Tiagabine Treatment is Associated with Neurochemical, Immune and Behavioural Alterations in the Olfactory Bulbectomized Rat Model of Depression

Abstract

Introduction: Affective disorders are often associated with immune and neuroendocrine disturbances. However, little information on the modulatory effects of antiepileptics on endocrine and immune functions is available. Some novel antiepileptics, including tiagabine, are considered as potential antidepressants.

Methods: We investigated the influence of tiagabine on stress hormone release, cellular immune function and behaviour in rats following olfactory bulbectomy (OB), a well-recognized animal model of depression.

Results: Hyperlocomotion in the open field, typical for the OB rodents, was attenuated by repeated treatment with tiagabine (12 mg/kg/day) in a similar fashion to standard antidepressants. OB led to significantly decreased lymphocyte and increased neutrophil counts, and suppressed leukocyte phagocytosis. The OB-induced changes in leukocyte differential counts were not found in the tiagabine-treated group. The OB-induced reduction in plasma noradrenaline levels was normalized following tiagabine treatment.

Discussion: The present data bring further evidence on the antidepressant-like action of tiagabine and encourage further research on its use in the treatment of affective disorders. The obser-ved changes in immune and endocrine functions may contribute to its mood stabilizing effect.

References

• 1 Barden N. Implication of the hypothalamic-pituitary-adrenal axis in the physiopathology of depression.  J Psychiatry Neurosci. 2004;  29 185-193
• 2 Bersudsky Y. Phenytoin: an anti-bipolar anticonvulsant?.  Int J Neuropsychopharmacol. 2006;  9 479-484
• 3 Carney R-M, Freedland K-E, Veith R-C. Depression, the autonomic nervous system, and coronary heart disease.  Psychosom Med. 2005;  67 ((Suppl 1)) S29-S33
• 4 Carta M-G, Hardoy M-C, Grunze H, Carpiniello B. The use of tiagabine in affective disorders.  Pharmacopsychiatry. 2002;  35 33-34
• 5 Cryan J-F, Mombereau C. In search of a depressed mouse: utility of models for studying depression-related behaviour in genetically modified mice.  Mol Psychiatry. 2004;  9 326-357
• 6 de Boer S-F, Slangen J-L, Van der Gugten J. Effects of chlordiazepoxide and buspirone on plasma catecholamine and corticosterone levels in rats under basal and stress conditions.  Endocrinol Exp. 1990;  24 229-239
• 7 Delbende C, Tranchand B-D, Tarozzo G, Grino M, Oliver C, Mocaer E. et al . Effect of chronic treatment with the antidepressant tianeptine on the hypothalamo-pituitary-adrenal axis.  Eur J Pharmacol. 1994;  251 245-251
• 8 Fenn H-H, Sommer B-R, Ketter T-A, Alldredge B. Safety and tolerability of mood-stabilising anticonvulsants in the elderly.  Expert Opin Drug Saf. 2006;  5 401-416
• 9 Franklin M, Hafizi S, Reed A, Hockney R, Murck H. Effect of sub-chronic treatment with Jarsin (extract of St John's wort, Hypericum perforatum) at two dose levels on evening salivary melatonin and cortisol concentrations in healthy male volunteers.  Pharmacopsychiatry. 2006;  39 13-15
• 10 Gajwani P, Forsthoff A, Muzina D, Amann B, Gao K, Elhaj O. et al . Antiepileptic drugs in mood-disordered patients.  Epilepsia. 2005;  46 ((Suppl 4)) 38-44
