Early Administration of Tiapride to Young Rats without Long-lasting Changes in the Development of the Dopaminergic System

Background: The benzamide tiapride, a selective dopamine D2/D3-receptor antagonist, can be used effectively in children to treat tic disorders and stuttering. Tiapride is a clinically safe substance (even during long-term treatment and when given to young children). Unfortunately, its probable effects on general brain development and the maturation of the dopaminergic system have not been investigated. Thus, important information for drug treatment in children is missing. Therefore, this study in rats describes tiapride’s effects on several parameters of dopaminergic activity (dopamine transporter, D2 receptor, dopamine, DOPAC, and homovanillic acid in the striatum) seen after tiapride administration (30 mg/kg/day) to prepubertal (from day 25-39) and postpubertal (from day 50-64) rats. Methods: Three groups of rats (n = 6) received tiapride within their drinking water for 14 days. Two groups were treated before puberty; one of those was killed at day 50, the other at day 90. The group treated after puberty was measured at day 90. A fourth group (n = 6) was treated from day 50 to day 53 and measured under tiapride at day 53. Changes were measured by ligand-binding assays (K_D and B_max values of dopamine transporter by [³H]-GBR binding and D2 receptor by [³H]- spiperone binding) and by HPLC (concentrations of dopamine, DOPAC, and homovanillic acid). Results: The density of dopamine transporters and D2 receptors remained unaffected after early (day 25) and late (day 50) tiapride administration. Only during the treatment period could a significant reduction of D2-receptor binding (displacement of spiperone) and of dopamine and DOPAC levels be stated. Conclusions: These data suggest that tiapride treatment during postnatal brain development causes no long-lasting changes in the development of the central dopaminergic system and is in line with clinical experience in children.

