Hypersensitivity to serotonin and its agonists in serotonin-hyperinnervated neostriatum after neonatal dopamine denervation.
Neonatal destruction of the nigrostriatal dopamine projection by intraventricular 6-hydroxydopamine leads to a serotonin (5-hydroxytryptamine, 5-HT) hyperinnervation of the adult neostriatum accompanied by increased radioligand binding to 5-HT1B, 5-HT1nonAB and 5-HT2 receptors. The consequences of such 5-HT receptor changes on neuronal responsiveness to 5-HT and corresponding receptor agonists were assessed with a quantitative iontophoretic approach. For comparative purposes, similar data were also obtained from rats 6-hydroxydopamine lesioned as adults, showing severe neostriatal dopamine denervation but no 5-HT hyperinnervation. In controls, 5-HT and its receptor agonists, m-chlorophenylpiperazine (mCPP; 5-HT1B/2C agonist) and dimethoxy-iodophenyl-aminopropane (DOI; 5-HT2A/2C agonist), depressed the firing rate of a majority of the unit tested. Three months after neonatal 6-hydroxydopamine lesion (5-HT-hyperinnervated tissue), inhibitory responses to all three agents were significantly increased and comparable results were obtained for 5-HT and DOI in the rostral versus caudal neostriatum. After 6-hydroxydopamine lesion in adults, neither responsiveness to 5-HT, mCPP or DOI nor the density of 5-HT1B or 5-HT2A binding were significantly different from control. Thus, the up-regulation of 5-HT1B, 5-HT2A and possibly 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 iontophoresed 5-HT and its receptor agonists. Under these conditions, neostriatal 5-HT transmission might be enhanced in spite of a basal release seemingly comparable to normal (Jackson and Abercrombie, 1992, J. Neurochem. 58, 890).(ABSTRACT TRUNCATED AT 250 WORDS)
el Mansari
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M
Centre de Recherche en Sciences Neurologiques, Faculté de Médecine, Université de Montréal, Québec, Canada.
Radja
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F
Ferron
A
A
Reader
T A
TA
Molina-Holgado
E
E
Descarries
L
L
D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects; D003714:Denervation; D004298:Dopamine / Q000502:physiology*; D004594:Electrophysiology; D005260:Female; D007478:Iontophoresis; D017072:Neostriatum / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012701:Serotonin / Q000494:pharmacology / Q000502:physiology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D000662:Amphetamines; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D017366:Serotonin Receptor Agonists; D012701:Serotonin; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; D004298:Dopamine