Chaouloff F, Aguerre S, Mormede P
NeuroGénétique et Stress, INSERM U471, Institut François Magendie, Bordeaux, France.
Neuropharmacology. 1998 Sep;37(9):1159-67. doi: 10.1016/s0028-3908(98)00107-5.
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.
与Wistar大鼠相比，Wistar - Kyoto（WKY）大鼠表现出较高的情绪反应（如焦虑）。血清素（5 - HT）1B/1D自身受体在5 - HT神经传递中的关键作用及其对情绪的影响，促使我们测量非选择性5 - HT1B/1D受体激动剂间三氟甲基苯基哌嗪（TFMPP）对雄性WKY和Wistar大鼠中枢色氨酸羟化酶活性的影响。除了中枢5 - HT合成存在品系依赖性差异（WKY > Wistar）外，急性给予TFMPP（1.5和3 mg/kg）可降低两种品系中海马、纹状体和皮质5 - 羟色氨酸（5 - HTP）经间羟基苄基肼诱导的积累幅度。然而，在中脑，TFMPP仅降低了WKY大鼠的5 - HTP积累（但不影响色氨酸水平），而5 - HT1A受体激动剂8 - 羟基 - 2 -（二正丙基氨基）四氢萘（8 - OH - DPAT，0.2 mg/kg）在两种品系中降低中脑5 - HTP水平的程度相似。用选择性5 - HT1B/1D受体拮抗剂N - [4 - 甲氧基 - 3 -（4 - 甲基 - 1 - 哌嗪基）苯基] - 2'-甲基 - 4' -（5 - 甲基 - 1,2,4 - 恶二唑 - ３ - 基） - 联苯 - 4 - 甲酰胺（GR 127935，1.5和3 mg/kg）预处理WKY大鼠，可轻微增加中脑色氨酸羟化酶活性，但不影响TFMPP对5 - HTP形成的负面影响。用5 - HT1A受体拮抗剂（+） - N - 叔丁基 - 3 -（4 - [2 - 甲氧基苯基]哌嗪 - 1 - 基） - 2 - 苯基丙酰胺（（+） - WAY 100135；3 mg/kg）预处理，可使8 - OH - DPAT对中脑5 - HTP水平的抑制作用降低50%，但不改变TFMPP的作用。最后，利血平（5 mg/kg）、酮色林（1 mg/kg）、米安色林（2 mg/kg）或咪唑克生（1 mg/kg）预处理均不影响TFMPP诱导的中脑5 - HTP形成抑制，排除了单胺释放、5 - HT2受体和α2 - 肾上腺素能受体的作用。我们的数据表明，常用于刺激5 - HT1B/1D受体的激动剂TFMPP可能通过非5 - 羟色胺能机制抑制中枢5 - HT合成。
