N-methyl-norsalsolinol modulates serotonin metabolism in the rat caudate nucleus: correlation with behavioural changes.
In earlier studies the dihydroxylated tetrahydroisoquinoline derivative 2(N)-methyl-norsalsolinol (NMNorsal) was identified in patients with Parkinson's disease. In the present study, NMNorsal (20 or 40 mg/kg) was given intraperitoneally to rats kept under normal light-dark cycles. Using brain microdialysis technique, serotonin (5-HT), 5-hydroxyindolacetic acid (HIAA), dopamine (DA), and 3,4-dihydroxyphenylacetic acid (DOPAC) were determined in the dialysate from caudate nucleus in vivo and from tissue in vitro at various times following NMNorsal administration. Even after high-dose NMNorsal administration (40 mg/kg) and measurements up to 48 h after administration, levels of DA and its metabolite DOPAC were not modified. In contrast to the DA metabolism, 5-HT levels in the dialysate increased to approx. 2-fold during the 48 h following administration of a single high-dose of NMNorsal while HIAA decreased to approx. 50%. These changes of 5-HT and HIAA were nearly identical in the homogenate preparation of the caudate nucleus when compared to the amounts present in the dialysate. During assessment controls and low-dose-treated animals were almost always sleeping. Only high-dose NMNorsal-treated rats were active, with maximum activity after 48 h, however, behavioural activity was clearly different to the classical 5-HT behavioural syndrome. Taken together, increased 5-HT levels in the striatum found in our studies seem to be linked to the behavioural activity induced by high-dose NMNorsal, and NMNorsal appeared to perturb normal diurnal rhythms of spontaneous locomotor activity. The precise mechanism by which NMNorsal acts on 5-HT metabolism and behaviour is, however, unclear and further investigation is required.
Thümen
Ansgar
A
Neurochemical Research Group, Department of Neurology, Medical University of Lübeck, Ratzeburger Allee 160, D-23538 Lübeck, Germany.
Behnecke
Anne
A
Qadri
Fatimunnisa
F
Moser
Andreas
A
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002421:Caudate Nucleus / Q000187:drug effects* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D017551:Microdialysis / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D012490:Salsoline Alkaloids / Q000494:pharmacology*; D012701:Serotonin / Q000378:metabolism*; D013997:Time Factors
D012490:Salsoline Alkaloids; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; C020784:norsalsolinol