Elevated serotonin is involved in hyperactivity but not in the paradoxical effect of amphetamine in mice neonatally lesioned with 6-hydroxydopamine

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 [H-3] 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. (C) 2004 Wiley-Liss, Inc.