schizophrenia. Ann N Y Acad Sci. 2003;1003:131–7.CrossRefPubMed
44.
45.
go back to reference Centonze D, Picconi B, Gubellini P, Bernardi G, Calabresi P. Dopaminergic control of synaptic plasticity in the dorsal striatum. Eur J Neurosci. 2001;13:1071–7.CrossRefPubMed Centonze D, Picconi B, Gubellini P, Bernardi G, Calabresi P. Dopaminergic control of synaptic plasticity in the dorsal striatum. Eur J Neurosci. 2001;13:1071–7.CrossRefPubMed
46.
Metadata
Title
Subchronic oral administration of crude khat extract (Catha edulis forsk) induces schizophernic-like symptoms in mice
Authors
Tegegne Bogale
Epherm Engidawork
Engida Yisma
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2016
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-016-1145-6

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