Skip to main content
SpringerLink
Log in

Synergistic anticataleptic effect of imipramine and nicotine in a rotenone-induced rat model

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

An Editorial Expression of Concern to this article was published on 21 May 2022

This article has been updated

Abstract

Rationale

Some antidepressants have been previously found to produce anti-parkinsonian effect; nicotine was known to mitigate experimental neurotoxic lesions. The anticataleptic efficacy of antidepressant-nicotine co-administration is unstudied.

Objectives

This work aimed to evaluate anticataleptic action of imipramine-nicotine combination in rotenone model.

Methods

Catalepsy was measured by the bar test. Concentrations of tyrosine hydroxylase, dopamine, and DOPAC were determined in the substantia nigra and dorsal striatum using ELISA and HPLC techniques; additionally, dopamine/DOPAC ratio was calculated for both areas.

Results

Imipramine and nicotine alone were ineffective; however, co-administration of the drugs significantly (p < 0.01) inhibited rotenone-induced catalepsy and mitigated neurochemical changes in the nigrostriatal system. Anticataleptic effect of the combination exceeded that of levodopa, a standard drug for anti-parkinsonian treatment.

Conclusion

The combined use of imipramine and nicotine at relatively low doses inhibits neurotoxin-induced catalepsy and nigrostriatal neurochemical changes. The co-administration of these drugs might be a new approach to the treatment of extrapyramidal dysfunctions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Change history

References

  • Alam M, Mayerhofer A, Schmidt WJ (2004) The neurobehavioral changes induced by bilateral rotenone lesion in medial forebrain bundle of rats are reversed by L-DOPA. Behav Brain Res 151:117–124

    Article  CAS  PubMed  Google Scholar 

  • Al-Khatib IM, Fujiwara M, Ueki S (1989) Relative importance of the dopaminergic system in haloperidol-catalepsy and the anticataleptic effect of antidepressants and methamphetamine in rats. Pharmacol Biochem Behav 33:93–97

    Article  CAS  PubMed  Google Scholar 

  • Ascherio A, Schwarzschild MA (2016) The epidemiology of Parkinson’s disease: risk factors and prevention. Lancet Neurol 15:1257–1272

    Article  PubMed  Google Scholar 

  • Augustine RA, Kokay IC, Andrews ZB, Ladyman SR, Grattan DR (2003) Quantitation of prolactin receptor mRNA in the maternal rat brain during pregnancy and lactation. J Mol Endocrinol 31:221–232

    Article  CAS  PubMed  Google Scholar 

  • Bertolucci PH, Andrade LA, Lima JG, Carlini EA (1987) Total sleep deprivation and Parkinson disease. Arq Neuropsiquiatr 45:224–230

    Article  CAS  PubMed  Google Scholar 

  • Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 3:1301–1306

    Article  CAS  PubMed  Google Scholar 

  • Blesa J, Phani S, Jackson-Lewis V, Przedborski S (2012) Classic and new animal models of Parkinson’s disease. J Biomed Biotechnol 2012:845618

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Capote HA, Rainka M, Westphal ES, Beecher J, Gengo FM (2018) Ropinirole in bipolar disorder: rate of manic switching and change in disease severity. Perspect Psychiatr Care 54(2):100–106

    Article  PubMed  Google Scholar 

  • Church WH, Sabol KE, Justice JB Jr, Neill DB (1986) Striatal dopamine activity and unilateral barpressing in rats. Pharmacol Biochem Behav 25:865–871

    Article  CAS  PubMed  Google Scholar 

  • Costa G, Abin-Carriquiry JA, Dajas F (2001) Nicotine prevents striatal dopamine loss produced by 6-hydroxydopamine lesion in the substantia nigra. Brain Res 888:336–342

    Article  CAS  PubMed  Google Scholar 

  • Cotzias GC, Papavasiliou PS, Gellene R (1969) Modification of parkinsonism—chronic treatment with L-dopa. New Engl J Med 280:337–345

    Article  CAS  PubMed  Google Scholar 

  • Denmark JC, David JD, McComb SG (1961) Imipramine hydrochloride (Tofranil) in parkinsonism. A preliminary report. Br J Clin Pract 15:523–524

