HYPERSENSITIVITY TO SEROTONIN AND ITS AGONISTS IN SEROTONIN-HYPERINNERVATED NEOSTRIATUM AFTER NEONATAL DOPAMINE DENERVATION

Neonatal destruction of the nigrostriatal dopamine projection by intra ventricular 6-hydroxydopamine leads to a serotonin (5-hydroxytryptamin e, 5-HT) hyperinnervation of the adult neostriatum accompanied by incr eased radioligand binding to 5-HT1B, 5-HT1nonAB and 5-HT2 receptors. T he consequences of such 5-HT receptor changes on neuronal responsivene ss to 5-HT and corresponding receptor agonists were assessed with a qu antitative iontophoretic approach. For comparative purposes, similar d ata were also obtained from rats 6-hydroxydopamine lesioned as adults, showing severe neostriatal dopamine denervation but no 5-HT hyperinne rvation. In controls, 5-HT and its receptor agonists, m-chlorophenylpi perazine (mCPP; 5-HT1B/2C agonist) and dimethoxy-iodophenyl-aminopropa ne (DOI; 5-HT2A/2C agonist), depressed the firing rate of a majority o f the units tested. Three months after neonatal 6-hydroxydopamine lesi on (5-HT-hyperinnervated tissue), inhibitory responses to all three ag ents were significantly increased and comparable results were obtained for 5-HT and DOI in the rostral versus caudal neostriatum. After 6-hy droxydopamine lesion in adults, neither responsiveness to 5-HT, mCPP o r DOI nor the density of 5-HT1B or 5-HT2A binding were significantly d ifferent from control. Thus, the up-regulation of 5-HT1B, 5-HT2A and p ossibly 5-HT2C receptors accompanying the 5-HT hyperinnervation after neonatal but not after adult dopamine denervation was associated with increased responsiveness (IT50) of neostriatal neurons to iontophorese d 5-HT and its receptor agonists. Under these conditions, neostriatal 5-HT transmission might be enhanced in spite of a basal release seemin gly comparable to normal (Jackson and Abercrombie, 1992, J. Neurochem. 58, 890). The elevated number of 5-HT2A receptors might also explain why systemic treatment with 5-HT2A receptor antagonists reverses the s pontaneous hyperactivity observed in these rats (Luthman et al., 1991, J. Psychopharmacol. 5, 418).