High and low affinity 5-HT2 and 5-HT1C binding sites: responses to neonatal 5,7-DHT lesions in rat brain.
5-HT receptor denervation supersensitivity has been proposed to explain behavioural supersensitivity to L-5-HTP in rats with 5,7-dihydroxytryptamine (5,7-DHT) lesions. No upregulation of 5-HT2 binding sites was found despite supersensitivity to putative 5-HT2,1C drugs. To test the hypothesis that the 5-HT1C properties of these drugs are involved instead, dose-response and time-course studies of 5-HT1C and 5-HT2 receptors were performed using several different radioligands in rat brain after making neonatal 5,7-DHT lesions by intraperitoneal injection. 5-HT1C sites labelled with [3H]-mesulergine showed a distinct regional distribution: brainstem > diencephalon > cortex > hippocampus > cerebellum, constituting 65, 70, 31, 70, and 73% of total sites labelled by [3H]-mesulergine in the absence of 20 nM spiperone to block 5-HT2 sites, respectively. 5,7-DHT lesions did not significantly alter BMAX, KD, or nH of [3H]-mesulergine-labelled 5-HT1C sites in cortex or other regions but did reduce the density of cortical [3H]-paroxetine sites (-55%). Cortical 5-HT1C sites labelled by [3H]-5-HT or [3H]-mianserin, and cortical 5-HT2 sites labelled by [3H]-DOB or [3H]-ketanserin, were also unaffected. These data suggest that although denervation supersensitivity of 5-HT1C or 5-HT2 receptors may occur at the level of the receptor transducer-effector, there is no evidence it occurs at the receptor recognition site.
Pranzatelli
M R
MR
Department of Neurology, George Washington University, Washington, D.C. 20010.
Gregory
C M
CM
D015116:5,7-Dihydroxytryptamine / Q000008:administration & dosage / Q000009:adverse effects*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites; D001932:Brain Neoplasms / Q000139:chemically induced* / Q000378:metabolism* / Q000648:ultrastructure; D001933:Brain Stem / Q000737:chemistry / Q000196:embryology / Q000648:ultrastructure; D002531:Cerebellum / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D002540:Cerebral Cortex / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D004027:Diencephalon / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D004873:Ergolines; D005260:Female; D006624:Hippocampus / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D007274:Injections, Intraperitoneal; D008803:Mianserin; D011247:Pregnancy; D011869:Radioligand Assay; D051381:Rats; D011985:Receptors, Serotonin / Q000032:analysis / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D013997:Time Factors; D014316:Tritium
D004873:Ergolines; D011985:Receptors, Serotonin; D014316:Tritium; D008803:Mianserin; D015116:5,7-Dihydroxytryptamine; D012701:Serotonin; C031649:mesulergine