Neonatal destruction of nigrostriatal dopamine neurons by cerebroventricular injection of 6-hydroxydopamine (6-OHDA) results in a serotonin (5-HT) hyperinnervation of the rostral neostriatum in adult rat. Quantitative ligand-binding autoradiography was used to compare the density of various 5-HT receptor subtypes in the adult brain of control and neonatally 6-OHDA-lesioned rats. 5-HT1A, 5-HT1B, 5HT1nonAB and 5-HT2 sites were labeled with [3H]8-OH-DPAT, [125I]cyanopindolol, [3H]5-HT and [125I]DOI, respectively, and measured in the rostral and caudal halves of neostriatum and selected forebrain or midbrain regions. 5-HT1A binding, measured after 6 months, was unchanged in all regions examined including the dorsal raphe nucleus. Three months after the lesion, 5-HT1B binding was increased throughout the neostriatum (30%), but also in the substantia nigra (50%) and globus pallidus (30%), suggesting an up-regulation and an increased axonal transport of these receptors in neostriatal projection neurons. 5-HT1nonAB binding was also increased throughout the neostriatum (40%) and in the substantia nigra (50%), but unchanged in the globus pallidus, as if this up-regulation preferentially involved striatonigral as opposed to striatopallidal neurons. 5-HT2 binding showed an even greater increase (60%), which was restricted to the rostral half of neostriatum and also seemed imputable to an up-regulation as heteroreceptors. Even though the exact cause(s) of these receptor increases could not be determined, their anatomical distribution suggested that they were somehow related to the initial dopamine denervation in the case of the 5-HT1B and 5-HT1nonAB receptors, and more tightly linked to the 5-HT hyperinnervation in the case of the 5-HT2 receptors. Such receptor changes could participate in adaptive mechanisms implicating other transmitters and behavioral disturbances observed in this particular experimental model. Interestingly, they could also account for an enhancement of neostriatal 5-HT function even in a condition where extracellular levels of 5-HT apparently remain normal because of increased uptake.