EFFECT OF LAMOTRIGINE TREATMENT ON ACTIVE AVOIDANCE PERFORMANCE IN A MODEL OF DIAZEPAM-INDUCED AMNESIA
Keywords:
Lamotrigine, Diazepam, learning, memory, shuttle boxAbstract
Introduction: Epilepsy is a neurological disorder that affects around 50 million people worldwide. It is
often associated with cognitive and behavioral dysfunction which could be а result of the disease or the applied
therapy. Memory is the process by which information is encoded, stored, and retrieved. Amnesia is a deficit in
memory. There are two main types of amnesia – retrograde and anterograde amnesia. Diazepam is widely used in
experimental models of drug-induced anterograde type of amnesia. Purpose: The present study was undertaken to
assess the effect of one widely applied in clinical practice anticonvulsant – lamotrigine (LTG) on cognitive function
in a model of drug-induced amnesia with diazepam (DZP). Materials and methods: We trained 24 male adult rats,
divided into three groups (n=8): the first group was treated with saline p.o. (C-veh); second – with saline p.o. and
2.5 mg/kg DZP i.p. (DZP-veh); and third – with 10 mg/kg LTG and 2.5 mg/kg DZP i.p. (DZP-LTG). We use a
Shuttle box (Ugo Basile, Italy) – apparatus for active and passive avoidances. The learning session was held for 5
consecutive days and consisted of 30 trials each. During each trial, subjects were given a conditioned light stimulus
(6 sec) and sound stimulus which were followed by 4-sec foot electrical stimulation (0.4 mA) and a 10-sec pause.
The measured behavioral parameters were: the number of avoidances, number of escapes, and number of intertrial
crossings. Results: The DZP-veh animals decreased significantly the number of avoidances during the learning
session on days 2 (p<0.01), 4 (p<0.01) and 5 (p < 0.001) and during the memory retention test (p < 0.01) compared
to the C-veh group. The DZP-LTG rats increased the number of conditioned responses on days 4 and 5 (p < 0.01) of
the learning session and during the re-test (p<0.01) in comparison with the DZP-veh animals. For the number of
escapes one-way ANOVA showed that the DZP-veh animals decreased significantly their number on days 1 (p <
0.01), 2 (p < 0.001), 3 (p < 0.001) and 4 (p < 0.01) of the learning session as well as on day 12 (p < 0.01) compared
to the C-veh rats. The DZP-LTG group increased the number of unconditioned responses compared to the DZP-veh
animas on days 1 (p < 0.01), 2 (p < 0.05), 3 (p < 0.001) and 4 (p < 0.05) and during the test for long-term memory
traces (p < 0.05). For the number of intertrial crossings, there was only a tendency for DZP-veh group to decrease
them during the learning session in comparison with the controls while the DZP-LTG animals increased them. The
difference reached statistical significance only on day 5 (p < 0.01) of the learning session compared to the DZP-veh
rats. Conclusion: Lamotrigine improves active learning abilities as well as the formation of long-term memory traces
in a model of drug-induces amnesia with diazepam.
References
Agarwal, N.B., Agarwal, N.K., Mediratta, P.K., & Sharma, K.K. (2011). Effect of lamotrigine, oxcarbazepine and topiramate on cognitive functions and oxidative stress in PTZ-kindled mice. Seizure, 20(3), 257-262.
Beracochea, D. (2006). Anterograde and retrograde effects of benzodiazepines on memory. Scientific World Journal, 6, 1460-1465.
Caroni, P., Donato, F., & Muller, D. (2012). Structural plasticity upon learning: regulation and functions. Nature Reviews Neuroscience, 13(7), 478-490.
Costa, J. C., Costa, K. M., & do Nascimento, J. L. (2010). Scopolamine- and diazepam-induced amnesia are blocked by systemic and intraseptal administration of substance P and choline chloride. Peptides, 31(9), 1756-1760.
