Pharmacological modulation of lateral habenular dopamine D2 receptors alters the anxiogenic response to cocaine in a runway model of drug self-administration.
Pharmacological modulation of lateral habenular dopamine D2 receptors alters the anxiogenic response to cocaine in a runway model of drug self-administration.
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DOI：
10.1016/j.bbr.2016.05.002
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发表时间：
2016-09-01
影响因子：
2.7
通讯作者：
Ettenberg A
中科院分区：
文献类型：
--
作者：
Shelton K;Bogyo K;Schick T;Ettenberg A
长期以来，人们都知道可卡因会产生最初的“兴奋”，然后是令人厌恶/焦虑的“崩溃”。虽然对可卡因的积极/奖励作用的神经生物学了解很多，但引起药物的消极/焦虑作用的机制仍不清楚。最近的研究表明，外侧缰核（LHb）参与了包括对可卡因的焦虑反应在内的厌恶事件的编码。在这方面特别感兴趣的是LHb和腹侧被盖区（VTA）之间的相互连接。腹侧被盖区DA神经元支配LHb细胞的不同亚群，LHb细胞反过来反馈并调节腹侧被盖区神经元的活动。在这里，我们研究了D2受体的激活和抑制的焦虑反应可卡因使用跑道模型的自我管理，是敏感的双重和相反的效果的药物。雄性大鼠在双侧LHb内输注D2受体拮抗剂顺式氟噻吨（0、7.5或15μg/侧）或D2受体激动剂舒马尼罗（0、5或10μg/侧）后，静脉注射可卡因（1.0 mg/kg）后，沿直线跑道奔跑。车辆预处理的控制开发的接近-回避冲突行为的目标框条目反映可卡因的双重积极和消极的影响。这些行为在LHb-D2受体拮抗剂作用期间显著减弱，而在LHb D2受体激动剂作用下增加。这些结果表明，在外侧缰的D2受体的活动，以调节可卡因的焦虑反应。
Cocaine has long been known to produce an initial “high” followed by an aversive/anxiogenic “crash”. While much is known about the neurobiology of cocaine’s positive/rewarding effects, the mechanisms that give rise to the drug’s negative/anxiogenic actions remain unclear. Recent research has implicated the lateral habenula (LHb) in the encoding of aversive events including the anxiogenic response to cocaine. Of particular interest in this regard are the reciprocal connections between the LHb and the ventral tegmental area (VTA). VTA-DA neurons innervate different subsets of LHb cells that in turn feedback upon and modulate VTA neuronal activity. Here we examined the impact of D2 receptor activation and inhibition on the anxiogenic response to cocaine using a runway model of self-administration that is sensitive to the dual and opposing effects of the drug. Male rats ran a straight alley for IV cocaine (1.0 mg/kg) following bilateral intra-LHb infusions of the D2 receptor antagonist, cis-flupenthixol (0, 7.5 or 15μg/side) or the D2 agonist, sumanirole (0, 5 or 10μg/side). Vehicle-pretreated controls developed approach-avoidance conflict behaviors about goal-box entry reflective of the dual positive and negative effects of cocaine. These behaviors were significantly diminished during LHb-D2 receptor antagonism and increased by the LHb D2 receptor agonist. These results demonstrate that activity at the D2 receptor in the lateral habenula serves to modulate the anxiogenic response to cocaine.