Postnatal iron overload destroys NA-DA functional interactions
First Online: 24 August 2006 Received: 12 November 2005 Accepted: 05 May 2006 DOI:
Cite this article as: Fredriksson, A. & Archer, T. J Neural Transm (2007) 114: 195. doi:10.1007/s00702-006-0522-6 Summary.
C57/BL6 mice were administered either postnatal iron (Fe
2+ 7.5 mg/kg, on postnatal days 10–12) or vehicle, followed by administration of either DSP4 (50 mg/kg, s.c., 30 min after injection of zimeldine, 20 mg/kg, s.c.) or vehicle (saline) at 63 days of age. Three weeks later, iron/vehicle treated, DSP4/vehicle treated mice were injected with either a low dose of MPTP (2 × 20 mg/kg, with a 24-hr interval between injections) or vehicle. Behaviour testing took place a further three weeks (spontaneous behaviour and L-Dopa induced) and two weeks (clonidine-L-Dopa induced) later. Postnatal iron administration exacerbated the bradykinesia induced by MPTP and virtually abolished all spontaneous motor activity in NA-denervated mice that were MPTP-treated. Postnatal iron administration reduced markedly the restoration of motor activity by suprathreshold L-Dopa (20 mg/kg) following a 60-min habituation to the test chambers. Pretreatment with DSP4 effectively eliminated the restorative effect of L-Dopa in the MPTP mice. The synergistic effects of co-administration of clinidine (1 mg/kg) with a subthreshold dose of L-Dopa (5 mg/kg) in elevating the motor activity of MPTP mice were reduced markedly by postnatal iron administration, as well as by pretreatment with DSP4. NA-denervation by DSP4, after postnatal iron treatment, totally abolished the activity-elevating effects of the α-adrenoceptor agonist + DA-precursor combination in MPTP mice, and virtually eliminated these effects in saline (non-MPTP) mice.
Postnatal iron administration caused enduring higher levels of total iron content in all the groups with an increased level in mice treated with DSP4 followed by MPTP. These divergent findings confirm the direct influence of NA innervation upon dopaminergic functional expression and indicate a permanent vulnerability both in the noradrenergic and dopaminergic pathways following the postnatal infliction of an iron overload.
Keywords: Postnatal iron, DSP4, MPTP, vehicle, motor deficits, locomotion, rearing, total activity, suprathreshold L-Dopa, restoration, clonidine, subthreshold L-Dopa, denervation, DA, NA, C57/BL6 mice, PD References Archer, T 1982 Serotonin and fear retention in the rat J Comp Physiol Psychol 96 491 516 PubMed CrossRef Archer, T, Fredriksson, A 2000 Effects of clonidine and adrenoceptor antagonists on motor activity in DSP4-treated mice I: dose, time- and parameter-dependency Neurotoxicity Res 1 235 247 Archer, T, Fredriksson, A 2001 Effects of α-adrenoceptor agonists in chronic morphine administered DSP4-treated rats: evidence for functional cross-sensitization Neurotoxicity Res 3 411 432 CrossRef Archer, T, Fredriksson, A 2003 An antihypokinesic action of α2-adrenoceptors upon MPTP-induced behaviour deficits in mice J Neural Transm 110 183 200 PubMed CrossRef
Archer T, Fredriksson A (2006) Influence of noradrenaline denervation on MPTP-induced deficits in mice. J Neural Transm (in press)
Archer, T, Ögren, S-O, Johansson, G, Ross, SB 1982 DSP4-induced two-way active avoidance impairment: involvement of central and not peripheral noradrenaline depletion Psychopharmacology 76 303 309 PubMed CrossRef Archer, T, Mohammed, AK, Ross, SB, Söderberg, U 1983 T-maze learning, spontaneous activity and food intake recovery following systemic administration of the noradrenaline neurotoxin, DSP4 Pharmacol Biochem Behav 19 121 130 PubMed CrossRef Archer, T, Jonsson, G, Ross, SB 1984 A parametric study of the effects of the noradrenaline neurotoxin DSP4 on avoidance acquisition and noradrenaline neurons in the CNS of the rat Br J Pharmacol 82 249 257 PubMed Archer, T, Jonsson, G, Ross, SB 1985 Active and passive avoidance following the administration of systemic DSP4, xylamine, or p-chloroamphetamine Behav Neural Biol 43 238 249 PubMed CrossRef Archer, T, Fredriksson, A, Jonsson, G, Lewander, T, Mohammed, AK, Ross, SB, Soderberg, U 1986a Central noradrenaline depletion antagonizes aspects of d-amphetamine-induced hyperactivity in the rat Psychopharmacology 88 141 146 CrossRef Archer, T, Jonsson, G, Minor, BG, Post, C 1986b Noradrenergic-serotonergic interactions and nociception in the rat Europ J Pharmacol 120 295 307 CrossRef Dooley, DJ, Bittiger, H, Hauser, KL, Bischoff, SL, Waldmeier, PC 1983a Alteration of central alpha 2- and beta-adrenergic receptors in the rat after DSP4, a selective noradrenergic neurotoxin Neuroscience 9 889 898 CrossRef Dooley, DJ, Mogilnicka, E, Delini-Stula, A, Waechter, F, Truog, A, Wood, J 1983b Functional supersensitivity to adrenergic agonists in the rat after DSP-4, a selective noradrenergic neurotoxin Psychopharmacology 81 1 5 CrossRef