    CAS  PubMed  Google Scholar 

  • Dijk S, Krugers HJ, Korf J (1991) The effect of theophylline and immobilization stress on haloperidol-induced catalepsy and on metabolism in the striatum and hippocampus, studied with lactography. Neuropharmacology 30:469–473

    Article  CAS  PubMed  Google Scholar 

  • Dilsauer SC, Hariharen M, Davidson RK (1988) Desipramine subsensitizes nicotinic mechanism involved in regulating core temperature. Psychiatry Res 25:105–108

    Article  CAS  PubMed  Google Scholar 

  • Duncan GE, Knapp DJ, Carson SW, Breese GR (1998) Differential effects of chronic antidepressant treatment on swim stress- and fluoxetine-induced secretion of corticosterone and progesterone. J Pharmacol Exp Ther 285:579–587

    CAS  PubMed  Google Scholar 

  • Erzin-Waters C, Muller P, Seeman P (1976) Catalepsy induced by morphine or haloperidol: effects of apomorphine and anticholinergic drugs. Can J Physiol Pharmacol 54:516–519

    Article  CAS  PubMed  Google Scholar 

  • Gillhespy RO, Mustard DM (1963) The evaluation of imipramine in the treatment of Parkinson’s disease. Br J Clin Pract 17:205–208

    CAS  PubMed  Google Scholar 

  • Goetz CG, Tanner CM, Klawans HL (1984) Bupropion in Parkinson’s disease. Neurology 34:1092–1094

    Article  CAS  PubMed  Google Scholar 

  • Hart A (2001) Mann-Whitney test is not just a test of medians: differences in spread can be important. Br Med J 323(7309):391–393

    Article  CAS  Google Scholar 

  • Hefti F, Enz A, Melamed E (1985) Partial lesions of the nigrostriatal pathway in the rat. Acceleration of transmitter synthesis and release of surviving dopaminergic neurones by drugs. Neuropharmacology 24:19–23

    Article  CAS  PubMed  Google Scholar 

  • Hefti F, Melamed E, Wurtman RJ (1980) Partial lesions of the dopaminergic nigrostriatal system in rat brain: biochemical characterization. Brain Res 195:123–137

    Article  CAS  PubMed  Google Scholar 

  • Hermann B, Pulver R (1960) Der Stoffwechsel des Psychopharmakons Tofranil. Arch Int Pharmacodyn Thér 126:454–469

    Google Scholar 

  • Holma IA, Holma KM, Melartin TK, Ketokivi M, Isometsä ET (2013) Depression and smoking: a 5-year prospective study of patients with major depressive disorder. Depress Anxiety 30:580–588

    Article  PubMed  Google Scholar 

  • Hornykiewicz O (1998) Biochemical aspects of Parkinson’s disease. Neurology 51(2 Suppl 2):S2–S9

    Article  CAS  PubMed  Google Scholar 

  • Högl B, Peralta C, Wetter TC, Gershanik O, Trenkwalder C (2001) Effect of sleep deprivation on motor performance in patients with Parkinson’s disease. Mov Disord 16:616–621

    Article  PubMed  Google Scholar 

  • Hsieh PF, Chia L, Ni D, Cheng L, Ho Y, Tzeng S, Chang M, Hong J (2002) Behavior, neurochemistry and histology after intranigral lipopolysaccharide injection. Neuroreport 13:277–280

    Article  CAS  PubMed  Google Scholar 

  • Ionov ID, Pushinskaya II, Gorev NP (2018) Cyclosomatostatin-induced catalepsy in the aged rat: a response to levodopa, diphenhydramine and nicotine. Curr Topics Pharmacol 22:45–54

    Article  CAS  Google Scholar 

  • Kalia LV, Lang AE (2015) Parkinson’s disease. Lancet 386(9996):896–912

    Article  CAS  PubMed  Google Scholar 

  • Kataoka Y, Ohta H, Fujiwara M, Oishi R, Ueki S (1987) Noradrenergic involvement in catalepsy induced by delta 9-tetrahydrocannabinol. Neuropharmacology 26:55–60

    Article  CAS  PubMed  Google Scholar 

  • Kheradmand A, Nayebi AM, Jorjani M, Haddadi R (2016) Effect of WR-1065 on 6-hydroxydopamine-induced catalepsy and IL-6 level in rats. Iran J Basic Med Sci 19:490–496

