title: Elevated serotonin is involved in hyperactivity but not in the paradoxical effect of amphetamine in mice neonatally lesioned with 6-hydroxydopamine.
abstract: The neonatal lesion with 6-hydroxydopamine (6-OHDA) in rodents induces juvenile hyperactivity and paradoxical hypolocomotor response to psychostimulants, in striking contrast to what is observed when similar lesions are carried out in adults. The early disruption of central dopaminergic pathways is followed by increased striatal serotonin (5-HT) contents although the functional role of this neurodevelopmental adaptation remains unclear. The aim of the present study is to investigate the participation of this neurochemical imbalance in the main behavioral phenotypes of this model. To this end, mice received a neonatal administration of 6-OHDA that induced an 80% striatal dopamine depletion together with 70% increase in 5-HT. Serotoninergic hyperinnervation was evidenced further by increased [(3)H] citalopram autoradiographic binding and 5-HT transporter immunohistochemistry in striatal sections. To investigate whether elevated 5-HT was implicated in hyperactivity, we treated control and 6-OHDA neonatally lesioned mice with the selective irreversible tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA) to induce 5-HT depletion. Normalization of striatal 5-HT in 6-OHDA neonatally lesioned mice to control levels reversed hyperactivity to normal locomotor scores, whereas the same extent of 5-HT depletion did not affect spontaneous locomotor activity of control mice. In turn, the paradoxical response to amphetamine in neonatal DA-depleted mice was not prevented by PCPA treatment. Taken together, our results suggest that the increased striatal 5-HT that follows neonatal DA depletion is involved in hyperlocomotor behavior but not in the paradoxical calming response to amphetamine observed in this mouse model.
authors.affiliation: Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (CONICET) and Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina.
authors.forename: María Elena
authors.initials: ME
authors.lastname: Avale
authors.forename: Sergio Iván
authors.initials: SI
authors.lastname: Nemirovsky
authors.forename: Rita
authors.initials: R
authors.lastname: Raisman-Vozari
authors.forename: Marcelo
authors.initials: M
authors.lastname: Rubinstein
mesh_terms: D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000502:physiology*; D050483:Dopamine Plasma Membrane Transport Proteins; D010134:Fenclonine / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016627:Oxidopamine / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism / Q000502:physiology*; D050486:Serotonin Plasma Membrane Transport Proteins; D014365:Tryptophan Hydroxylase / Q000037:antagonists & inhibitors
chemical_list: D002352:Carrier Proteins; D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D012701:Serotonin; D016627:Oxidopamine; D000661:Amphetamine; D014365:Tryptophan Hydroxylase; D010134:Fenclonine; D004298:Dopamine