CAJ | 학술논문

为确定左旋千金藤啶碱(SPD)对中脑边缘DA神经系统的作用特性, 本研究采用细胞外记录的电生理学方法, 观察微电泳和尾静脉给药对6-OHDA损毁及未损毁大鼠的伏核(NAc)单位放电的影响.结果显示: SPD累积给药(0.02～2 mg/kg, iv)可诱发NAc神经元双相放电特征, 即小剂量抑制、大剂量兴奋.预先给予D2受体拮抗剂spiperone, SPD则仅产生兴奋效应, 并被D1拮抗剂SCH-23390所翻转或阻断, 提示SPD对NAc神经元放电有D1激动特性.另一方面, 大剂量SPD完全翻转D2激动剂LY-171555和D1/D2混合型激动剂阿朴吗啡对NAc神经元的抑制作用, 表明SPD还具有D2受体的阻滞特性.与静脉给药不同, NAc内微电泳SPD (30 mmol/L, 20～80 nA)很难诱发该神经核的兴奋或抑制性放电, 而微电泳D1激动剂SKF-38393能产生明显的放电抑制效应.然而, 在6-OHDA损毁大鼠, 微电泳SPD可使绝大多数NAc神经元(91%)放电抑制, 并为D1阻滞剂SCH-23390所完全拮抗, 而不受D2阻滞剂spiperone的影响.以上结果表明, SPD对NAc神经元活动具有‘D2阻滞-D1激动'的双重药理作用特性, 后者与SPD作用于mPFC的D1受体有密切关系, 这有利于治疗精神分裂症.
위학정좌선천금등정감(SPD)대중뇌변연DA신경계통적작용특성, 본연구채용세포외기록적전생이학방법, 관찰미전영화미정맥급약대6-OHDA손훼급미손훼대서적복핵(NAc)단위방전적영향.결과현시: SPD루적급약(0.02～2 mg/kg, iv)가유발NAc신경원쌍상방전특정, 즉소제량억제、대제량흥강.예선급여D2수체길항제spiperone, SPD칙부산생흥강효응, 병피D1길항제SCH-23390소번전혹조단, 제시SPD대NAc신경원방전유D1격동특성.령일방면, 대제량SPD완전번전D2격동제LY-171555화D1/D2혼합형격동제아박마배대NAc신경원적억제작용, 표명SPD환구유D2수체적조체특성.여정맥급약불동, NAc내미전영SPD (30 mmol/L, 20～80 nA)흔난유발해신경핵적흥강혹억제성방전, 이미전영D1격동제SKF-38393능산생명현적방전억제효응.연이, 재6-OHDA손훼대서, 미전영SPD가사절대다수NAc신경원(91%)방전억제, 병위D1조체제SCH-23390소완전길항, 이불수D2조체제spiperone적영향.이상결과표명, SPD대NAc신경원활동구유‘D2조체-D1격동'적쌍중약리작용특성, 후자여SPD작용우mPFC적D1수체유밀절관계, 저유리우치료정신분렬증.
Our previous work has demonstrated that (-)-stepholidine (SPD) has dual action, ie D1 agonistic-D2 antagonistic action on DA receptors in the nigra-striatal dopamine (DA) system. The present study attempted to ascertain its dual action on the mesolimbic DA system. The firing activities of the nucleus accumbens (NAc) neurons were extracellularly recorded with intravenous and iontophoretic administration of the drug in 6-hydroxydopamine (6-OHDA)-lesioned and intact rats. The results showed that SPD produced a consistently biphasic firing of NAc neurons during the cumulative doses of 0.02～2 mg/kg, iv. When the rats were pretreated with D2 antagonist spiperone, SPD only exerted an increasing effect, which was subsequently reversed by the D1 antagonist SCH-23390. Moreover, SCH-23390 could prevent the rate of increase elicited by SPD at high doses, presumably due to the D1 agonistic action of SPD on the activity of NAc neuron. On the other hand, the inhibition of NAc firing elicited by either D2 agonist LY171555 or D1/D2 agonists apomorphine was completely reversed by SPD, suggesting an antagonistic action of SPD to D2 receptors. In 6-OHDA-lesioned rats, iontophoresis of SPD also had an inhibitory effect in the majority of NAc neurons (91%) as SKF-38393 did. This inhibition could be completely blocked by the ejection of SCH-23390, but not by spiperone. These results indicate that SPD also has a D1 agonistic-D2 antagonistic dual action on NAc neuron activity, which may be beneficial to the treatment of schizophrenia.