Psychiatry Neuroimaging Branch, University Medical Center Hamburg-Eppendorf, Department of Psychiatry and Psychotherapy, Psychiatry Neuroimiaging Branch, Hamburg, Germany.
Biol Psychiatry. 2013 Feb 15;73(4):337-44. doi: 10.1016/j.biopsych.2012.09.004. Epub 2012 Oct 8.
Benzodiazepines modulate γ-aminobutyric acid type A (GABA(A)) receptors throughout the brain. However, it is not fully understood which brain regions within anxiety-related brain circuits are really responsible for their anxiolytic effects and how these regions interact.
We investigated whether the benzodiazepine alprazolam affects activity in distinct brain regions within anxiety-related circuits during an experimental anxiety paradigm by means of functional magnetic resonance imaging (fMRI). Panic symptoms were elicited by a bolus injection of the neuropeptide cholecystokinin-tetrapeptide (CCK-4) in 16 healthy male subjects in a double-blind, placebo-controlled design. Functional brain activation patterns were determined before and during the CCK-4-challenge without pretreatment and after treatment with either placebo or 1 mg alprazolam.
The CCK-4 induced anxiety and elicited widely distributed activation patterns in anxiety-related brain circuits, especially in the rostral anterior cingulate cortex (rACC), which was attenuated after alprazolam treatment. In contrast to placebo, alprazolam abolished the activation of the rACC after challenge with CCK-4 (p<.005, corrected for multiple comparisons) and increased functional connectivity between the rACC and other anxiety-related brain regions such as amygdala and prefrontal cortex. Moreover, the reduction in the CCK-4 induced activation of the rACC correlated with the anxiolytic effect of alprazolam (r(p) = .52; p = .04).
These findings put forward the rACC as a target for benzodiazepines and suggest that the CCK-4/fMRI paradigm might represent a human translational model for the investigation of anxiolytic drugs.
苯二氮䓬类药物通过调节整个大脑中的γ-氨基丁酸 A 型（GABA(A)）受体来发挥作用。然而，人们并不完全清楚与焦虑相关的大脑回路中的哪些脑区真正负责其抗焦虑作用，以及这些区域如何相互作用。
我们通过功能磁共振成像（fMRI）研究了在实验性焦虑范式中，苯二氮䓬类药物阿普唑仑是否会影响与焦虑相关回路中不同脑区的活动。在一项双盲、安慰剂对照设计中，16 名健康男性受试者静脉内注射神经肽胆囊收缩素-四肽（CCK-4），引发惊恐症状。在没有预处理的情况下，在 CCK-4 挑战之前和期间确定功能大脑激活模式，并在接受安慰剂或 1 毫克阿普唑仑治疗后进行。
CCK-4 引起的焦虑引起了与焦虑相关的大脑回路中广泛分布的激活模式，特别是在前扣带皮层（rACC）的头部，阿普唑仑治疗后减轻。与安慰剂相比，阿普唑仑在 CCK-4 挑战后消除了 rACC 的激活（p<.005，经多重比较校正），并增加了 rACC 与其他与焦虑相关的大脑区域（如杏仁核和前额叶皮层）之间的功能连接。此外，rACC 中 CCK-4 诱导的激活减少与阿普唑仑的抗焦虑作用相关（r(p) =.52；p =.04）。
这些发现提出了 rACC 作为苯二氮䓬类药物的靶点，并表明 CCK-4/fMRI 范式可能代表了研究抗焦虑药物的人类转化模型。