• 11 Gilmor M-L, Skelton K-H, Nemeroff C-B, Owens M-J. The effects of chronic treatment with the mood stabilizers valproic acid and lithium on corticotropin-releasing factor neuronal systems.  J Pharmacol Exp Ther. 2003;  305 434-439
• 12 Invitti C, Danesi L, Dubini A, Cavagnini F. Neuroendocrine effects of chronic administration of sodium valproate in epileptic patients.  Acta Endocrinol (Copenh). 1988;  118 381-388
• 13 Jezova D, Guillaume V, Jurankova E, Carayon P, Oliver C. Studies on the physiological role of ANF in ACTH regulation.  Endocr Regul. 1994;  28 163-169
• 14 Jezova D, Makatsori A, Duncko R, Moncek F, Jakubek M. High trait anxiety in healthy subjects is associated with low neuroendocrine activity during psychosocial stress. Prog. Neuropsychopharmacol.  Biol Psychiatry. 2004;  28 1331-1336
• 15 Jezova D. Control of ACTH secretion by excitatory amino acids: functional significance and clinical implications.  Endocrine. 2005;  28 287-294
• 16 Kelly J-P, Wrynn A-S, Leonard B-E. The olfactory bulbectomized rat as a model of depression: an update.  Pharmacol Ther. 1997;  74 299-316
• 17 Knyszynski A, Fischer H. Circadian fluctuations in the activity of phagocytic cells in blood, spleen, and peritoneal cavity of mice as measured by zymosan-induced chemiluminescence.  J Immunol. 1981;  127 2508-2511
• 18 Leonard B-E. The immune system, depression and the action of antidepressants.  Prog Neuropsychopharmacol Biol Psychiatry. 2001;  25 767-780
• 19 Leonard B-E, Tuite M. Anatomical, physiological, and behavioral aspects of olfactory bulbectomy in the rat.  Int Rev Neurobiol. 1981;  22 251-286
• 20 Lilius E-M, Mertsola J, Leivo P, Kuronen T, Ruuskanen O. A rapid and simple method for evaluation of serum opsonic capacity against Bordetella pertussis by chemiluminescence.  Dev Biol Stand. 1985;  61 373-377
• 21 Lloyd K-G, Morselli P-L, Depoortere H, Fournier V, Zivkovic B, Scatton B. et al . The potential use of GABA agonists in psychiatric disorders: evidence from studies with progabide in animal models and clinical trials.  Pharmacol Biochem Behav. 1983;  18 957-966
• 22 Makatsori A, Duncko R, Moncek F, Loder I, Katina S, Jezova D. Modulation of neuroendocrine response and non-verbal behavior during psychosocial stress in healthy volunteers by the glutamate release-inhibiting drug lamotrigine.  Neuroendocrinology. 2004;  79 34-42
• 23 Marcilhac A, Faudon M, Anglade G, Hery F, Siaud P. An investigation of serotonergic involvement in the regulation of ACTH and corticosterone in the olfactory bulbectomized rat.  Pharmacol Biochem Behav. 1999;  63 599-605
• 24 Moffitt J-A, Grippo A-J, Holmes P-V, Johnson A-K. Olfactory bulbectomy attenuates cardiovascular sympathoexcitatory reflexes in rats.  Am J Physiol Heart Circ Physiol. 2002;  283 H2575-H2583
• 25 Molina P-E. Neurobiology of the stress response: contribution of the sympathetic nervous system to the neuroimmune axis in traumatic injury.  Shock. 2005;  24 3-10
• 26 Montilla P, Varo A, Munoz M-C. Effect of olfactory bulbectomy on plasma levels of glucose, lipids and corticosterone in the rat.  Rev Esp Fisiol. 1984;  40 47-51
• 27 Peuler J-D, Johnson G-A. Simultaneous single isotope radioenzymatic assay of plasma norepinephrine, epinephrine and dopamine.  Life Sci. 1977;  21 625-636
• 28 Pistovcakova J, Makatsori A, Sulcova A, Jezova D. Felbamate reduces hormone release and locomotor hypoactivity induced by repeated stress of social defeat in mice.  Eur Neuropsychopharmacol. 2005;  15 153-158