References

• 1 Apud J A, Masotto C, Monopoli A, Ongini E, Rovescalle A C, Racagni G. Effects of repeated tiapride administration on anterior pituitary dopamine receptors and prolactin release in the rat.  Pharmacol Res Comm. 1987;  19 119-128
• 2 Arima T, Samura N, Nomura Y, Segewa T. Comparison of effects of tiapride and sulpiride on D-1, D-2, D-3 and D-4 subtypes of dopamine receptors in rat striatal and bovine caudate nucleus membranes.  Japan J Pharmacol. 1986;  41 419-423
• 3 Bischoff S, Bittiger H, Delina-Stula A, Ortmann R. Septo-hippocampal system: target for Substituted benzamides?.  European Journal of Pharmacology. 1982;  79 225-232
• 4 Breese G R, Duncan G E, Napier T C, Bondy S C, Iorio L C, Mueller R A. 6-hydroxy dopamine treatments enhance behavioral responses to intracerebral microinjection of D1 and D2 dopamine agonists into nucleus accumbens and striatum without changing dopamine antagonist binding.  J Pharmacol Exp Ther. 1987;  240 167-176
• 5 Chivers J K, Gommeren W, Jenner P, Leysen J, Marsden P D, Reavill C, Theodorou A. Comparison of in vivo and in vitro actions of tiapride in rodents.  Abstract, British Journal of Pharmacology. 1983;  79 (Suppl.) 398P
• 6 Chivers J K, Gommeren W, Leysen J, Jenner P, Marsden P D. Comparison of the in-vitro receptor selectivity of substituted benzamide drugs for brain neurotransmitter receptors.  Journal of Pharmacy and Pharmacology. 1988;  40 415-421
• 7 Dose M, Lange H W. The benzamide tiapride: Treatment of extrapyramidal motor and other clinical syndromes.  Pharmacopsychiatry. 2000;  33 19-27
• 8 Eggers C, Rothenberger A, Berghaus U. Clinical and neurobiological findings in children suffering from tic disease following treatment with tiapride.  Eur Arch Psychiatr Neurol Sci. 1988;  137 223-229
• 9 Furukawa S, Furukawa Q, Satoyoshi E, Hayashi K. Regulation of nerve growth factor synthesis/secretion by cathecholamine in cultured mouse astroglial cells.  Biochem Biophys Res Comm. 1987;  147 1048-1054
• 10 Furukawa Y, Tomioka N, Sato W, Satoyoshi E, Hayashi K, Furukawa S. Catecholamin increase nerve growth factor mRNA content in both mouse astroglial cells and fibroblast cells.  FEBS Lett. 1989;  247 463-467
• 11 Inou S, Susukids M, Ikeda K, Murase K, Hayashi K. Dopaminergic transmitter up-regulation of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) synthesis in mouse astrocytes in culture.  Biochem Biophys Res Commun. 1997;  238 468-472
• 12 Ishida-Tokuda K, Ohno Y, Sakamoto H, Ishibashi T, Wakabayashi J, Tojima R, Morita T, Nakamura M. Evaluation of perospirone (SM-9018), a novel serotonin-2 and dopamine-2 receptor antagonist and other antipsychotics in the conditioned fear stress-induced freezing behavior model in rats.  Jpn J Pharmacol. 1996;  72 119-126
• 13 Lin C W, Wilk S. A comparison of the effect of substituted benzamides in radioreceptor binding assay with their effects on brain dopaminergic systems in vivo. In Rotrosen and Stanley, editors. The benzamides: pharmacology, neurobiology, and clinical aspects, advances in biochemical psychopharmacology. Vol 35 New York; Raven Press 1982: 51-60
• 14 Moll G H, Mehnert C, Wicker M, Bock N, Rothenberger A, Rüther E, Huether G. Age-associated changes in the densities of presynaptic monoamine transporters in different regions of the rat brain from early juvenile life to late adulthood.  Developmental Brain research. 2000;  119 251-257
• 15 Moll G H, Hauser S, Rüther E, Rothenberger A, Huether G. Early methylphenidate administration to young rats causes a persistent reduction in the density of striatal dopamine transporers.  J Child Adolesc Psychopharmacol. 2001;  11 15-24
• 16 Neal B S, Joyce J N. Neonatal 6-OHDA lesions differentially affect striatal D1 and D2 receptors.  Synapse. 1992;  11 35-46
• 17 Okazawa H, Murata M, Watanabe M, Kamei M, Kanazawa I. Dopaminergic stimulation up-regulates the in vivo expression of brain-derived neurotrophic factor (BDNF) in the striatum.  FEBS Lett. 1992;  313 138-142
• 18 Parent M, Jadot M, Toussaint C. Tiapride and alcohol withdrawal symptoms.  Revue Medicale de Liege. 1978;  33 672-677
• 19 Renaudin C, Lemant P. Essai comperatif de l’atrium 300 et du tiapride per os dans le traitement de syndrome de sevrage alcoholique.  Psychologie Médicale. 1981;  13 161-168
• 20 Robertson M, Stern J S. Gilles de la Tourette Syndrome: symptomatic treatment based on evidence.  Euro Child Adol Psychiatry. 2000;  9, Suppl. 1 60-75
• 21 Rothenberger A, Eggers C. The influence of tiapride on the ERPs of children with multiple tics. In Rothenberger A Event-related potentials in children. Developments in Neurology. Vol. 6 Amsterdam; R. Elsevier 1982: 423-428
• 22 Rothenberger A, Johannsen H S, Schulze H, Amorosa H, Rommel D. Use of tiapride on stuttering children and adolescents.  Perceptual and Motor Skills. 1994;  79 1163-1170
• 23 Rothenberger A, Banaschewski T. Diagnose und Behandlung von Tourette Syndrom und anderen Tic-Störungen. Arbeitsgemeinschaft Medizinischer Fachgesellschaften (AWMF, Hrsg.) Leitlinien zu Diagnostik und Therapie von psychischen Störungen. Internet bzw. Köln; Deutscher Ärzte-Verlag 2003: 311-317
• 24 Rothenberger A, Banaschewski T, Siniatchkin M. Tic-Störungen. In Herpertz-Dahlmann B, Resch F, Schulte-Markwort M, Warnke A (Hrsg.) Entwicklungspsychiatrie. Stuttgart; Schattauer 2003: 548-569
• 25 Satoh H, Kuwaki T, Shirakawa K, Kohjimoto Y, Ono T, Shibayama F, Nomura Y. Effect oflong-term dosing with tiapride on brain dopamine receptors and metabolism in rats comperative study with sulpiride and haloperidol.  Japan j Pharmacol. 1987;  44 393-403
• 26 Scatton B, Cohen C, Perrault G, Oblin A, Claustre Y, Schoemaker H, Sanger D J. Rouquier L, Porsolt R. The preclinical pharmacologic profile of tiapride.  Eur Psychiatry. 2001;  16 Suppl 1 29s-34 s
• 27 Sedval G. The current status of PET scanning with respect to schizophrenia.  Neuropsychopharmacol. 1992;  7 41-54
• 28 Steele J W, Faulds D, Sorkin E M. Tiapride. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in geriatric agitation.  Drugs and Aging. 1993;  3 460-478
• 29 Stefanini E, Clément-Cormier Y, Vernaleone F, Devoto P, Marchisio A M, Collu R. Sodium-dependent interaction of benzamides with dopamin receptors in rat and dog anterior pituitary glans.  Neuroendocrinology. 1981;  32 103-107
• 30 Tarazi F I, Baldessarini R J. Comparative postnatal development of dopamine D1, D2 and D4 receptors in rat forebrain.  Int J Dev Neuroscience. 2000;  18 29-37
• 31 Volkow N, Wang G J, Fowler J S, Logan J, Gerasimov M, Maynard L, Ding Y S, Gatley S J, Gifford A, Franceschi D. Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain. J Neurosci 2001 21
• 32 Zhou J, Bradford H F, Stern G M. The stimulatory effect of brain-derived neurotrophic factor on dopaminergic phenotype expression of embryonic rat cortical neurons in vitro.  Dev Brain Res. 1994;  81 318-324