    PubMed  PubMed Central  Google Scholar 

  • Kleiber AC, Zheng H, Schultz HD, Peuler JD, Patel KP (2008) Exercise training normalizes enhanced glutamate-mediated sympathetic activation from the PVN in heart failure. Am J Phys Regul Integr Comp Phys 294:R1863–R1872

    CAS  Google Scholar 

  • Laitinen L (1969) Desipramine in treatment of Parkinson’s disease. A placebo-controlled study. Acta Neurol Scand 45:109–113

    Article  CAS  PubMed  Google Scholar 

  • Lavielle S, Tassin JP, Thierry AM, Blanc G, Herve D, Barthelemy C, Glowinski J (1979) Blockade by benzodiazepines of the selective high increase in dopamineturnover induced by stress in mesocortical dopaminergic neurons of the rat. Brain Res 168:585–594

    Article  CAS  PubMed  Google Scholar 

  • Li X, Li W, Liu G, Shen X, Tang Y (2015) Association between cigarette smoking and Parkinson’s disease: a meta-analysis. Arch Gerontol Geriatr 61:510–516

    Article  CAS  PubMed  Google Scholar 

  • Liang T, Habegger K, Spence JP, Foroud T, Ellison JA, Lumeng L, Li TK, Carr LG (2004) Glutathione S-transferase 8-8 expression is lower in alcohol-preferring than in alcohol-nonpreferring rats. Alcohol Clin Exp Res 28:1622–1628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mandell AJ, Markham C, Fowler W (1961) Parkinson’s syndrome, depression and imipramine. A preliminary report. Calif Med 95:12–14

    CAS  PubMed  PubMed Central  Google Scholar 

  • Onodera K (1991) Effects of antidepressants and antihistaminics on catalepsy induced by intracerebroventricular administration of histamine in mice. Methods Find Exp Clin Pharmacol 13:397–403

    CAS  PubMed  Google Scholar 

  • Palkovits M (1973) Isolated removal of hypothalamic or other brain nuclei of the rat. Brain Res 59:449–450

    Article  CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. Academic Press, San Diego

    Google Scholar 

  • Pflug B, Tölle R (1971) Therapie endogener Depressionen durch Schlafentzug. Nervenarzt 42:117–124

    CAS  PubMed  Google Scholar 

  • Popik P, Kozela E, Krawczyk M (2003) Nicotine and nicotinic receptor antagonists potentiate the antidepressant-like effects of imipramine and citalopram. Br J Pharmacol 139:1196–1202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rampello L, Chiechio S, Raffaele R, Vecchio I, Nicoletti F (2002) The SSRI, citalopram, improves bradykinesia in patients with Parkinson’s disease treated with L-dopa. Clin Neuropharmacol 25:21–24

    Article  CAS  PubMed  Google Scholar 

  • Reist C, Sokolski KN, Chen CC, Coskinas E, Demet EM (1995) The effect of sleep deprivation on motor impairment and retinal adaptation in Parkinson’s disease. Prog Neuro-Psychopharmacol Biol Psychiatry 19:445–454

    Article  CAS  Google Scholar 

  • Ryan RE, Ross SA, Drago J, Loiacono RE (2001) Dose-related neuroprotective effects of chronic nicotine in 6-hydroxydopamine treated rats, and loss of neuroprotection in alpha4 nicotinic receptor subunit knockout mice. Br J Pharmacol 132:1650–1656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sanberg PR, Pisa M, Fibiger HC (1981) Kainic acid injections in the striatum alter the cataleptic and locomotor effects of drugs influencing dopaminergic and cholinergic systems. Eur J Pharmacol 74:347–357

    Article  CAS  PubMed  Google Scholar 

  • Schulte W (1966) Kombinierte Psycho- und Pharmakotherapie bei Melancholikern. In: Kranz H, Petrilowitsch N (eds) Probleme der pharmakopsychiatrischen Kombinations- und Langzeitbehandlung. Karger, Basel, pp 150–169

    Google Scholar 

  • Sigwald J, Bouttier D, Marques M, Basset J, Gal JC (1959) Amélioration de l’akinésie parkinsonienne par deux derives de l’iminodibenzyle. Rev Neurol (Paris) 101:583–584

