Abstract
Neonatal intracisternal administration of 6-hydroxydopamine (6-OHDA, 50 μg on day 1 after birth) caused a marked hyperactivity when the rats were tested as adults. These rats also showed severe DA depletions in striatum and nucleus accumbens. Pretreatment with the noradrenaline (NA) uptake inhibitor desipramine provided protection against NA depletion in frontal cortex and nucleus accumbens. Pretreatment with DNA uptake inhibitors, amfolenic acid or GBR 12909, before 6-OHDA, provided full protection against DA depletion but produced marked NA depletion in frontal cortex. These rats did not demonstrate any degree of hyperactivity. Low doses ofd-amphetamine (0.25 mg/kg SC) or methylphenidate (1 mg/kg SC) reversed the hyperactivity in DA-depleted rats but increased motor activity in vehicle-treated and NA-depleted rats. Higher doses ofd-amphetamine (1 mg/kg) or methylphenidate (4 mg/kg) produced potentiated levels of locomotion but attenuated levels of rearing in DA-depleted animals. The results further suggest the utility of the neonatal DA lesion in rats as a potential animal model for derivation of therapeutic agents that may be efficacious in the treatment of the hyperkinetic syndrome.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Archer T, (1989) Neurotoxin-induced cognitive and motor activity modifications: a catecholamine connection. In: Sagvolden T, Archer T (eds) Attention deficit disorder: clinical and basic research. Lawrence Erlbaum, Hillsdale, New Jersey, pp 287–322
Archer T, Fredriksson A, Jonsson G, Lewander T, Mohammed AK, Ross SB, Söderberg U (1986) Central noradrenalin depletion antagonizes aspects ofd-amphetamine-induced hyperactivity in the rats. Psychopharmacology 88:141–146
Archer T, Danysz W, Fredriksson A, Luthman J, Sundström E, Teiling A (1988) Neonatal 6-hydroxydopamine induced dopamine depletions: motoractivity and learning performance in radial-arm maze. Pharmacol Biochem Behav 31:357–364
Creese I, Iversen SD (1973) Blockade of amphetamine-induced motor stimulation and stereotypy in the adult rat following neonatal treatment with 6-hydroxydopamine. Brain res 55:369–382
Erinoff L, MacPhail RC, Heller A, Seiden LS (1979) Age-dependent effects of 6-hydroxydopamine on locomotor activity in the rat. Brain Res 164:195–205
Heffner TG, Seiden LS (1982) Possible involvement of serotonergic neurons in the reduction of locomotor hyperactivity caused by amphetamine in neonatal rats depleted of brain dopamine. Brain Res 244:81–90
Jonsson G, Sachs C (1976) Regional changes in [3H]-noradrenaline uptake, catecholamines and catecholamine synthetic and catabolic enzymes in rat brain following neonatal 6-hydroxydopamine treatment. Med Biol 54:286–297
Jonsson G, Hallman H, Mefford I, Adams RN (1980) The use of liquid chromatography with electrochemical detection for the determination of adrenaline and other biogenic monoamines in the CNS. In: Fuxe K, Goldstein M, Hökfelt B, Hökfelt (eds) Central adrenaline neurons. Pergamon, Oxford New York, pp 59–71
Keller R, Oke A, Mefford I, Adams RN (1980) The use of liquid chromatographic analysis of catecholamines — routine assay for regional brain mapping. Life Sci 19:995–1004
Kelly PH, Seviour PW, Iversen SD (1975) Amphetamine and apomorphine responses in the rat following 6-OHDA lesions of the nucleus accumbens septi and corpus striatum. Brain Res 94:507–522
Kirk RE (1968) Experimental design: procedures for the behavioral sciences. Brooks/Cole, Belmont, California
Lewander T (1977) Effects of amphetamine in animals. In: Martin WR (ed) Drug Addictions II, Handbook of experimental pharmacology. Springer, Berlin Heidelberg New York, pp 33–264
