Effect of flunarizine on memory function by using step down passive avoidance test in albino rats

Vinod Shinde, Radha Yegnanarayan, Khyati Doshi, Akhil Agarwal


Background: Aim of the study was to evaluate effect of flunarizine on memory function by using step down passive avoidance test in albino rats.

Methods: The study approved by IAEC was conducted using 24 albino rats (n= 6 in each group). Effect of normal saline (0.1 ml/100g), fluoxetine (10 mg/kg, intraperitoneally (ip)), and flunarizine (2 and 10 mg/kg, ip) on memory retrieval in rats was evaluated by using Step-down passive avoidance test. One day prior to conducting the test, each rat was trained to stay on central shock free zone platform (SFZ) for at least 90s. For the training, animals were applied shock of 15s every time when the rat stepped down placing all the paws on the grid floor. On the consecutive day retention of the memory was tested thirty minutes after administration of all test drugs. Step down latency (SDL) and number of mistakes was observed for a period of 5 min in all rats.

Results: The data was analyzed by one-way analysis of variance (ANOVA) and Student’s t-test and P <0.05 was considered significant. Mean Step down latency was significantly increased in fluoxetine (10mg/kg, i.p) group as compared to the normal saline (P<0.05). SDL was increased in flunarizine (10mg/kg, i.p) group but it was not statistically significant (p>0.05). Number of mistakes was reduced in both fluoxetine and flunarizine (10mg/kg, i.p) group and was statistically significant when compared to vehicle treated group.

Conclusions: The results of the present study indicate beneficial effects of flunarizine in memory retrieval in albino rats.


Flunarizine, Fluoxetine, Memory, Step down avoidance test

Full Text:



Heikkinen R, Malm T, Heikkila J, Muona A, Tanila H, Koistinaho M, et al. Susceptibility to focal and global brain ischemia of Alzheimer mice displaying abeta deposits: effect of immunoglobulin. Aging Dis. 2014;5(2):76-87.

Mandel SA, Youdim MB. In the rush for green gold: can green tea delay age-progressive brain neurodegeneration? Recent Pat CNS Drug Discov. 2012;7(3):205-17.

Ando S. Neuronal dysfunction with aging and its amelioration. Proc Jpn Acad Ser B Phys Biol Sci. 2012;88(6):266-82.

Prasad KN, William CC, Prasad KC. Risk factors for Alzheimer's disease: Role of multiple antioxidants, non-steroidal anti-inflammatory and cholinergic agents alone or in combination in prevention and treatment. J Am Coll Nutr. 2002;21(6):506-22.

Moschovos C, Papatheodoropoulos C. The L-type voltage-dependent calcium channel long-term potentiation is higher in the dorsal compared with the ventral associational/commissural CA3 hippocampal synapses. Neurosci Res. 2015 Nov 2. pii: S0168-0102 (15)00259-X.

Brooks SP, Croft AP, Norman G, Shaw SG, Little HJ. Nimodipine prior to alcohol withdrawal prevents memory deficits during the abstinence phase. Neuroscience. 2008;157(2):376-84.

Deyo RA, Straube KT, Disterhoft JF. Nimodipine facilitates associative learning in aging rabbits. Science. 1989;243(4893):809-11.

Zupan G, Mrsic J, Simonic A. Effects of nicardipine, felodipine and nifedipine on passive avoidance behavior of intact and hypoxia-exposed rats. Arch Int Pharmacodyn Ther. 1993;325:61-9.

Ban TA, Morey L, Aguglia E, Azzarelli O, Balsano F, Marigliano V, et al. Nimodipine in the treatment of old age dementias. Prog Neuropsychopharmacol Biol Psychiatry. 1990;14(4):525-51.

Gibson GE, Peterson C. Calcium and the aging nervous system. Neurobiol Aging. 1987;8(4):329-43.

Tripathi KD. 5-Hydroxytryptamine, its Antagonists and Drug Therapy of Migraine, In: Tripathi KD, editor. Essentials of Medical Pharmacology, 7th ed. New Delhi: Jaypee Brothers; 2013:180.

Agarwal VK, Jain S, Vaswani M, Padma MV, Maheshwari MC. Flunarizine as add-on therapy in refractory epilepsy: A open trial. J Epilepsy. 1996;9(1):20-2.

Huwiler A. Inhibitory (passive) avoidance test. In: Vogel HG, editor. Drug Discovery and Evaluation: Pharmacological Assays. 3rd ed, Vol. 1. Springer-Verlag: Berlin, New York; 2008:619-20.

