Postnatal iron overload destroys NA-DA functional interactions
First Online: 24 August 2006 Received: 12 November 2005 Accepted: 05 May 2006 DOI:
10.1007/s00702-006-0522-6 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 Google Scholar 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 Google Scholar 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 Google Scholar 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 Google Scholar
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