TANDOSPIRONE AND ITS METABOLITE, 1-(2-PYRIMIDINYL)-PIPERAZINE .2. EFFECTS OF ACUTE ADMINISTRATION OF 1-PP AND LONG-TERM ADMINISTRATION OF TANDOSPIRONE ON NORADRENERGIC NEUROTRANSMISSION

被引:31
|
作者
BLIER, P
CURET, O
CHAPUT, Y
DEMONTIGNY, C
机构
[1] Neurobiological Pscyhiatry Unit, Department of Psychiatry, McGill University, Montréal, Que. H3A 1A1
基金
英国医学研究理事会;
关键词
ANTIDEPRESSANTS; ANXIOLYTICS; AUTORECEPTORS; HIPPOCAMPUS; LOCUS-CERULEUS; NORADRENALINE;
D O I
10.1016/0028-3908(91)90176-C
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
1-(2-Pyrimidinyl)-piperazine (1-PP) is a common metabolite of the antidepressant/anxiolytic 5-HT1A agonists, tandospirone (SM-3997), gepirone, buspirone and ipsapirone. The present electrophysiological studies were undertaken to characterize in vivo the effect of 1-PP on noradrenergic (NE) neurotransmission in rat brain. At small doses, 1-PP (ED50 = 80-mu-g/kg, i.v.) reversed the depressant effect of the alpha-2-adrenoceptor agonist, clonidine (20-mu-g/kg, i.v.) on the firing activity of NE neurones of the locus coeruleus. After long-term treatment with tandospirone (10 mg/kg/day, s.c. x 14 days), the responsiveness of these NE neurones to intravenous administration of clonidine was decreased but their mean firing frequency remained within the control range. The effect of 1-PP on the postsynaptic alpha-2-adrenoceptor of pyramidal neurones in the hippocampus was investigated: intravenous administration of 1-PP (2-8 mg/kg, i.v.) reduced the effect of microiontophoretically-applied NE on CA3 pyramidal neurones of the dorsal hippocampus, without affecting their responsiveness to GABA and 5-HT. The effect of the electrical stimulation of NE neurones of the locus coeruleus in reducing firing activity of pyramidal neurones, which is mediated by postsynaptic alpha-1-adrenoceptors, was increased by 47% after acute administration of 1-PP (4 mg/kg, i.v.), presumably as a result of blockade of terminal alpha-2-autoreceptors. The effectiveness of these stimulations remained unchanged after long-term treatment with tandospirone. Furthermore, the decrease in the effectiveness of stimulation of the locus coeruleus, obtained by increasing the frequency from 1 to 5 Hz, a phenomenon due to an increased activation of terminal alpha-2-adrenergic autoreceptors by endogenous NE, remained unaltered after long-term treatment with tandospirone. In addition to the initial depressant effect, stimulation of the locus coeruleus induces a late activation of these neurones which is mediated by a beta-adrenoceptor. The degree of activation induced by stimulation of the locus coeruleus was similar in controls and in long-term tandospirone-treated rats. It is concluded that 1-PP acts as an antagonist at somatodendritic and terminal alpha-2-adrenergic autoreceptors, as well as at postsynaptic alpha-2-adrenoceptors, in the central nervous system of the rat. However, the levels of 1-PP attained after long-term administration of tandospirone were not sufficient to modify NE neurotransmission.
引用
收藏
页码:691 / 701
页数:11
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