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Nelson DL, Herbet A, Pichat L, Glowinski J. Hamon M.
“In vitro and in vivo Disposition of 3H-Methiothepin in Brain Tissues. Relationship to the Effects of Acute Treatment with Methiothepin on Central Serotoninergic Receptors”.
Arch.Pharmacol.. 1979;310(1):25-33.
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Abstract
The in-vitro and in-vivo disposition of (3H)-methiothepin (MT) in brain tissues was studied. Methods (3H)-MT, (3H)-spiroperidol (SP), 3H-haloperidol (HP) or 3H 5HT was added to tubes containing 1 ml octanol and 1 ml buffer pH 6.0-8.5 (phosphate or Tris.HCl) and shaken. This was centri fuged and the radioactivity in each layer determined. Male Sprague-Dawley rats (250-350 g) were given i.p. injections of (3H)MT and unlabeled MT was given i.p. at (20 mg/kg, Roche). Rats were killed at various times after injection and the radio activity in various brain regions determined. In-vitro, (3H)5HT (0.5-4.6 nM) was incubated with brain membranes for 7 min at 37 ¡, and radioactivity determined. Striatal membranes were in cubated with (3H) SP (0.098-0.426 nM) for 45 min or with (3H) HP (0.050-3.10 nM) for 10 min at 37¡ and following centrifugation binding was determined. Similarly (3H) MT binding was deter mined. Results MT and SP inhibited both the binding of (3H) 5HT to forebrain synaptosomal membranes, and the stimulatory effect of 5HT on adenylate cyclase activity of homogenates of colliculi from new born rats. (3H)-MT bound rapidly to various membrane prepa rations at pH 7.4, which plateaued at 3 min when 45-550f the total radioactivity was bound to lysed Pz fraction from whole fore brain. In the presence of cold MT, (3H) MT binding was inhibited 11% by 10 mcM MT, 26% and 51% by 0.1 and 1 mM MT, respectively. Na improved the efficiency of 0.1 mM MT in displacing bound ligand (26 to 36%). Promethazine (Specie), metergoline (Farmi talia), chlorpromazine and haloperidol (Rhone-Poulenc) all 0.1 mM, slightly inhibited the binding of MT to forebrain membranes. d-LSD (Sandoz), (+)-butaclamol (Ayers") dopamine (DA, Calbiochem) and 5HT (Merck), hardly altered (3H)-MT binding. MT (20 mg/kg, i.p.) 1 hr before death, significantly reduced capacity of the fore brain to bind (3H)-5HT to specific high affinity sites. MT induced as early as the 2nd day after injection, a significant increase (20 35%) in the number of specific (3H)-5HT binding sites in the fore brain particularly the hippocampus. (3H)-MT was firmly bound to membranes, hence blocking 5HT receptors for 10-12 hr after i.p. administration.
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