• 29 Reul J-M, Stec I, Soder M, Holsboer F. Chronic treatment of rats with the antidepressant amitriptyline attenuates the activity of the hypothalamic-pituitary-adrenocortical system.  Endocrinology. 1993;  133 312-320
• 30 Roche M, Harkin A, Kelly J-P. Chronic fluoxetine treatment attenuates stressor-induced changes in temperature, heart rate, and neuronal activation in the olfactory bulbectomized rat.  Neuropsychopharmacology. 2007;  32 1312-1320
• 31 Rosenthal M. Tiagabine for the treatment of generalized anxiety disorder: a randomized, open-label, clinical trial with paroxetine as a positive control.  J Clin Psychiatry. 2003;  64 1245-1249
• 32 Rozanski A, Blumenthal J-A, Kaplan J. Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy.  Circulation. 1999;  99 2192-2217
• 33 Schmitt U, Luddens H, Hiemke C. Anxiolytic-like effects of acute and chronic GABA transporter inhibition in rats.  J Neural Transm. 2002;  109 871-880
• 34 Schousboe A, Sarup A, Larsson O-M, White H-S. GABA transporters as drug targets for modulation of GABAergic activity.  Biochem Pharmacol. 2004;  68 1557-1563
• 35 Slotkin T-A, Cousins M-M, Tate C-A, Seidler F-J. Serotonergic cell signaling in an animal model of aging and depression: olfactory bulbectomy elicits different adaptations in brain regions of young adult vs aging rats.  Neuropsychopharmacology. 2005;  30 52-57
• 36 Song C, Leonard B-E. The olfactory bulbectomised rat as a model of depression.  Neurosci Biobehav Rev. 2005;  29 627-647
• 37 Song C, Horrobin D-F, Leonard B-E. The comparison of changes in behavior, neurochemistry, endocrine, and immune functions after different routes, doses and durations of administrations of IL-1beta in rats.  Pharmacopsychiatry. 2006;  39 ((3)) 88-99
• 38 Tichomirowa M-A, Keck M-E, Schneider H-J, Paez-Pereda M, Renner U, Holsboer F. et al . Endocrine disturbances in depression.  J Endocrinol Invest. 2005;  28 89-99
• 39 Torpy D-J, Grice J-E, Hockings G-I, Crosbie G-V, Walters M-M, Jackson R-V. Effect of sodium valproate on naloxone-stimulated ACTH and cortisol release in humans.  Clin Exp Pharmacol Physiol. 1995;  22 441-443
• 40 Tunnicliff G, Malatynska E. Central GABAergic systems and depressive illness.  Neurochem Res. 2003;  28 965-976
• 41 Vielhaber K, Riemann D, Feige B, Kuelz A, Kirschbaum C, Voderholzer U. Impact of experimentally induced serotonin deficiency by tryptophan depletion on saliva cortisol concentrations.  Pharmacopsychiatry. 2005;  38 ((2)) 87-94
• 42 Wang D, Noda Y, Tsunekawa H, Zhou Y, Miyazaki M, Senzaki K. et al . Behavioural and neurochemical features of olfactory bulbectomized rats resembling depression with comorbid anxiety.  Behav Brain Res. 2007;  178 262-273
• 43 Williams G-W, McGinnis M-Y, Lumia A-R. The effects of olfactory bulbectomy and chronic psychosocial stress on serum glucocorticoids and sexual behavior in female rats.  Physiol Behav. 1992;  52 755-760
• 44 Young A-H, Geddes J-R, Macritchie K, Rao S-N, Vasudev A. Tiagabine in the maintenance treatment of bipolar disorders.  Cochrane Database Syst Rev. 2006a;  3 CD005173
• 45 Young A-H, Geddes J-R, Macritchie K, Rao S-N, Watson S, Vasudev A. Tiagabine in the treatment of acute affective episodes in bipolar disorder: efficacy and acceptability.  Cochrane Database Syst Rev. 2006b;  3 CD004694

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