Hakami, T. (2021). Neuropharmacology of Antiseizure Drugs. Neuropsychopharmacology reports, 41(3), 336-351.
Hu, H., Real, E., Takamiya, K., Kang, M. G., Ledoux, J., Huganir, R. L., & Malinow, R. (2007). Emotion enhances learning via norepinephrine regulation of AMPA receptor trafficking. Cell, 131, 160-173.
Kaster, M. P., Raupp, I., Binfaré, R.W., Andreatini, R., & Rodrigues, A.L.S. (2007). Antidepressant-like effect of lamotrigine in the mouse forced swimming test: Evidence for the involvement of the noradrenergic system. European Journal of Pharmacology, 565, 119–124.
Kilova, K., & Kitova, Т. (2021). Student opinion on the quality of distance medical learning in pandemic conditions. Journal of Environmental Protection and Ecology; 22(4), 1706-1714.
Lee, S. A., Lee, H. W., Heo, K., Shin, D. J., Song, H. K., Kim, O. J., Lee, S.M., Kim, S. O., Lee, B. I. (2011). Cognitive and behavioral effects of lamotrigine and carbamazepine monotherapy in patients with newly diagnosed or untreated partial epilepsy. Seizure, 20, 49-54.
McGaugh, J. L. (2000). Memory - a century of consolidation. Science, 287, 248-251.
McIntyre, R. S., Berk, M., Brietzke, E., Goldstein, B. I., López-Jaramillo, C., Kessing, L.V., Malhi, G.S, Nierenberg, A. A., Rosenblat, J. D., Majeed, A., Vieta, E., Vinberg, M., Young, A.H., Mansur, R. B. (2020). Bipolar disorders. Lancet, 396(10265), 1841-1856. doi: 10.1016/S0140-6736(20)31544-0.
Miller, T. D., Butler, C. R. (2022). Acute-onset amnesia: transient global amnesia and other causes. Practical Neurology, 22(3), 201-208. doi: 10.1136/practneurol-2020-002826.
Perucca, P., Bahlo, M., & Berkovic, S.F. (2020). The Genetics of Epilepsy. Annual Review of Genomics and Human Genetics, doi: 10.1146/annurev-genom-120219-074937.
Savić, M. M., Obradović, D.I., Ugresić, N.D., & Bokonjić, D.R. (2005). Memory effects of benzodiazepines: memory stages and types versus binding-site subtypes. Neural Plasticity, 12(4), 289-98.
Segura, I. A., McGhee, J., Della Sala, S., Cowan, N., & Pompéia, S. (2021). A reappraisal of acute doses of benzodiazepines as a model of anterograde amnesia. Human Psychopharmacology, 2021; 36(3):e2774.
Shannon, H. E., & Love, P.L. (2007). Effects of antiepileptic drugs on learning as assessed by a repeated acquisition of response sequences task in rats. Epilepsy and Behavior, 10(1), 16-25. doi: 10.1016/j.yebeh.2006.11.004.
Shannon, H.E., & Love, P.L. (2005). Effects of antiepileptic drugs on attention as assessed by a five-choice serial reaction time task in rats. Epilepsy and Behavior, 2005, 7(4), 620-628.
Tully, K., & Bolshakov V. (2010). Eemviewotional enhancement of memory: how norepinephrine enables synaptic plasticity. Molecular Brain, 2010; 3, 15.
Verwey, B., Muntendam, A., Ensing, K., Essink, G., Pasker-de Jong, P.C., Willekens, F.L., & Zitman, F.G. (2005). Clinically relevant anterograde amnesia and its relationship with blood levels of benzodiazepines in suicide attempters who took an overdose. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 29(1), 47-53.
Watkins, L.V., Pickrell, W.O., & Kerr, M.P. (2019). Treatment of psychiatric comorbidities in patients with epilepsy and intellectual disabilities: Is there a role for the neurologist? Epilepsy and Behavior, 98(Pt B), 322-327.
