抗抑郁剂对大白鼠脑内激活剂刺激的5- HT 1A 与[ 35 S] GTP结合的影响

( M illhauser Laboratories, Department of Psychiat ry, N ew Y ork U niversit y M edical Cent er, N ew York, N Y 10016)
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Abstract: Electrophysiological studies hav e led to the pr oposal that the neurobiological mechanism( s) under ly ing drug therapy of anx iety and depr ession involve ( s) regionally - specific adaptations in 5 - hydro x ytr yptamine1A ( 5- HT 1A ) recepto r sensitivity . Fur thermore, the net effect of clinically - relev ant repeated tr eatment wit h anx iolyt ic/ antidepressant dr ugs, regardless of chemical class, appears to reflect an enhance ment of 5- HT neurotransmission in fo rebrain targets, most notably in t he hippocampus. Depending on the drug utilized, a decrease in sensitivity of inhibitor y somatodendritic autoreceptors, an increase in sensitiv ity of postsynaptic recepto rs, or both alter atio ns, occurs after 2- 3 w eeks of treatment . T his hypot hesis w as tested using N , N - dipropy l- 5- carbox amidotry ptamine ( N, N- DP - 5- CT ) - stimulated guanosine- 5 - O ( 3- thio) triphosphate ( [ 35 S] GT P S) binding assessed by autoradiography. R ats w er e treated for 21 days w ith saline or drug ( in mg / kg ) once ( fluox etine, 10; imipramine, 10; clorgy line, 1) or twice daily ( ip sapirone, 20) and three brain regions r ich in 5- HT 1A receptors were ex amined: the dorsal raphe ( somatoden dritic) , the dorsal hippocampus ( postsynaptic) , and the later al septum ( postsy naptic) . Only imipr amine ( + 17% ) and fluoxetine ( + 54% ) significantly increased ago nist- stimulated binding in the dorsal hippocampus; all drugs except imipr amine significantly decreased binding in the dorsal raphe ( - 19 to - 41% ) . A lthough t hese r esults g enerally support the concept of a net enhancement of hippocampal 5- HT neurotransmission, t he pattern of changes in receptor sensitiv ity differed somew hat from the results of electro physiolog ical studies. T he most consistent effect, however, was a sig nificant decrease in stimulated [ 35S] G T P S binding in the lat eral septum after all four treatments ( - 14 to - 23% ) , a finding previously reported also after chronic bus pirone treatment, sugg est ing t his may be a her etofore unreco gnized common outcome of antidepr essant tr eat ment deserv ing further study. Key words: antidepr essants; 5- HT 1A; [ S] GT P S; dorsal raphe; dorsal hippocampus; lateral septum CLC number: Q 426 Document code: A
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摘要 : 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 5HT 1A 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] GT P S) 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 21d, 每天处理 1 次 ( mg/ kg : fluox etine, 10; imipramine, 10; clorg yline, 1) 或 每天处理 2 次 ( ipsapirone, 20mg/ kg ) 。检测了 3 个富含 5- HT 1A 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 imipr amine( + 17% ) 和 fluoxetine( + 54% ) 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 ( - 19 到 - 41%) 。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 ( L S) 降 低 [ 35 S] G T P S 结 合( - 14 到 - 23% ) , 前人在慢性的丁 螺旋酮 处理后也 有报道 , 这 也许是 抗忧郁剂 治疗至 今 尚无被普遍认可的 结果 , 建议对此进一步研究。 关键词 : 抗抑郁剂 ; 5- HT 1A; [ 35S] GT P S; 背中缝核 ; 背侧海 马 ; 外侧隔区 中图分类号 : Q 426 文献标识码 : A
Abbreviations: 5- H T , 5- hydroxyt rypt am ine hydrochloride ( serotonin) ; N, N - DP - 5- CT , N , N - dipropyl - 5 - carboxamidotrypt amine maleat e; 8 - OH - DPAT , 8 - hy drox y - dipropy lam inotet ralin hydrobromide; WAY100, 635, N - [ 2- [ 4- ( 2- met hox yphenyl ) - 1- piperazinyl ] et hyl] - N - 2 - py ridinyl - cyclohex anecarboxamide m aleate; DPCPX, 8 - cyclopent yl - 1, 3 dipropylxanthine; GDP, guanosine diphosphate; GT P S, guanosine - 5 - O - ( 3 - t hio ) t riphos phate; SSRI, select ive serotonin reupt ake inhibitor; MAO, monoam ine ox idase; T CA, t ricy clic an t idepressant ; T wo opposing t heories have been advanced regarding alt erations in 5- HT neurot ransm ission oc curring on t reatment w it h anxioly tics/ ant idepressant s. Due t o 5 - HT 1A agonist s ( buspirone, g epirone, ipsapirone) display anx iolytic/ antidepressive act ivit y in various animal models ( review ed in De Vry et al. , 1991) and humans ( Cott et al. , 1988; Robinson, 1991) , inhibit 5- H T neuronal fir ing ( Sprouse and Aghajanian, 1988) , and decrease t ransmit t er synt hesis ( M eller et al. , 1990) and re lease ( H jorth and Sharp, 1991) in forebrain areas, one hypot hesis suggested t hat a decrease in 5- HT transmission underlies t heir t herapeut ic effect s ( De Vry et al. , 1991; Sommermeyer et al. , 1993) . How ever, it is well know n t hat several weeks of treat ment wit h anxiolyt ics/ ant idepressant s are re quired before the t herapeut ic ef fects become apparent . T hus, t he acute r educt ion in 5- HT neuro t ransmission elicit ed by t hese agents is unlikely to be relat ed to their t herapeut ic ef fects. T he opposite hypot hesis, championed principally by De Montigny and colleagues ( Blier and De M ont igny, 1994; Haddjeri et al. , 1998) , proposes that an enhancement of 5- HT neurot ransmission in f orebrai n tar gets underlies t herapeut ic ef fects, and that t his occurs only aft er r ep eat ed anxiolyt ic/ ant idepressant treatm ent. Ut ilizing elect rophysiolog ical approaches, t hese invest igat ors show ed that repeated treat ment w ith 5- H T 1A agonists ( Blier and De Montigny , 1990; Blier and De Montigny, 1994; Dong et al. , 1997) , select ive serot onin reupt ake inhibit ors ( SSRIs; e. g. , fluoxetine) ( Chaput et al. , 1986; De M ont igny et al. , 1990; Blier and De Mont igny, 1994) or monoamine ox idase inhibitors ( M AOIs;