Atypical antipsychotic profile of flunarizine in animal models

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 D 2 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 dizocilpineinduced 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.

The behavioral actions of lithium in rodent models: Leads to develop novel therapeutics

“…Inasmuch as amphetamine-induced hyperlocomotion is a model relevant to mania, the effect of other mood-stabilizers on the model is of interest. A wide range of antipsychotics are capable of attenuating both hyperlocomotion and stereotypy (Arnt, 1995), and for this reason the model is often used in the screening of new antipsychotic drugs (Skuza et al, 1997;Lautar et al, 2005;Tort et al, 2005). As antipsychotics are frequently used to treat bipolar disorder, their efficacy in this model is supportive of its use in the study of mania.…”

Epinephrine potentiates antipsychotic, but not cataleptogenic effect of haloperidol in rats

“…These behavioral disorders (hyperlocomotion, stereotypy, ataxia) are characteristic signs of schizophrenia model in rats induced by a high dose of MK-801 [11,14]. It was shown that epinephrine and haloperidol injected intramuscularly in threshold doses of 0.01 and 0.03 mg/kg, respectively, exhibited no antipsychotic activity (did not prolong the latency from the moment of MK-801 injection to the onset of stereotypy, hyperlocomotion, and ataxia in rats).…”

“…Experiments were carried out on the model of schizophrenia induced in outbred albino male rats (180-200 g) by intramuscular injection of MK-801 in a dose of 0.4 mg/kg [11,14]. Antipsychotic effects of epinephrine, haloperidol, and haloperidol+ epinephrine were quantitatively evaluated on the basis of their minimum effective doses preventing (after intramuscular injection) the development of stereotypy, hyperlocomotion, and ataxia in 100% rats within 60 min after injection of MK-801.…”

Modulation of the Antipsychotic Effect of Ziprasidone with Nimodipine

“…The amphetamine method has been predominantly used, compared to other models that explore probable antipsychotic activity of new substances in animals. This model has been also reported to increase dopaminergic activity in patients with schizophrenia which improves its value (17).…”