抗抑郁剂对大白鼠脑内激活剂刺激的5-HT_(1A)与[^(35)S]GTPγS结合的影响(英文)

Repeated Treatment with Antidepressants Differentially Alters 5-HT_(1A) Agonist-Stimulated [^(35)S] GTPγS Binding in Rat Brain Regions

电生理研究证明 ,焦虑与忧郁剂治疗的神经生物学机制取决于影响特异性的解剖区域对 5 -HT1A受体敏感的适应性。此外 ,临床上用相应的抗焦虑 /抗忧郁药剂重复处理 ,在前脑的作用表现为增进 5 -HT的神经传导 ,尤以海马最显著。药物处理 2～ 3周后 ,可减少抑制性体树突自动受体的敏感性 ,增加突触后的受体敏感性 ,或两者兼备。使用对氮 ,氮 -二丙基 -5 -氨基色胺刺激的鸟苷 -5 '-氧-( 3-硫代 )三磷酸盐 ( [35S]GTPγS)结合体进行放射自显影照相的方法评估 ,测定了该假设。将大白鼠用生理盐水或药剂处理 2 1d ,每天处理 1次 (mg/kg :fluoxetine ,1 0 ;imipramine ,1 0 ;clorgyline ,1 )或每天处理 2次 (ipsapirone,2 0mg/kg)。检测了 3个富含 5 -HT1A受体的脑区 :背中缝核 (DR ;体树突 ) ,背侧海马 (DH)和外侧隔区 (LS) (突触后 )。只有imipramine( +1 7% )和fluoxetine( +5 4 % )显著地增加了背侧海马上激活剂结合在背侧海马。除了imipramine ,所有药剂均减少在背侧中缝核的结合 ( -1 9到-4 1 % )。尽管总的说来结果支持增进海马 5 -HT的神经传导的概念 ,但受体敏感性变化的模式与电生理的研究结果仍稍有不同。然而 ,最一致和最显著的结果是四种药剂处理均在外侧隔区 (LS)降低 [35S]GTPγS结合 ( -1 4到

Electrophysiological studies have led to the proposal that the neurobiological mechanism(s) underlying drug therapy of anxiety and depression involve(s) regionally-specific adaptations in 5-hydroxytryptamine 1A (5-HT 1A ) receptor sensitivity. Furthermore, the net effect of clinically-relevant repeated treatment with anxiolytic/antidepressant drugs, regardless of chemical class, appears to reflect an enhancement of 5-HT neurotransmission in forebrain targets, most notably in the hippocampus. Depending on the drug utilized, a decrease in sensitivity of inhibitory somatodendritic autoreceptors, an increase in sensitivity of postsynaptic receptors, or both alterations, occurs after 2-3 weeks of treatment. This hypothesis was tested using N,N-dipropyl-5-carboxamidotryptamine (N,N-DP-5-CT)-stimulated guanosine-5'-O-(3-thio)triphosphate (GTPγS) binding assessed by autoradiography. Rats were treated for 21 days with saline or drug (in mg/kg) once (fluoxetine, 10; imipramine, 10; clorgyline, 1) or twice daily (ipsapirone, 20) and three brain regions rich in 5-HT 1A receptors were examined: the dorsal raphe (somatodendritic), the dorsal hippocampus (postsynaptic), and the lateral septum (postsynaptic). Only imipramine (+17%) and fluoxetine (+54%) significantly increased agonist-stimulated binding in the dorsal hippocampus; all drugs except imipramine significantly decreased binding in the dorsal raphe (-19 to -41%). Although these results generally support the concept of a net enhancement of hippocampal 5-HT neurotransmission, the pattern of changes in receptor sensitivity differed somewhat from the results of electrophysiological studies. The most consistent effect, however, was a significant decrease in stimulated GTPγS binding in the lateral septum after all four treatments (-14 to -23%), a finding previously reported also after chronic buspirone treatment, suggesting this may be a heretofore unrecognized common outcome of antidepressant treatment deserving further study.