Fornai, F, Bassi, L, Torracca, MT, Alessandri, MG, Scalori, V, Corsini, GU 1996 Region- and neurotransmitter-dependent species and strain differences in DSP4-induced monoamine depletion in rodents Neurodegeneration 5 241 249 PubMed CrossRef Fornai, F, Alessandri, MG, Torracca, MT, Bassi, L, Corsini, GU 1997 Effects of noradrenergic lesions on MPTP/MPP+ kinetics and MPTP-induced nigrostriatal dopamine depletions J Pharmacol Exp Ther 283 100 107 PubMed Fredriksson, A, Archer, T 1994 MPTP-induced behavioural and biochemi_cal deficits: a parametric analysis J Neural Transm Park Dis Dement Sect 7 123 132 PubMed CrossRef Fredriksson, A, Archer, T 2000 Effects of clonidine and α-adrenoceptor antagonists on motor activity in DSP4-treated mice II: interactions with apomorphine Neurotoxicity Res 1 249 259 CrossRef Fredriksson, A, Archer, T 2003 Effect of postnatal iron administration on MPTP-induced behavioural deficits and neurotoxicity: behavioural enhancement by L-Dopa-MK-801 co-administration Behav Brain Res 139 31 46 PubMed CrossRef Fredriksson, A, Plaznik, A, Sundström, E, Jonsson, G, Archer, T 1990 MPTP-induced hypoactivity in mice: reversal by L-Dopa Pharmacol Toxicol 67 295 301 PubMed CrossRef Fredriksson, A, Palomo, T, Chase, TN, Archer, T 1999 Tolerance to a suprathreshold dose of L-Dopa in MPTP mice: effects of glutamate antagonists J Neural Transm 106 283 300 PubMed CrossRef Fredriksson, A, Schroder, N, Eriksson, P, Izquierdo, I, Archer, T 2001 Neonatal iron potentiates adult MPTP-induced neurodegenerative and functional deficits Parkinsonism Relat D 7 97 105 CrossRef Glowinski, J, Iversen, LL 1966 Regional studies of catecholamines in the rat brain. I. The disposition of [3H]norepinephrine, [3H]dopamine and [3H]dopa in various regions of the brain J Neurochem 13 655 669 PubMed CrossRef Heal, DJ, Butler, SA, Prow, MR, Buckett, WR 1993 Quantification of alpha 2-adrenoceptors in rat brain after short-term DSP-4 lesioning Europ J Pharmacol 249 37 41 CrossRef Heikkila, RE, Sieber, B-A, Manzino, L, Sonsalla, PK 1989 Some features of the nigrostriatal dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the mouse Mol Chem Neuropathol 10 171 183 PubMed CrossRef Jonsson, G, Hallman, H 1982 Response of central monoamine neurons following an early neurotoxic lesion Bibl Anat 23 76 92 PubMed Jonsson, G, Hallman, H, Ponzio, F, Ross, SB 1981 DSP4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) – a useful denervation tool for central and peripheral noradrenaline neurons Europ J Pharmacol 72 173 188 CrossRef Jonsson, G, Hallman, H, Sundström, E 1982 Effects of the noradrenaline neurotoxin DSP4 on the postnatal development of central noradrenaline neurons in the rat Neuroscience 7 2895 2907 PubMed CrossRef Kirk, R 1995Experimental design: procedures for the behavioural sciences Brooks/Cole Belmont, Calif Langston, JW 1985 MPTP neurotoxicity: an overview and characterization of phases of toxicity Life Sci 36 201 206 PubMed CrossRef Latigan, AJ, Marien, MR, Colpaert, FC 1992 Suppression of nigrostriatal and mesolimbic dopamine release in vivo following noradrenaline depletion by DSP-4: a microdialysis study Life Sci 50 995 999 CrossRef Marien, MR, Briley, M, Colpaert, FC 1993 Noradrenaline depletion exacerbates MPTP-induced striatal dopamine loss in mice Europ J Pharmacol 236 487 489 CrossRef Marien, MR, Colpaert, FC, Rosenquist, AC 2004 Noradrenergic mechanisms in neurodegenerative diseases: a theory Brain Res Rev 45 38 78 PubMed CrossRef Nishi, K, Kondo, T, Narabayashi, H 1991 Destruction of norepinephrine terminals in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice reduces locomotor activity induced by L-dopa Neurosci Lett 123 244 247 PubMed CrossRef Ponzio, F, Hallman, H, Jonsson, G 1981 Noradrenaline and dopamine interaction in rat brain during development Med Biol 59 161 169 PubMed Post, C, Persson, ML, Archer, T, Minor, BG, Danysz, W, Sundström, E 1987 Increased antinociception by alpha-adrenoceptor drugs after spinal cord noradrenaline depletion Europ J Pharmacol 137 107 116 CrossRef Riekkinen, M, Kejonen, K, et al. 1998 Reduction of noradrenaline impairs attention and dopamine depletion slows response in Parkinson’s disease Europ J Neurosci 10 1429 1435 CrossRef Ross, SB 1976 Long-term effects of N-2-chloroethyl-N-ethyl-2-bromobenzylamine hydrochloride on noradrenergic neurons in the rat brain and heart Brit J Pharmacol 58 521 527 Ross, SB, Renyi, L 1976 On the long-lasting inhibitory effect of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) on the active uptake of noradrenaline J Pharmacol Pharmac 28 458 459 Sonsalla, PK, Heikkila, RE 1986 The influence of dose and dosing interval on MPTP-induced dopaminergic neurotoxicity in mice Europ J Pharmacol 129 339 345 CrossRef Sundström, E, Fredriksson, A, Archer, T 1990 Chronic neurochemical and behavioural changes in MPTP-lesioned C57 Bl/6 mice: a model for Parkinson’s disease Brain Res 528 181 188 PubMed CrossRef