Aim To investigate the inhibitory effects of urocortin2 (UCN2) on ventral tegmental area (VTA) nervous activity of morphine addiction rats and the mechanism. Methods Morphine addiction rats and the microiontophoresis method were used to observe the effects of UCN2 on VTA neuron′s spontaneous dis-charge changing rule, as well as the inhibitory effects of UCN2 on DA neuron′s cluster spontaneous dis-charge, to identify UCN2 and DA on the same VTA neuron. Morever, the inhibitor of corticotropin-regula-ting factor′s receptor ( CRF-2 R ) and the blocker of protein kinase A ( PKA ) , AST-2 B and H89 , were used to investigate the effects of UCN2 on VTA neuron′s of morphine addiction rats. Results UCN2 could inhibit the firing rate 82% (31/38) of the tested VTA neuron ( P<0. 01 ) , the discharge frequency changed from (20. 89 ± 2. 86) Hz to (13. 66 ± 3. 93) Hz (P<0. 01). Further, the inhibitor of PKA, AST-2B and H89 could ablolish the inhibitory effects of UCN2 . Morever, the excitatory firing of VTA neurons was at-tenuated by addition of UCN2 , while AST application could inhibit the UCN2′s inhibitory effects. Conclu-sion UCN2 could regulate the effects of VTA via PKA pathway and may thereby contribute to the improvement of drug addiction.%目的：明确神经肽urocortin2(UCN2)在吗啡成瘾中抑制丘脑腹侧背盖区( ventral tegmental area,VTA)神经活动的机制。方法建立吗啡成瘾大鼠模型,采用七管微电泳方法,电泳UCN2对吗啡成瘾大鼠VTA神经元自发放电的改变,及UCN2对多巴胺( dopamine, DA)能神经元簇发放电模式的影响,明确UCN2在VTA神经元中与DA存在汇聚作用。另外,给予促皮质激素释放因子( coticortropin-releasing factor, CRF)受体阻断剂及蛋白激酶 A ( protein kinase A, PKA)抑制剂,明确UCN抑制吗啡成瘾中发挥关键作用。结果 UCN2使82%(31/38)吗啡成瘾大鼠VTA神经元放电频率减慢,平均放电频率由微电泳前的(20．89±2．86) Hz减少到(13．66±3．93)Hz,给药前后放电频率降低具有显著性( P<0．01), UCN2抑制作用可被PKA抑制剂H89及CRF-2R阻断剂AST-2B取消。另外,微电泳UCN2可抑制吗啡成瘾大鼠VTA中DA神经元的爆发放电,AST-2B可增强 DA的兴奋效应。结论 UCN2与CRF-2R 结合后,通过PKA信号途径,抑制VTA内DA神经元异常放电,在吗啡类药物成瘾中发挥抑制作用,为其用于临床治疗阿片类药物成瘾提供理论依据。
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