Cinnarizine has an atypical antipsychotic profile in animal models of psychosis

Abstract

Cinnarizine, a drug known as a calcium channel blocker, is currently used for the treatment of migraine and vertigo. Induction of extrapyramidal signs by cinnarizine has been reported in the elderly, which is related to its moderate antagonistic properties at dopamine D2 receptors, resembling the mechanism of action of most antipsychotic drugs. Despite this effect, cinnarizine has never been tested as a putative antipsychotic drug. Here we evaluate the potential effect of cinnarizine in two pharmacological models of psychosis, namely amphetamine- and MK-801-induced hyperlocomotion, as well as its ability to induce catalepsy. Cinnarizine significantly counteracted MK-801 (0.25mg/kg) and amphetamine (5mg/kg) locomotor effects at doses as low as 20mg/kg, having no incremental effect at 60 or 180mg/kg. Regarding side-effects, cinnarizine induced no catalepsy in mice at the effective dose of 20mg/kg, inducing only mild catalepsy at the doses of 60 and 180mg/kg. Based on these results and on the antagonist effect of cinnarizine on dopamine D2 receptors, we suggest that it has a potential antipsychotic effect with an atypical profile that should be evaluated clinically.

Keywords

cinnarizine MK-801 amphetamine catalepsy locomotion schizophrenia psychosis mice

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References

Anand A , Charney D S , Oren D A , Berman R M , Hu X S , Cappiello A , Krystal J H (2000) Attenuation of the neuropsychiatric effects of ketamine with lamotrigine: support for hyperglutamatergic effects of N-methyl-D-aspartate receptor antagonists . Arch Gen Psychiatry 57: 270-276

Brucke T , Wober C , Podreka I , Wober-Bingol C , Asenbaum S , Aull S , Wenger S , Ilieva D , Harasko-van der Meer C , Wessely P (1995) D2 receptor blockade by flunarizine and cinnarizine explains extrapyramidal side effects. A SPECT study . J Cereb Blood Flow Metab 15: 513-518

Bymaster F P , Calligaro D O , Falcone J F , Marsh R D , Moore N A , Tye N C , Seeman P , Wong D T (1996) Radioreceptor binding profile of the atypical antipsychotic olanzapine . Neuropsychopharmacology 14: 87-96

Dall’Igna O P , Da Silva A L , Dietrich M O , Hoffmann A , de Oliveira R V , Souza D O , Lara D R (2003) Chronic treatment with caffeine blunts the hyperlocomotor but not cognitive effects of the N-methyl-D-aspar-tate receptor antagonist MK-801 in mice . Psychopharmacology (Berl) 166: 258-263

Daniel J R , Mauro V F (1995) Extrapyramidal symptoms associated with calcium-channel blockers . Ann Pharmacother 29: 73-75

Eichler M E , Dubinsky J M , Tong J , Rich K M (1994) The ability of diphenylpiperazines to prevent neuronal death in dorsal root ganglion neurons in vitro after nerve growth factor deprivation and in vivo after axotomy . J Neurochem 62: 2148-2157

Farber N B , Jiang X P , Heinkel C , Nemmers B (2002) Antiepileptic drugs and agents that inhibit voltage-gated sodium channels prevent NMDA antagonist neurotoxicity . Mol Psychiatry 7: 726-733

Fernandez P M , Fernandez P J , Micheli F (1988) Aggravation of Parkinson’s disease by cinnarizine . J Neurol Neurosurg Psychiatry 51: 158-159

Garcia Ruiz P J , Mena M A , Penafiel N , De Yebenes J G (1992) Cinnarizine-induced parkinsonism in primates . Clin Neuropharmacol 15: 152-154

10.

Geyer M A , Ellenbroek B (2003) Animal behavior models of the mechanisms underlying antipsychotic atypicality . Prog Neuropsychopharmacol Biol Psychiatry 27: 1071-1079

11.

Kapur S , Mamo D (2003) Half a century of antipsychotics and still a central role for dopamine D2 receptors . Prog Neuropsychopharmacol Biol Psychiatry 27: 1081-1090

12.

Kapur S , Seeman P (2001) Does fast dissociation from the dopamine d(2) receptor explain the action of atypical antipsychotics? A new hypothesis . Am J Psychiatry 158: 360-369

13.

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

14.

Mena M A , Garcia de Yebenes M J , Tabernero C , Casarejos M J , Pardo B , Garcia de Yebenes J (1995) Effects of calcium antagonists on the dopamine system . J Clin Neuropharmacol 18: 410-426

15.

Moghaddam B , Adams B , Verma A , Daly D (1997) Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex . J Neurosci 17: 2921-2927

16.

Moghaddam B , Adams B W (1998) Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats . Science 281: 1349-1352

17.

Ninan I , Kulkarni S K (1999) Preferential inhibition of dizocilpine-induced hyperlocomotion by olanzapine . Eur J Pharmacol 368: 1-7

18.

O’Neill M F , 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 (Berl) 145: 237-250

19.

Ossowska G , Klenk-Majewska B , Lupina T (1994) The effect of calcium channel antagonists on the aggressive behavior in chronically stressed rats . Pol J Pharmacol 46: 403-408

20.

Pianese C P , Hidalgo L O , Gonzalez R H , Madrid C E , Ponce J E , Ramirez A M , Moran L M , Arenas J E , Rubio A T , Uribe J O , Abiuso J , Hanuch E , Alegria J , Volpi C , Flaskamp R , Sanjuan A P , Gomez J M , Hernandez J , Pedraza A , Quijano D , Martinez C , Castaneda J R , Guerra O J , Valencia F G (2002) New approaches to the management of peripheral vertigo: efficacy and safety of two calcium antagonists in a 12-week, multinational, double-blind study . Otol Neurotol 23: 357-363

21.

Rossi P , Fiermonte G , Pierelli F (2003) Cinnarizine in migraine prophylaxis: efficacy, tolerability and predictive factors for therapeutic responsiveness . An open-label pilot trial. Funct Neurol 18: 155-159

22.

Seeman P , Corbett R , Van Tol H H (1997) Atypical neuroleptics have low affinity for dopamine D2 receptors or are selective for D4 receptors . Neuropsychopharmacology 16: 93-110

23.

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

24.

Tauscher J , Kufferle B , Asenbaum S , Tauscher-Wisniewski S , Kasper S (2002) Striatal dopamine-2 receptor occupancy as measured with [123I]iodobenzamide and SPECT predicted the occurrence of EPS in patients treated with atypical antipsychotics and haloperidol . Psychopharmacology (Berl) 162: 42-49

25.

Terrian D M , Dorman R V , Gannon R L (1990) Characterization of the presynaptic calcium channels involved in glutamate exocytosis from rat hippocampal mossy fiber synaptosomes . Neurosci Lett 119: 211-214

26.

Tong J X , Rich K M (1997) Diphenylpiperazines enhance regeneration after facial nerve injury . J Neurocytol 26: 339-347

27.

Velly J , Grima M , Marciniak G , Spach M O , 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 Schmiedebergs Arch Pharmacol 335: 176-182