Abstract
Rationale
Flunarizine is known as a calcium channel blocker commonly used in many countries to treat migraine and vertigo. Parkinsonism has been described as one of its side-effects in the elderly, which is in agreement with its recently characterized moderate D2 receptor antagonism.
Objectives
To perform a pre-clinical evaluation of flunarizine as a potential antipsychotic.
Methods
We evaluated the action of orally administered flunarizine in mice against hyperlocomotion induced by amphetamine and dizocilpine (MK-801) as pharmacological models of schizophrenia, induction of catalepsy as a measure for extrapyramidal symptoms and impairment induced by dizocilpine on the delayed alternation task for working memory.
Results
Flunarizine robustly inhibited hyperlocomotion induced by both amphetamine and dizocilpine at doses that do not reduce spontaneous locomotion (3–30 mg/kg). Mild catalepsy was observed at 30 mg/kg, being more pronounced at 50 mg/kg and 100 mg/kg. Flunarizine (30 mg/kg) improved dizocilpine-induced impairment on the delayed alternation test.
Conclusions
These results suggest a profile comparable to atypical antipsychotics. The low cost, good tolerability and long half-life (over 2 weeks) of flunarizine are possible advantages for its use as an atypical antipsychotic. These results warrant clinical trials with flunarizine for the treatment of schizophrenia.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ambrosio C, Stefanini E (1991) Interaction of flunarizine with dopamine D2 and D1 receptors. Eur J Pharmacol 197:221–223
Brücke T, Wober C, Podreka I, Wober-Bingol C, Asenbaum S, Aull S, Wenger S, Ilieva D, Harasko-van der Meer C, Wessely P et al. (1995) D2 receptor blockade by flunarizine and cinnarizine explains extrapyramidal side effects. A SPECT study. J Cereb Blood Flow Metab 15:513–518
Chouza C, Scaramelli A, Caamano JL, De Medina O, Aljanati R, Romero S (1986) Parkinsonism, tardive dyskinesia, akathisia, and depression induced by flunarizine. Lancet 1:1303–1304
Ellenbroek BA (1993) Treatment of schizophrenia: a clinical and preclinical evaluation of neuroleptic drugs. Pharmacol Ther 57:1–78
Farber NB, Jiang XP, Heinkel C, Nemmers B (2002) Antiepileptic drugs and agents that inhibit voltage-gated sodium channels prevent NMDA antagonist neurotoxicity. Mol Psychiatry 7:726–733
Feinberg I, Campbell IG (1998) Haloperidol potentiates the EEG slowing of MK-801 despite blocking its motor effects: implications for the PCP model of schizophrenia. Neuroreport 9:2189–2193
Grebb JA (1986) Nifedipine and flunarizine block amphetamine-induced behavioral stimulation in mice. Life Sci 38:2375–2381
Haraguchi K, Ito K, Kotaki H, Sawada Y, Iga T (1998) Catalepsy induced by calcium channel blockers in mice. Biopharm Drug Dispos 19:115–122
Holmes B, Brogden RN, Heel RC, Speight TM, Avery GS (1984) Flunarizine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use. Drugs 27:6–44
Hori Y, Takeda H, Tsuji M, Matsumiya T (1998) Differentiation of the inhibitory effects of calcium antagonists on abnormal behaviors induced by methamphetamine or phencyclidine. Pharmacology 56:165–174
Kapur S (2003) Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry 160:13–23
Kapur S, Seeman P (2001) Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics? A new hypothesis. Am J Psychiatry 158:360–369
Kariya S, Isozaki S, Masubuchi Y, Suzuki T, Narimatsu S (1995) Possible pharmacokinetic and pharmacodynamic factors affecting parkinsonism inducement by cinnarizine and flunarizine. Biochem Pharmacol 50:1645–1650
Karow A, Naber D (2002) Subjective well-being and quality of life under atypical antipsychotic treatment. Psychopharmacology 162:3–10
