Serotonin regulation of neostriatal tachykinins following neonatal 6-hydroxydopamine lesions

In order to determine whether dopamine mediates the effects of serotonin on tachykinin biosynthesis in the neostriatum, serotonin neurotransmission was altered following depletion of dopamine. Neonatal rats received intracisternal injections of saline or the dopamine neurotoxin 6-hydroxydopamine (6HD). This lesion caused significant reductions in the neostriatum of substance P-like immunoreactivity as well as levels of mRNA coding for preprotachykinin (PPT; the prohormone precursor to tachykinins substance P, neurokinin A and related peptides). Two months later, rats were treated for 5-6 days with saline or the serotonin-uptake inhibitor, zimelidine. Zimelidine treatment of unlesioned animals significantly increased PPT mRNA levels in the neostriatum. However, zimelidine treatment failed to increase PPT mRNA content in 6HD-treated animals. By contrast, neostriatal substance P-like immunoreactivity was restored by zimelidine treatment of 6HD-lesioned animals. These results suggest that an intact nigrostriatal pathway may be required for serotonin neurotransmission to alter PPT mRNA levels in the neostriatum. However, neostriatal tachykinins may be regulated by direct serotonin innervation.