Jafary L, Reisi P, Naghsh N. Effects of fluoxetine on memory under forced treadmill exercise conditions in male rats. Adv Biomed Res. 2015;4:235.

Stagni F, Giacomini A, Guidi S, Ciani E, Ragazzi E, Filonzi M et al. Long-term effects of neonatal treatment with fluoxetine on cognitive performance in Ts65Dn mice. Neurobiol Dis. 2015;74;204-18.

Guidance for Industry, Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. U. S. Dept of Health and Human Services, Food and Drug Administration and Center for Drug Evaluation and Research 2005. (Accessed August 5, 2015, at

Shinde V, Yegnanarayan R, Shah P, Gupta A, Pophale P. Antidepressant-like activity of flunarizine in modified tail suspension test in rats. N Am J Med Sci. 2015;7(3):100-3.

Vignisse J, Steinbusch HW, Grigoriev V, Bolkunov A, Proshin A, Bettendorff L, et al. Concomitant manipulation of murine NMDA- and AMPA-receptors to produce pro-cognitive drug effects in mice. Eur Neuropsychopharmacol. 2014;24(2):309-20.

Khurana N, Ishar MP, Gajbhiye A, Goel RK. PASS assisted prediction and pharmacological evaluation of novel nicotinic analogs for nootropic activity in mice. Eur J Pharmacol. 2011;662(1-3):22-30.

Foster TC, Kumar A. Calcium dysregulation in the aging brain. Neuroscientist. 2002;8(4):297-301.

Thibault O, Gant JC, Landfield PW. Expansion of the calcium hypothesis of brain aging and Alzheimer’s disease: minding the store. Aging Cell. 2007;6(3):307-17.

Thibault O, Hadley R, Landfield PW. Elevated postsynaptic [Ca2+]i and L-type calcium channel activity in aged hippocampal neurons: relationship to impaired synaptic plasticity. J Neurosci. 2001;21(24):9744-56.

Miyashita T, Kubik S, Lewandowski G, Guzowski JF. Networks of neurons, networks of genes: an integrated view of memory consolidation. Neurobiol Learn Mem. 2008;89(3):269-84.

Berridge MJ. Calcium signalling and Alzheimer's disease. Neurochem Res. 2011;36(7):1149-56.

Mattson MP, Cheng B, Davis D, Bryant K, Lieberburg I, Rydel RE. Beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J Neurosci. 1992;12(2):376-89.

Thibault O, Landfield PW. Increase in single L-type calcium channels in hippocampal neurons during aging. Science. 1996;272(5264):1017-20.

Forette F, Seux ML, Staessen JA, Thijs L, Babarskiene MR, Babeanu S, et al. The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study. Arch Intern Med. 2002;162(18):2046-52.

López-Arrieta JM, Birks J. Nimodipine for primary degenerative, mixed and vascular dementia. Cochrane Database Syst Rev. 2002;3:CD000147.

McAfee DA, Yarowksy PJ. Calcium-dependent potentials in the mammalian sympathetic neurone. J Physiol. 1979;290(2):507-23.

Andrade R, Foehring RC, Tzingounis AV. The calcium-activated slow AHP: cutting through the Gordian knot. Front Cell Neurosci. 2012;6:47.

Kuga T, Sadoshima J, Tomoike H, Kanaide H, Akaike N, Nakamura M. Actions of Ca2+ antagonists on two types of Ca2+ channels in rat aorta smooth muscle cells in primary culture. Circ Res. 1990;67(2):469-80.

Thompson LT, Moyer JR, Black J, Disterhoft JF. Cellular mechanisms for nimodipine's reduction of aging-related learning deficits. Adv Behav Biol. 1992;40:241-56.

Quartermain D, Hawxhurst A, Ermita B, Puente J. Effect of the calcium channel blocker amlodipine on memory in mice. Behav Neural Biol. 1993;60(3):211- 9.

Wilmott LA, Thompson LT. Sex- and dose-dependent effects of post-trial calcium channel blockade by magnesium chloride on memory for inhibitory avoidance conditioning. Behav Brain Res. 2013;257:49-53.

Quartermain D, deSoria VG, Kwan A. Calcium channel antagonists enhance retention of passive avoidance and maze learning in mice. Neurobiol Learn Mem. 2001;75(1):77-90.

Schafe GE. Rethinking the role of L-type voltage-gated calcium channels in fear memory extinction. Learn Mem. 2008;15(5):324-5.