Luthman J, Bolioli B, Tsutsumi T, Verhofstad A, Jonsson G (1987) Sprouting of striatal serotonin nerve terminals following selective lesions of nigro-striatal dopamine neurons in the neonatal rat. Brain Res Bull 19:269–274
Luthman J, Fredriksson A, Sundström E, Jonsson G, Archer T (1989) Selective neonatal lesion of central dopamine or noradrenaline neuron systems in the neonatal rat: motor behavior and monoamine alterations at adult stage. Behav Brain Res (in press)
Miller FE, Heffner TG, Kotake C, Seiden LS (1982) Magnitude and duration of hyperactivity following neonatal 6-hydroxydopamine is related to the extent of brain dopamine depletion. Brain Res 229:123–132
Moore K (1978) Amphetamines: biochemical and behavioral actions in animals. In: Iversen LL, Iversen SD, Snyder SA (eds) Handbook of psychopharmacology. Plenum Press, New York, pp 41–98
Pappas BA, Galliver JV, Dugas T, Saari M, Ings R (1980) Intraventricular 6-hydroxydopamine in the newborn rat and locomotor responses to drugs in infancy: no support for the dopamine depletion model of minimal brain dysfunction. Psychopharmacology 70:41–46
Robbins TW, Jones GH, Sahakian BJ (1989) Central stimulants, transmitters and attentional disorders: a perspective from animal studies. In: Sagvolden T, Archer T (eds) Attention deficit disorder: clinical and basic research. Lawrence Erlbaum, Hillsdale, New Jersey, pp 199–222
Seiden L, Miller FE, Heffner TJ (1989) Neurotransmitters in ADD. In: Sagvolden T, Archer T (eds) Attention deficit disorder: clinical and basic research. Lawrence Erlbaum, Hillsdale, New Jersey, pp 223–234
Shaywitz SE, Shaywitz BA (1989) Critical issues in attention deficit disorder. In: Sagvolden T, Archer T (eds) Attention deficit disorder: clinical and basic research. Lawrence Erlbaum, Hillsdale, New Jersey, pp 53–70
Shaywitz BA, Klopper JH, Gordon JW (1976a) Paradoxical response to amphetamine in developing rats treated with 6-hydroxydopamine. Nature 261:153–155
Shaywitz BA, Klopper JH, Yager RD, Gordon JW (1976b) Paradoxical response to amphetamine in developing rats treated with 6-hydroxydopamine. Nature 261:153–155
Shaywitz BA, Yager RD, Klopper JH (1976c) Selective brain dopamine depletion in developing rats: an experimental model of minimal brain dysfunction. Science 191:305–307
Shaywitz SE, Heint RD, Jatlow P, Cohen D, Young GJ, Pierce RN, Anderson GM, Shaywitz BA (1982) Psychopharmacology of attention deficit disorder: pharmacokinetic neuroendocrine and behavioral measures following acute and chronic treatment with methylphenidate. Pediatrics 69:688–694
Solanto MV (1986) Behavioral effects of low dose methylphenidate in childhood attention deficit disorder: implication for a mechanism of stimulant drug action. J Am Acad Child Psychiatry 25:96–101
Sorenson CA, Vayer JS, Goldberg CS (1977) Amphetamine reduction of motor activity in rats after neonatal administration of 6-hydroxydopamine. Biol Psychiatry 12:133–137
Stoof JC, Dijkstra H, Hillegers JPM (1978) Changes in the behavioral response to a novel environment following lesioning of the central dopaminergic system in rat pups. Psychopharmacology 57:163–166
Teicher MH, Barber NI, Reichheld JH, Baldessarini RJ, Finklestein SP (1986) Selective depletion of cerebral norepinephrine with 6-hydroxydopamine and GBR-12909 in neonatal rat. Dev Brain Res 30:124–128
Thieme RE, Dijkstra H, Stoof JC (1980) An evaluation of the young dopamine-lesioned rat as a model for minimal brain dysfunction (MBD). Psychopharmacology 67:165–169
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Luthman, J., Fredriksson, A., Lewander, T. et al. Effects ofd-amphetamine and methylphenidate on hyperactivity produced by neonatal 6-hydroxydopamine treatment. Psychopharmacology 99, 550–557 (1989). https://doi.org/10.1007/BF00589907
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00589907