Download PDF
Arzneimittelforschung 2010; 60(6): 307-314
DOI: 10.1055/s-0031-1296292
CNS-active Drugs · Hypnotics · Psychotropics · Sedatives
Editio Cantor Verlag Aulendorf (Germany)

Effect of lamotrigine and environmental enrichment on spatial memory and other behavioral functions in rats

Elzbieta Nowakowska
Department of Pharmacoeconomics and Social Pharmacy, University of Medical Sciences, Poznan, Poznan (Poland)
,
Anna Czubak
Department of Pharmacoeconomics and Social Pharmacy, University of Medical Sciences, Poznan, Poznan (Poland)
,
Krzysztof Kus
Department of Pharmacoeconomics and Social Pharmacy, University of Medical Sciences, Poznan, Poznan (Poland)
,
Jana Metelska
Department of Pharmacoeconomics and Social Pharmacy, University of Medical Sciences, Poznan, Poznan (Poland)
,
Kinga Burda
Department of Pharmacoeconomics and Social Pharmacy, University of Medical Sciences, Poznan, Poznan (Poland)
,
Anna Nowakowska
Department of Pharmacoeconomics and Social Pharmacy, University of Medical Sciences, Poznan, Poznan (Poland)
› Author Affiliations
Further Information

Publication History

Publication Date:
02 December 2011 (online)

    Permissions and Reprints

Abstract

Epileptic patients are at risk of experiencing cognitive deficits as a result of pharmacotherapy as well as etiology of epilepsy. Antiepileptic drugs increase inhibitory neurotransmission and reduce the responsiveness of neurons, and thereby may have a negative impact on memory. The enriched environment intensifies exploration of the new area behavior, which may have a positive impact on spatial memory in rats.

Depression is among the most common affective disorders in epileptic patients, and using antidepressant drugs together with antiepileptics brings about the risk of interactions and intensifying side effects.

The aim of the study was to assess the effects of lamotrigine (CAS 84057-84-1, LTG) (10 mg/kg i. p.), a new anticonvulsant with antidepressant and neuroprotective properties, for memory and other behavioral functions in rats in standard and enriched environments (EE). LTG improved spatial memory upon repeated administration of the drug both in the rats housed in standard conditions and those housed in EE. Exposure to an enriched environment significantly improved spatial learning. LTG showed antidepressant effect on the forced swimming test both in the rats housed in standard conditions and those housed in EE. In rats housed in EE the antidepressant effect occurred earlier. LTG had a low profile of adverse effects (activity meter, chimney test).

Key words

Antiepileptics - CAS 84057-84-1 - Enriched environment - Lamotrigine, antidepressant effect - Spatial memory
 

