Chaput Y, de Montigny C
Department of Psychiatry, McGill University, Montréal, Québec, Canada.
J Pharmacol Exp Ther. 1988 Jul;246(1):359-70.
In the present electrophysiological studies, the effects of the putative 5-hydroxytryptamine (5-HT) receptor antagonist, BMY 7378, on the response of dorsal raphe nucleus 5-HT neurons and of CA3 dorsal hippocampus pyramidal neurons to 5-HT and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) were investigated in chloral hydrate-anesthetized rats. The effectiveness of microiontophoretically applied 5-HT and 8-OH-DPAT in suppressing the firing activity of both neuronal populations was assessed before and during the microiontophoretic application of BMY 7378. BMY 7378 reduced the effectiveness of 8-OH-DPAT, but not that of 5-HT, in depressing 5-HT neuron firing rate, whereas that of both agonists was reduced by concurrent application of BMY 7378 in the hippocampus. To assess whether endogenous 5-HT also could be antagonized, the response of pyramidal neurons to electrical activation of the 5-HT pathway was determined before and after i.v. BMY 7378. Low doses enhanced the efficacy of the stimulation, whereas higher doses decreased it. The latter finding suggests that BMY 7378 antagonizes the effect of endogenous 5-HT. Three procedures were used to investigate the enhancing effect of BMY 7378 on 5-HT synaptic transmission: 1) administration of BMY 7378 after terminal 5-HT autoreceptor blockade by methiothepin: methiothepin abolished the enhancing effect of BMY 7378; 2) blockade of the effect of RU 24969, a terminal 5-HT autoreceptor agonist: pretreatment with methiothepin, but not with BMY 7378, blocked the effect of RU 24969 on 5-HT synaptic transmission; and 3) administration of BMY 7378 during a reduced level of activation of terminal 5-HT autoreceptors, obtained by lowering the stimulation frequency from 1 to 0.5 Hz: the enhancing effect of BMY 7378 was reduced when the stimulation was delivered at 0.5 Hz. It is concluded that BMY 7378 is an effective antagonist of 5-HT1A receptors in vivo and that the mechanism of its enhancing effect on 5-HT transmission at low doses, although still undetermined, is not due to a competitive interaction at the terminal 5-HT autoreceptor.
在目前的电生理研究中，在水合氯醛麻醉的大鼠中，研究了假定的5-羟色胺（5-HT）受体拮抗剂BMY 7378对中缝背核5-HT神经元和CA3背侧海马锥体神经元对5-HT和8-羟基-2-（二正丙基氨基）四氢萘（8-OH-DPAT）反应的影响。在微电泳施加BMY 7378之前和期间，评估了微电泳施加的5-HT和8-OH-DPAT抑制这两种神经元群体放电活动的有效性。BMY 7378降低了8-OH-DPAT抑制5-HT神经元放电率的有效性，但未降低5-HT的有效性，而在海马中同时施加BMY 7378时，两种激动剂的有效性均降低。为了评估内源性5-HT是否也能被拮抗，在静脉注射BMY 7378之前和之后，测定了锥体神经元对5-HT通路电激活的反应。低剂量增强了刺激的效果，而高剂量则降低了刺激效果。后一发现表明BMY 7378拮抗内源性5-HT的作用。采用三种方法研究BMY 7378对5-HT突触传递的增强作用：1）在甲硫噻平阻断终末5-HT自身受体后给予BMY 7378：甲硫噻平消除了BMY 7378的增强作用；2）阻断终末5-HT自身受体激动剂RU 24969的作用：用甲硫噻平预处理可阻断RU 24969对5-HT突触传递的作用，而用BMY 7378预处理则不能；3）在通过将刺激频率从1Hz降低到0.5Hz获得的终末5-HT自身受体激活水平降低期间给予BMY 7378：当以0.5Hz进行刺激时，BMY 7378的增强作用降低。得出的结论是，BMY 7378在体内是一种有效的5-HT1A受体拮抗剂，其低剂量时对5-HT传递增强作用的机制虽然仍未确定，但不是由于在终末5-HT自身受体处的竞争性相互作用。