Lara DR, Souza DO (2000) Schizophrenia: a purinergic hypothesis. Med Hypoth 54:157–166
Leone M, Grazzi L, La Mantia L, Bussone G (1991) Flunarizine in migraine: a minireview. Headache 31:388–391
Le Marec N, Ethier K, Rompre PP, Godbout R (2002) Involvement of the medial prefrontal cortex in two alternation tasks using different environments. Brain Cogn 48:432–436
Meltzer HY, Davidson M, Glassman AH, Vieweg WV (2002) Assessing cardiovascular risks versus clinical benefits of atypical antipsychotic drug treatment. J Clin Psychiatry 63:25–29
Ninan I, Kulkarni SK (1999) Preferential inhibition of dizocilpine-induced hyperlocomotion by olanzapine. Eur J Pharmacol 368:1–7
O’Neill MF, Shaw G (1999) Comparison of dopamine receptor antagonists on hyperlocomotion induced by cocaine, amphetamine, MK-801 and the dopamine D1 agonist C-APB in mice. Psychopharmacology 145:237–250
Pani L, Kuzmin A, Stefanini E, Gessa GL, Rossetti ZL (1990) Flunarizine potentiates cocaine-induced dopamine release and motor stimulation in rats. Eur J Pharmacol 190:223–227
Pauwels PJ, Leysen JE, Janssen PA (1991) Ca++ and Na+ channels involved in neuronal cell death. Protection by flunarizine. Life Sci 48:1881–1893
Perkins DO (2002) Predictors of noncompliance in patients with schizophrenia. J Clin Psychiatry 63:1121–1128
Phillis JW, Wu PH, Coffin VL (1983) Inhibition of adenosine uptake into rat brain synaptosomes by prostaglandins, benzodiazepines and other centrally active compounds. Gen Pharmacol 14:475–479
Popoli P, Pezzola A, Scotti de Carolis A (1990) Possible involvement of the adenosinergic system in flunarizine anticonvulsant activity in rats. Arch Int Pharmacodyn Ther 306:45–56
Popoli P, Pezzola A, Benedetti M, Scotti de Carolis A (1992) Verapamil and flunarizine inhibit phencyclidine-induced effects: an EEG and behavioural study in rats. Neuropharmacology 31:1185–1191
Rosenzweig-Lipson S, Barrett JE (1995) Modification of the behavioral effects of (±) BAY k 8644, cocaine and d-amphetamine by L-type calcium channel blockers in squirrel monkeys. J Pharmacol Exp Ther 274:842–851
Schmidt R, Oestreich W (1991) Flunarizine in the treatment of vestibular vertigo: experimental and clinical data. J Cardiovasc Pharmacol 18:S27–S30
Seeman P, Tallerico T (1998) Antipsychotic drugs which elicit little or no Parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors. Mol Psychiatry 3:123–134
Seeman P, Corbett R, Van Tol HH (1997) Atypical neuroleptics have low affinity for dopamine D2 receptors or are selective for D4 receptors. Neuropsychopharmacology 16:93–110
Sukhotina IA, Dravolina OA, Medvedev IO, Bespalov AY (1999) Effects of calcium channel blockers on behaviors induced by the N-methyl-d-aspartate receptor antagonist, dizocilpine, in rats. Pharmacol Biochem Behav 63:569–580
Todd PA, Benfield P (1989) Flunarizine. A reappraisal of its pharmacological properties and therapeutic use in neurological disorders. Drugs 38:481–499
Velly J, Grima M, Marciniak G, Spach MO, Schwartz J (1987) Effects of some antianginal and vasodilating drugs on sodium influx and on the binding of 3H-batrachotoxinin-A 20-alpha-benzoate and 3H-tetracaine. Naunyn-Schmiedeberg’s Arch Pharmacol 335:176–182
Volavka J, Czobor P, Sheitman B, Lindenmayer JP, Citrome L, McEvoy JP, Cooper TB, Chakos M, Lieberman JA (2002) Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder. Am J Psychiatry 159:255–262
Acknowledgements
This work was supported by grants of CNPq and CAPES.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Tort, A.B.L., Dall’Igna, O.P., de Oliveira, R.V. et al. Atypical antipsychotic profile of flunarizine in animal models. Psychopharmacology 177, 344–348 (2005). https://doi.org/10.1007/s00213-004-1955-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-004-1955-y