Behavioral Pharmacology Laboratory, Department of Psychological and Brain Sciences, University of California, Santa Barbara, California 93106-9660.
J Neurosci. 2014 Mar 5;34(10):3467-74. doi: 10.1523/JNEUROSCI.3861-13.2014.
Cocaine has been shown to produce both initial rewarding and delayed anxiogenic effects. Although the neurobiology of cocaine's rewarding effects has been well studied, the mechanisms underlying its anxiogenic effects remain unclear. We used two behavioral assays to study these opposing actions of cocaine: a runway self-administration test and a modified place conditioning test. In the runway, the positive and negative effects of cocaine are reflected in the frequency of approach-avoidance conflict that animals develop about entering a goal box associated with cocaine delivery. In the place conditioning test, animals develop preferences for environments paired with the immediate/rewarding effects of cocaine, but avoid environments paired with the drug's delayed/anxiogenic actions. In the present study, these two behavioral assays were used to examine the role of norepinephrine (NE) transmission within the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST), each of which has been implicated in drug-withdrawal-induced anxiety and stress-induced response reinstatement. Rats experienced 15 single daily cocaine-reinforced (1.0 mg/kg, i.v.) runway trials 10 min after intracranial injection of the β1 and β2 NE receptor antagonists betaxolol and ICI 118551 or vehicle into the CeA or BNST. NE antagonism of either region dose dependently reduced approach-avoidance conflict behavior compared with that observed in vehicle-treated controls. In addition, NE antagonism selectively interfered with the expression of conditioned place aversions while leaving intact cocaine-induced place preferences. These data suggest a role for NE signaling within the BNST and the CeA in the anxiogenic actions of cocaine.
可卡因已被证明既能产生初始的奖赏效应，又能产生延迟的焦虑效应。尽管可卡因奖赏效应的神经生物学已经得到了很好的研究，但它产生焦虑效应的机制仍不清楚。我们使用了两种行为学测试来研究可卡因的这些相反作用：一个是跑道自我给药测试，另一个是改良的位置条件测试。在跑道上，可卡因的正负效应反映在动物对进入与可卡因递送相关的目标箱的回避冲突的频率上。在位置条件测试中，动物对与可卡因的即时/奖赏效应相关的环境产生偏好，但回避与药物的延迟/焦虑效应相关的环境。在本研究中，这两种行为学测试被用来研究去甲肾上腺素（NE）在杏仁中央核（CeA）和终纹床核（BNST）内的传递作用，这两个核团都与药物戒断引起的焦虑和应激引起的反应恢复有关。大鼠在颅内注射β1和β2去甲肾上腺素受体拮抗剂倍他洛尔和 ICI 118551或载体到 CeA 或 BNST 10 分钟后，经历了 15 次每日单次可卡因强化（1.0mg/kg，iv）的跑道试验。与在载体处理的对照组相比，两种区域的 NE 拮抗作用都能剂量依赖性地减少回避-接近冲突行为。此外，NE 拮抗作用选择性地干扰了条件性位置厌恶的表达，而不影响可卡因引起的位置偏好。这些数据表明，NE 信号在 BNST 和 CeA 内参与了可卡因的焦虑作用。