  • References

  • 1 Aldenkamp AP, Baker G. A systematic review of the effects of lamotrigine on cognitive function and quality of life. Epilepsy Behav. 2001; 2: 85-91
    CrossrefPubMedGoogle Scholar
  • 2 Alonso R, Griebel G, Pavone G, Stemmelin J, Le FG, Soubrie P. Blockade of CRF(l) or V(lb) receptors reverses stress-induced suppression of neurogenesis in a mouse model of depression. Mol. Psychiatry. 2004; 9: 278-86
    CrossrefPubMedGoogle Scholar
  • 3 Balu DT, Lucki I. Adult hippocampal neurogenesis: Regulation, functional implications, and contribution to disease pathology. Neurosci Behav Rev. 2009; 33: 232-52
    CrossrefPubMedGoogle Scholar
  • 4 Boisser JR, Tardy J, Diverres JC. Ue nouvelle methode simple pour explorer l’action tranquilisante: le test de la cheminee. Med Exp. 1960; 3: 81-4
    PubMedGoogle Scholar
  • 5 Bourin M, Masse F, Hascoet M. Evidence for the activity of lamotrigine at 5-HT1A receptors in the mouse forced swimming test. J Psychiatry Neurosci. 2005; 30 (4) 275-82
    PubMedGoogle Scholar
  • 6 Bourin M, Prica C. The role of mood stabilizers in the treatment of the depressive facet of bipolar disorders. Neurosci Biobehav Rev. 2007; 31 (6) 963-75
    CrossrefPubMedGoogle Scholar
  • 7 Bowden Cl, Mitchell P, Suppes T. Lamotrigine in the treatment of bipolar depression. Eur Neuropsychopharmacol. 1999; 9: 113-7
    CrossrefPubMedGoogle Scholar
  • 8 Bowden CL. New concepts in mood stabilization: evidence for the effectiveness of valproate and lamotrigine. Neuropsychopharmacology. 1998; 19: 194-9
    CrossrefPubMedGoogle Scholar
  • 9 Brodie MJ, Schachter SC. Epilepsy. Oxford: Health Press; 2001
    Google Scholar
  • 10 Consoni FT, Vital MA, Andreatini R. Dual monoamine modulation for the antidepressant like effect of lamotrigine in the modified forced swimming test. Eur Neuropsychopharmacol. 2006; 16: 451-8
    CrossrefPubMedGoogle Scholar
  • 11 Faverjon S, Silveira DC, Fu DD, Cha BH, Akman C, Hu Y et al Beneficial effects of enriched environment following status epilepticus in immature rats. Neurology. 2002; 59 (9) 1302-3
    CrossrefPubMedGoogle Scholar
  • 12 Ghaemi SN, Gaughan S. Novel anticonvulsants: a new generation of mood stabilizers. Harvard Rev Psychiatry. 2000; 8: 1-7
    PubMedGoogle Scholar
  • 13 Halogen T, Nissinen Jari, Pitkanen A. Effect of lamotrigine treatment on status epilepticus-induced neuronal damage and memory impartment in rat. Epilepsy Res. 2001; 46: 205-23
    CrossrefPubMedGoogle Scholar
  • 14 Hattori S, Hashimoto R, Miyakawa T. Enriched enviroments influence depression-related behavior in adult mice and the survival of newborn cells in their hippocampi. Behav Brain Res. 2007; 180: 69-76
    CrossrefPubMedGoogle Scholar
  • 15 Holmes GL, Gaiarsa JL, Chevassus-Au-Louis N, Ben-Ari Y. Consequences of neonatal seizures in the rat: morphological and behavioral effect. Ann Neurol. 1998; 44: 845-57
    CrossrefPubMedGoogle Scholar
  • 16 Jedynak P, Jaholkowski P, Filipkowski RK. Neurogeneza doroslych a depresja. Neuropsychiatry Neuropsychol. 2007; 2: 57-65
    PubMedGoogle Scholar
  • 17 Kuo CC, Lu L. Characterization of lamotrigine inhibition of Na+ channels in rat hippocampal neurons. Br J Pharmacol. 1997; 121: 1231-8
    CrossrefPubMedGoogle Scholar
  • 18 Leach MJ, Marden CM, Miller AA. Pharmacological studies of lamotrigine, a novel potential antipsychotic drug: II neurochemical, and clinical studies of the mechanism of action. Epilepsia. 1986; 27: 490-7
    CrossrefPubMedGoogle Scholar
  • 19 Lizasoain I, Knowles RG, Monada S. Inhibition by lamotrigine of the generation of nitric oxide in rat forebrain slices. J Neurochem. 1995; 64 (2) 636-42
    PubMedGoogle Scholar
  • 20 Longo R, Domenici MR, deCarolis S, Sagratella S. Falba-mate selectively blocks in vitro hippocampal kainate-induced irreversible electrical changes. Life Sci. 1995; 56 (21) 409-14