    CAS  Google Scholar 

  • Soto-Otero R, Méndez-Alvarez E, Hermida-Ameijeiras A, López-Real AM, Labandeira-García JL (2002) Effects of (-)-nicotine and (-)-cotinine on 6-hydroxydopamine-induced oxidative stress and neurotoxicity: relevance for Parkinson’s disease. Biochem Pharmacol 64:125–135

    Article  CAS  PubMed  Google Scholar 

  • Strang RR (1965) Imipramine in treatment of parkinsonism: a double-blind placebo study. Br Med J 2:33–34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tang SP, Kuttulebbai Nainamohamed Salam S, Jaafar H, Gan SH, Muzaimi M, Sulaiman SA (2017) Tualang honey protects the rat midbrain and lung against repeated paraquat exposure. Oxidative Med Cell Longev 2017:4605782. https://doi.org/10.1155/2017/4605782

    Article  CAS  Google Scholar 

  • Tatara A, Shimizu S, Shin N, Sato M, Sugiuchi T, Imaki J, Ohno Y (2012) Modulation of antipsychotic-induced extrapyramidal side effects by medications for mood disorders. Prog Neuro-Psychopharmacol Biol Psychiatry 38:252–259

    Article  CAS  Google Scholar 

  • Tikhonova MA, Alperina EL, Tolstikova TG, Bazovkina DV, Di VY, Idova GV, Kulikov AV, Popova NK (2010) Effects of chronic fluoxetine treatment on catalepsy and the immune response in mice with a genetic predisposition to freezing reactions: the roles of types 1A and 2A serotonin receptors and the tph2 and SERT genes. Neurosci Behav Physiol 40:521–527

    Article  CAS  PubMed  Google Scholar 

  • Tretiakoff C (1919) Contribution a l’étude de l’Anatomie pathologique du Locus Niger de Soemmering avec quelques déductions relatives à la pathogenie des troubles du tonus musculaire et de la maladie de Parkinson (Thèse de Doctorat). Université de Paris, Paris

    Google Scholar 

  • Visanji NP, O'Neill MJ, Duty S (2006) Nicotine, but neither the alpha4beta2 ligand RJR2403 nor an alpha7 nAChR subtype selective agonist, protects against a partial 6-hydroxydopamine lesion of the rat median forebrain bundle. Neuropharmacology 51:506–516

    Article  CAS  PubMed  Google Scholar 

  • Yang Y, Liu X, Long Y, Wang F, Ding JH, Liu SY, Sun YH, Yao HH, Wang H, Wu J, Hu G (2006) Activation of mitochondrial ATP-sensitive potassium channels improves rotenone-related motor and neurochemical alterations in rats. Int J Neuropsychopharmacol 9:51–61

    Article  CAS  PubMed  Google Scholar 

  • Zetler G (1968) Cataleptic state and hypothermia in mice, caused by central cholinergic stimulation and antagonized by anticholinergic and antidepressant drugs. Int J Neuropharmacol 7:325–335

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. I.D.I. is indebted to his long-standing mentors, Prof. Igor Efimovich Kovalev and Prof. Lev Aramovich Piruzyan. The study was supported by the Ministry of Science and Higher Education of the Russian Federation (project АААА-А18-118012390247-0).

Author information

Authors and Affiliations

  1. Centre on Theoretical Problems in Physical and Chemical Pharmacology, Russian Academy of Sciences, Leninsky prospect 123-4-63, Moscow, 117513, Russia

    Ilya D. Ionov

  2. Timpharm LTD, Moscow, Russia

    Irina I. Pushinskaya, Nicholas P. Gorev & Larissa A. Shpilevaya

Authors
  1. Ilya D. Ionov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Irina I. Pushinskaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nicholas P. Gorev
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Larissa A. Shpilevaya
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ilya D. Ionov.

Ethics declarations

All experimental animal procedures were conducted according to the European Communities Council Directive 2010/63/EU and approved by the local Ethics Committee for Animal Experimentation.

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ionov, I.D., Pushinskaya, I.I., Gorev, N.P. et al. Synergistic anticataleptic effect of imipramine and nicotine in a rotenone-induced rat model. Psychopharmacology 236, 3125–3133 (2019). https://doi.org/10.1007/s00213-019-05261-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-019-05261-9

Keywords

Search

Navigation