Oral alprazolam acutely increases nucleus accumbens perfusion.
Oral alprazolam acutely increases nucleus accumbens perfusion.
复制标题
口服阿普唑仑可急剧增加伏隔核灌注。
DOI：
10.1038/mp.2012.139
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发表时间：
2013
影响因子：
11
通讯作者：
Gur,RE
中科院分区：
文献类型：
--
作者：
Wolf,DH;Pinkham,AE;Satterthwaite,TD;Ruparel,K;Elliott,MA;Valdez,J;Smith,MA;Detre,JA;Gur,RC;Gur,RE
苯二氮卓类药物治疗焦虑，但也会产生欣快效果，导致滥用。利用灌注磁共振成像技术，我们首次在人类中提供了直接证据，证明阿普唑仑（Xanax）会急剧增加伏隔核（一个与成瘾相关的关键奖励处理区域）的灌注。苯二氮卓类药物不仅具有抗焦虑的治疗作用，而且还具有通过广泛表达的受体增强GABA信号传导的不良副作用。苯二氮卓受体富集于人类腹侧纹状体/伏隔核1，这是正常和病理动机过程的关键区域。最近的非人类研究表明，苯二氮卓类药物通过α -1 GABA受体介导的中边缘多巴胺向伏隔核的释放解除抑制，以及通过对α -2 GABA受体的直接作用激活伏隔核。然而，没有直接证据表明苯二氮卓类药物对人类伏隔核有影响。药物对局部脑功能的影响与局部脑血流（CBF）的变化相耦合，可以通过动脉自旋标记（ASL）灌注MRI检测到。我们使用脉冲ASL （PASL）和先前描述的获取和分析方法4，在平衡交叉安慰剂对照双盲设计中，在MRI前1h口服阿普唑仑（1mg）的效果（详见Wolf et al. 5，研究程序、样本和功能MRI结果的详细信息；PASL在功能MRI前进行）。所有程序均经书面知情同意和宾夕法尼亚大学机构审查委员会批准。可用的PASL数据来自47名健康成人受试者中的45名，包括19名精神分裂症患者未受影响的亲属。由于阿普唑仑引起的灌注改变没有因家族史而异，因此将受试者纳入联合分析。为了确定阿普唑仑对局部脑功能的影响，我们检查了相对脑血流变化，并按全脑平均脑血流归一化。6阿普唑仑没有显著改变整体CBF， 5和绝对区域CBF结果在质量上与这些归一化结果相似。与安慰剂相比，单剂量口服阿普唑仑增加伏隔脑CBF（图1）。此外，阿普唑仑高伏隔区灌注的受试者在灌注扫描后的记忆任务中表现出更快的反应（r¼À 0.35, P¼0.020）和更低的反应（r¼À 0.30, P¼0.045）。5相反，横跨后丘脑和后中脑的脑束CBF减少。阿普唑仑后丘脑灌注较低的受试者反应时间较慢（r¼À 0.31, P¼0.040），与准确性无关（r¼0.004,P¼0.98）。伏隔核和丘脑/中脑的药物作用不相关（r = 0.12, P = 0.43），表明它们可能反映了药物作用的不同方面。这些结果首次在人类中直接证明了苯二氮卓类药物对伏隔核的选择性作用，这与gaba能激活中脑边缘多巴胺系统是一致的。然而，确定这种效应的精确神经元来源需要进一步的研究（见补充讨论）。苯二氮卓类药物的抗焦虑作用与杏仁核活性降低有关。我们认为伏隔核灌注增加反映了苯二氮卓类药物的已知作用，包括欣快感、去抑制、冲动、冒险和成瘾。观察到的阿普唑仑诱导的伏隔核静息灌注与随后认知任务中更多的冲动反应之间的关系支持了这一解释。阿普唑仑也可能有抗抑郁作用，7并可能产生……
Benzodiazepines treat anxiety, but can also produce euphoric effects, contributing to abuse. Using perfusion magnetic resonance imaging, we provide the first direct evidence in humans that alprazolam (Xanax) acutely increases perfusion in the nucleus accumbens, a key reward-processing region linked to addiction. Benzodiazepines exert not only therapeutic anxiolytic effects but also undesirable side effects by enhancing GABA signaling through receptors expressed widely in the brain. Benzodiazepine receptors are enriched in human ventral striatum/nucleus accumbens, 1 a critical region for normal and pathological motivational processes. Recent non-human studies demonstrated that benzodiazepines activate accumbens through alpha-1 GABA receptor-mediated disinhibition of mesolimbic dopamine projections to accumbens, 2 as well as through direct effects on alpha-2 GABA receptors. 3 However, there is no direct evidence of benzodiazepine effects on accumbens in humans. Pharmacological effects on regional brain function are coupled to changes in regional cerebral blood flow (CBF) and can be detected using arterial spin labeled (ASL) perfusion MRI. We used pulsed ASL (PASL) with previously described acquisition and analysis methods4 to examine the effects of oral alprazolam (1 mg) administered 1h before MRI in a balanced crossover placebocontrolled double-blind design (see Wolf et al. 5 for details of study procedures, sample and fMRI results; PASL was performed before fMRI). All procedures were performed with written informed consent and Penn Institutional Review Board approval. Usable PASL data were obtained from 45 of 47 healthy adult subjects including 19 unaffected relatives of patients with schizophrenia. As alprazolam-induced perfusion changes did not differ by family history, subjects were pooled in a combined analysis. To localize the effects of alprazolam on regional brain function, we examined relative CBF changes, normalized by whole brain mean CBF. 6 Alprazolam did not significantly change global CBF, 5 and absolute regional CBF results were qualitatively similar to these normalized results.A single dose of oral alprazolam increased CBF in accumbens (Figure 1), compared with placebo. Furthermore, subjects with higher accumbens perfusion on alprazolam showed faster (r¼ À 0.35, P¼ 0.020) and less accurate (r¼ À 0.30, P¼ 0.045) responses in a memory task following the perfusion scan. 5 In contrast, CBF was reduced in a cluster spanning posterior thalamus and posterior midbrain. Subjects with lower thalamus perfusion after alprazolam had slower reaction times (r¼ À 0.31, P¼ 0.040) with no relationship to accuracy (r¼ 0.004, P¼ 0.98). Drug effects in accumbens and thalamus/midbrain were not correlated (r¼ 0.12, P¼ 0.43), suggesting they may reflect different aspects of drug action. These results provide the first direct demonstration in humans of selective benzodiazepine effects on accumbens, consistent with GABAergic activation of the mesolimbic dopamine system. However, identifying the precise neuronal source of this effect requires further investigation (see Supplementary discussion). Anxiolytic effects of benzodiazepines have been linked to reduced amygdala activity. We suggest that increased accumbens perfusion reflects known effects of benzodiazepines including euphoria, disinhibition, impulsivity, risk-taking and addiction. The observed relationship between greater alprazolam-induced accumbens resting perfusion and more impulsive responding in a subsequent cognitive task supports this interpretation. Alprazolam may also have antidepressant effects, 7 and may produce …