title: GR 127935 and (+)-WAY 100135 do not affect TFMPP-induced inhibition of 5-HT synthesis in the midbrain and hippocampus of Wistar-Kyoto rats.
abstract: Wistar-Kyoto (WKY) rats display high emotivity (e.g. anxiety), compared to Wistar rats. The key role of serotonin (5-HT)1B/1D autoreceptors in 5-HT neurotransmission, and its consequences on emotivity, led us to measure the effects of the nonselective 5-HT1B/1D) receptor agonist m-trifluoromethyl-phenylpiperazine (TFMPP) on central tryptophan hydroxylase activity in male WKY and Wistar rats. In addition to strain-dependent differences in central 5-HT synthesis (WKY > Wistar), acute administration of TFMPP (1.5 and 3 mg/kg) decreased the amplitude of m-hydroxy-benzylhydrazine-elicited accumulation of hippocampal, striatal and cortical 5-hydroxytryptophan (5-HTP) in both strains. In midbrain, however, TFMPP decreased 5-HTP accumulation (but not tryptophan levels) in WKY rats only, whereas the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.2 mg/kg) decreased midbrain 5-HTP levels to a similar extent in both strains. Pretreatment of WKY rats with the selective 5-HT1B/1D receptor antagonist N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1, 2,4-oxadiozol-3-yl)-biphenyl-4-carboxamide (GR 127935, 1.5 and 3 mg/kg) slightly increased midbrain tryptophan hydroxylase activity but did not affect the negative effect of TFMPP on 5-HTP formation. Pretreatment with the 5-HT1A receptor antagonist (+)-N-tert-butyl-3-(4-[2-methoxyphenyl]piperazin-1-yl)-2-phenylpro panamide ((+)-WAY 100135; 3 mg/kg), which decreased the inhibitory effect of 8-OH-DPAT on midbrain 5-HTP levels by 50%, did not alter that of TFMPP. Lastly, neither reserpine (5 mg/kg), ketanserin (1 mg/kg) mianserin (2 mg/kg) nor idazoxan (1 mg/kg) pretreatments affected TFMPP-induced inhibition of midbrain 5-HTP formation, ruling out a role for monoamine release, 5-HT2 receptors and alpha2-adrenoceptors. Our data show that TFMPP, an agonist often used to stimulate 5-HT1B/1D receptors, may inhibit central 5-HT synthesis through nonserotonergic mechanisms.
authors.affiliation: NeuroGénétique et Stress, INSERM U471, Institut François Magendie, Bordeaux, France. francis.chaouloff@bordeaux.inserm.fr
authors.forename: F
authors.initials: F
authors.lastname: Chaouloff
authors.forename: S
authors.initials: S
authors.lastname: Aguerre
authors.forename: P
authors.initials: P
authors.lastname: Mormede
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D019329:Idazoxan / Q000494:pharmacology; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D008636:Mesencephalon / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008803:Mianserin / Q000494:pharmacology; D009411:Nerve Endings / Q000187:drug effects / Q000201:enzymology; D010069:Oxadiazoles / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D017208:Rats, Wistar; D012110:Reserpine / Q000494:pharmacology; D012701:Serotonin / Q000096:biosynthesis*; D018490:Serotonin Agents / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013045:Species Specificity; D014365:Tryptophan Hydroxylase / Q000187:drug effects / Q000378:metabolism
chemical_list: D018759:Adrenergic Uptake Inhibitors; D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D010069:Oxadiazoles; D010879:Piperazines; D018490:Serotonin Agents; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C081293:WAY 100135; D008803:Mianserin; C018406:1-(3-trifluoromethylphenyl)piperazine; C090701:GR 127935; D012701:Serotonin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D012110:Reserpine; D007650:Ketanserin; D014365:Tryptophan Hydroxylase; D019329:Idazoxan