    PubMedGoogle Scholar
  • 21 Loscher W. Animal models of epilepsy for the development of antiepileptogenic and disease-modifying drugs: a comparison of the pharmacology of kindling and post status epilepticus models of temporal lobe epilepsy. Epilepsy Res. 2002; 50: 105-23
    CrossrefPubMedGoogle Scholar
  • 22 Luszczki JJ, Sielski M, Kominek M, Swiader MJ. Effect of lamotrigine combined with tiagabine on locomotor activity in mice. Ann Universitatis Marie Curie-Sklodowska, Lublin, Polonia Sectio D 2006. 2. 167
    Google Scholar
  • 23 Luszczki JJ. Effects of lamotrigine alone or in combination with conventional antiepileptic drugs on locomotor activity in mice. Ind J Pharmacol. 2004; 36: 306-11
    PubMedGoogle Scholar
  • 24 Lynch M, Sayin U, Brownds J, Janumpali S, Sutula T. Long term consequences of early postnatal seizure on hippocampal learning and plasticity. Eur J Neurosci. 2000; 12: 2252-64
    CrossrefPubMedGoogle Scholar
  • 25 Martin R, Kuzniecky R, Hetherington H. Cognitive effects of topiramate, gabapentin, and lamotrigine in healthy young adults. Neurology. 1999; 52: 321-7
    CrossrefPubMedGoogle Scholar
  • 26 Meador KJ, Loring DW, Ray PG. Differential cognitive effects of carbamazepine and gabapentin. Epilepsia. 1999; 40: 1279-85
    CrossrefPubMedGoogle Scholar
  • 27 Mohammed AH, Zhu SW, Darmopil S, Hjerling-Leffler J, Ernfors P, Winblad B et al Environmental enrichment and the brain. Prog Brain Res. 2002; 138: 109-33
    PubMedGoogle Scholar
  • 28 Mora F, Segovia G, Del AA. Aging, plasticity and environmental enrichment: structural changes and neurotransmitter dynamics in several areas of the brain. Brain Res Rev. 2007; 55: 78-88
    CrossrefPubMedGoogle Scholar
  • 29 Morris R. development of a water-maze procedure for studying spatial learning in a rat. J Neurosci Methods. 1984; 11: 47-60
    CrossrefPubMedGoogle Scholar
  • 30 Nithianantharajah J, Hannan AJ. Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nat Rev Neurosci. 2006; 7: 697-709
    CrossrefPubMedGoogle Scholar
  • 31 Nowakowska E, Chodera A, Kus K. Behavioral and memory improving effects of mirtazapine in rats. Pol J Pharmacol. 1999; 51: 463-9
    PubMedGoogle Scholar
  • 32 Nowakowska E, Kus K, Chodera A, Rybakowski J. Behavioural effects of fluoxetine and tianeptine, two antidepressants with opposite action mechanisms, in rats. Arzneimittelforschung. 2000; 50 (1) 5-10
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Nowakowska E, Kus K, Chodera A. Comparison of behavioural effects of venlafaxine and imipramine in rats. Arzneimittelforschung. 2003; 53 (4) 237-42
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Nowakowska E, Kus K, Chodera A, Rybakowski J. Investigating potential anxiolytic, antidepressant and memory enhancing activity of deprenyl. J Physiol Pharmacol. 2001; 52: 863-73
    PubMedGoogle Scholar
  • 35 Nowakowska E, Kus K, Czubak A, Jedrzejewska A. Memory improving and antidepressant effects of topiramate in rats. Arzneimittelforschung. 2009; 59 (10) 487-492
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Nowakowska E, Kus K, Florek E, Czubak A, Jodynis-Liebert J. The influence of tobacco smoke and nicotine on antidepressant and memory improving effects of venlafaxine. Hum Exp Toxicol. 2006; 25 (4) 199-209
    CrossrefPubMedGoogle Scholar
  • 37 Olson AK, Eadie BD, Ernst C, Christie BR. Environmental enrichment and voluntary exercise massively increase neurogenesis in the adult hippocampus via dissociable pathways. Hippocampus. 2006; 16: 250-60
    CrossrefPubMedGoogle Scholar
  • 38 Perrine K, Kiolbasa T. Cognitive deficits in epilepsy and contribution to psychopathology. Neurology. 1999; 53 (2) 39-48
    PubMedGoogle Scholar
