MODULATION OF 5-HT RELEASE IN THE GUINEA-PIG BRAIN FOLLOWING LONG-TERM ADMINISTRATION OF ANTIDEPRESSANT DRUGS
MODULATION OF 5-HT RELEASE IN THE GUINEA-PIG BRAIN FOLLOWING LONG-TERM ADMINISTRATION OF ANTIDEPRESSANT DRUGS
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DOI：
10.1111/j.1476-5381.1994.tb17015.x
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发表时间：
1994-10-01
影响因子：
7.3
通讯作者：
BOUCHARD, C
中科院分区：
文献类型：
--
作者：
BLIER, P;BOUCHARD, C
1本研究的目的是确定长期阻断5-羟色胺(5-HT)再摄取和抑制A型单胺氧化酶(MAO-A)是否导致预先加载[H-3]-5-HT的豚鼠脑片电诱发的氚释放增加，并评估5-HTID末端自身受体的敏感性，α(2)-肾上腺素能受体也位于5-HT末端，2.5-羟色胺再摄取阻滞剂帕罗西汀和可逆MAO-A抑制剂贝氟沙酮治疗21天后，在去除用于递送药物的渗透压小泵后48小时，下丘脑、海马区和额叶皮质预加载脑片的5-HT3受体对氚释放的抑制作用显著增强。3 5-羟色胺自身受体激动剂5-甲氧基色胺对氚诱导释放的抑制作用在帕罗西汀治疗后，下丘脑、海马片和额叶皮质的氚释放没有减弱。在贝氟沙酮组，5-甲氧基色胺的有效性在相同的脑结构中没有改变。4用UK 14.304评估，5-羟色胺终末上的α(2)-肾上腺素受体的敏感性在下丘脑、海马区被减弱，但从贝氟沙酮治疗的豚鼠制备的额叶皮质脑片中预加[H-3]-5-羟色胺并没有减弱。帕罗西汀治疗没有改变这种α(2)肾上腺素受体在下丘脑的敏感性。5同样用UK 14.304评估的去甲肾上腺素终末的α(2)肾上腺素受体的敏感性，在长期使用贝氟沙酮治疗后，在海马区和下丘脑片中没有改变，预先加载了[H-3]-去甲肾上腺素的脑片。6在额叶皮质脑片中，用帕罗西汀治疗21天后，[H-3]-5-羟色胺摄取不再显著减弱，但在下丘脑片中仍明显受到抑制。帕罗西汀对灌流液中[H-3]-5-羟色胺诱发性释放的促进作用在帕罗西汀组额叶脑片中不再明显。这些数据表明，长期的5-羟色胺再摄取阻断使额叶皮质的5-羟色胺转运体失去敏感性。7在贝氟沙酮治疗的豚鼠下丘脑、海马区和额叶皮质脑片中，5-HT3受体激动剂2-甲基-5-羟色胺增强氚电诱发释放的能力没有改变，但在帕罗西汀治疗21天后显著减弱。帕罗西汀治疗2天后，2-甲基-5-羟色胺对大脑皮层脑片氚释放的促进作用没有改变。
1 The aims of the present study were to determine whether long-term 5-hydroxytryptamine (5-HT) reuptake blockade and inhibition of type-A monoamine oxidase (MAO-A) lead to an enhancement of the electrically evoked release of tritium from guinea-pig brain slices preloaded with [H-3]-5-HT, and to assess the sensitivity of the terminal 5-HTID autoreceptor, the alpha(2)-adrenoceptor also located on 5-HT terminals, and the 5-HT3 receptor that modulates 5-HT release following these two types of antidepressant treatments.2 The electrically evoked release of tritium was significantly enhanced following a 21-day treatment with the 5-HT reuptake blocker, paroxetine and the reversible MAO-A inhibitor, befloxatone, in preloaded slices of the hypothalamus, hippocampus and frontal cortex 48 h after removal of the osmotic minipumps used to deliver the drugs.3 The inhibitory effect of the terminal 5-HT autoreceptor agonist, 5-methoxytryptamine, on the evoked release of tritium was attenuated in slices of the hypothalamus, hippocampus, but not frontal cortex, following the paroxetine treatment. In the befloxatone group, the effectiveness of 5-methoxytryptamine was unaltered in the same brain structures.4 The sensitivity of the alpha(2)-adrenoceptor on 5-HT terminals, assessed using UK 14.304, was attenuated in hypothalamus, hippocampus, but not frontal cortex slices prepared from befloxatone-treated guinea-pigs and preloaded with [H-3]-5-HT. The paroxetine treatment did not alter the sensitivity of this alpha(2)-adrenoceptor in the hypothalamus.5 The sensitivity of the alpha(2)-adrenoceptor on noradrenaline terminals, also assessed using UK 14.304, was not altered in hippocampus and hypothalamus slices preloaded with [H-3]-noradrenaline following the long-term befloxatone treatment.6 In frontal cortex slices, [H-3]-5-HT uptake was no longer significantly attenuated after a 21-day treatment with paroxetine, whereas it was still markedly inhibited in hypothalamus slices. The enhancing effect of paroxetine on the evoked release of [H-3]-5-HT in the superfusion medium was no longer evident in frontal cortex slices of the paroxetine group. These data indicate that long-term 5-HT reuptake blockade desensitized the 5-HT transporter in the frontal cortex.7 The capacity of the 5-HT3 receptor agonist, 2-methyl-5-HT, to enhance the electrically evoked release of tritium was not altered in hypothalamus, hippocampus, and frontal cortex slices prepared from befloxatone-treated guinea-pigs, but was significantly attenuated in the paroxetine group also treated for 21 days. Following a 2-day paroxetine treatment, the enhancing effect of 2-methyl-5-HT on tritium release was unaltered in frontal cortex slices.