SEROTONIN NEURAL ADAPTATIONS TO ONTOGENIC LOSS OF DOPAMINE NEURONS INRAT-BRAIN

In rat, the neonatal destruction of nigrostriatal dopamine (DA) neuron s by intracerebral administration of 6-hydroxydopamine entails dramati c changes in serotonin (5-hydroxytryptamine, 5-HT) as well as DA funct ion, Most striking is the 5-HT hyperinnervation of the adult neostriat um, associated with increases in density of various 5-HT receptor subt ypes and enhanced neuronal responsiveness to the iontophoretic applica tion of 5-HT and its 5-HT1B/2C and 5-HT2A/2C receptor agonists, m-chlo rophenylpiperazine and iododimethoxyphenylaminopropane. The topographi cal distribution of these changes is consistent with up-regulation and /or increased production and transport of 5-HT1B and 5-HT2A receptors by the neostriatal projection neurons, as confirmed for the 5-HT2A rec eptor in a recent in situ hybridization study. it is interesting that this study has also shown that increases in both 5-HT2A binding and mR NA level were abolished by chronic pretreatment with the DA agonists, apomorphine and SKF 38393, suggesting a regulatory influence of DA in the expression of this 5-HT receptor, D-1 receptor binding is known to be slightly reduced in the rostral neostriatum of these rats, a down- regulation apparently imputable to a reduced rate of synthesis of the receptor, In contrast, D-2 receptor binding is increased throughout th e DA-denervated and 5-HT-hyperinnervated neostriatum perhaps due to so me posttranscriptional modifications, Stereotyped and motor behaviors induced by systemic treatment with D-1 and D-2 agonists are markedly e nhanced in these rats (behavioral supersensitivity), although priming is commonly required to unmask a latent D-1 supersensitivity. In the c ase of oral activity, however, overt behavioral supersensitivity is in duced by D-1 as well as D-2 agonists. Moreover, there is overt superse nsitivity of oral activity in response to the 5-HT receptor agonist m- chlorophenylpiperazine, which is presumably imputable to 5-HT2C recept ors and may be demonstrated even in the absence of supersensitivity to D-1 receptor agonist, 5-HT adaptations, therefore, seem to play a rol e not only in the abnormal spontaneous behavior, but also in the behav ioral supersensitivity to 5-HT as well as DA receptor agonists in thes e rats.