  • 39 Porsolt RD, Anton G, Blavet N, Jalfre M. Behavioural despair in rats: a new model sensitive to antidepressant treatments. Eur J Pharmacol. 1978; 47: 379-91
    CrossrefPubMedGoogle Scholar
  • 40 Prica C, Hascoet M, Bourin M. Antidepressant-like effect of lamotrigine is reversed by veratrine: A possible role of sodium channels in bipolar depression. Behav Brain Res. 2008; 191: 49-54
    CrossrefPubMedGoogle Scholar
  • 41 Rocha FL, hara C. Lamotrigine augmentation in unipolar depression. Int Clin Psychopharmacol. 2003; 18: 97-9
    CrossrefPubMedGoogle Scholar
  • 42 Scoville WB, Milner B. Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry. 1957; 20: 11-21
    CrossrefPubMedGoogle Scholar
  • 43 Shannon HE, Love PL. Effects of antiepileptic drugs on working memory as assessed by spatial alternation performance in rats. Epilepsy Behav. 2004; 5: 857-65
    CrossrefPubMedGoogle Scholar
  • 44 Shannon HE, Love PL. Effects of antiepileptic drugs on attention as assessed by a 5-choice serial reaction time task in rats. Epilepsy Behav. 2005; 7: 620-8
    CrossrefPubMedGoogle Scholar
  • 45 Shannon HE, Love PL. Effects of antiepileptic drugs on learning as assessed by a repeated acquisition of response sequences task in rats. Epilepsy Behav. 2007; 10 (1) 16-25
    CrossrefPubMedGoogle Scholar
  • 46 Sheline YI, Gado MH, Kraemer HC. Untreated depression and hippocampal volume loss. Am J Psychiatry. 2003; 160: 1516-8
    CrossrefPubMedGoogle Scholar
  • 47 Sloviter RS. Status epilepticus-induced neuronal injury and network reorganization. Epilepsia. 2000; 40 (1) 34-41
    PubMedGoogle Scholar
  • 48 Smith D, Baker G, Davies G, Dewey M, Chadwick DW. Outcomes of add-on treatment with lamotrigine in partial epilepsy. Epilepsia. 1993; 34: 312-22
    CrossrefPubMedGoogle Scholar
  • 49 Southam E, Kirkby D, Higgins GA, Hagan RM. Lamotrigine inhibits monoamine uptake in vitro and modulates 5-hy-droxytryptamine uptake in rats. Eur J Pharmacol. 1998; 358: 19-24
    CrossrefPubMedGoogle Scholar
  • 50 Southam E, Pereira R, Stratton SC, Sargent R, Ford AJ, Butterfield LJ et al Effect of lamotrigine on the activities of monoamine oxidases A and B in vitro and on monoamine disposition in vivo. Eur J Pharmacol. 2005; 591: 237-45
    PubMedGoogle Scholar
  • 51 Squire LR. The neuropsychology of human memory. Annu Rev Neurosci. 1982; 5: 241-73
    CrossrefPubMedGoogle Scholar
  • 52 Stefani A, Calabresi P, Pisami A, Mercuri NB, Siniscalchi A, Bernardi G. Falbamate inhibits dihydropyridine-sensitive calcium channels in central neurons. J Pharmacol Exp Ther. 1996; 277: 121-7
    PubMedGoogle Scholar
  • 53 Stefani A, Spadowi F, Bernardi G. Voltage-activated calcium channels: targets of antiepileptic drug therapy?. Epilepsia. 1997; 38: 959-65
    CrossrefPubMedGoogle Scholar
  • 54 Trullas R, Skolnick P. Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur J Pharmacol. 1990; 185: 1-10
    CrossrefPubMedGoogle Scholar
  • 55 Uead S, Sakakibara S, Yoshimoto K. Effect of long-lasting serotonin depletion on enviromental enrichment-induced neurogenesis in adult rat hippocampus and spatial learning. Neuroscience. 2005; 135: 395-402
    CrossrefPubMedGoogle Scholar
  • 56 VanPraag H, Kempermann G, Gage FH. Neural consequences of enviromental enrichment. Neuroscience. 2002; 1: 191-8
    PubMedGoogle Scholar
  • 57 Veena J, Strikumar BN, Raju TR, Shankaranarayana Rao BS. Exposure to enriched environment restores the survival and differentiation of new born cells in the hippocampus and ameliorates depressive symptoms in chronically stressed rats. Neurosci Lett. 2009; 455: 178-82
    CrossrefPubMedGoogle Scholar
  • 58 Young D, Lawlor PA, Leone P, Dragunow M, During MJ. Enviromental enrichment inhibits spontaneous apoptosis, prevents seizures and is neuroprotective. Nat Med. 1999; 5: 448-53
    CrossrefPubMedGoogle Scholar