Stokes Paul R A, Myers Jim F, Kalk Nicola J, Watson Ben J, Erritzoe David, Wilson Sue J, Cunningham Vincent J, Riano Barros Daniela, Hammers Alexander, Turkheimer Federico E, Nutt David J, Lingford-Hughes Anne R
Centre for Neuropsychopharmacology, Division of Brain Sciences, Burlington Danes Building, Imperial College London, W12 0NN, UK; Centre for Affective Disorders, Department of Psychological Medicine, Institute of Psychiatry, King's College London, London SE5 8AF, UK.
Centre for Neuropsychopharmacology, Division of Brain Sciences, Burlington Danes Building, Imperial College London, W12 0NN, UK; Psychopharmacology Unit, School of Social and Community Medicine, University of Bristol, Oakfield House, BS8 2BN, UK.
Neuroimage. 2014 Oct 1;99:158-65. doi: 10.1016/j.neuroimage.2014.05.035. Epub 2014 May 17.
The inhibitory γ-aminobutyric acid (GABA) neurotransmitter system is associated with the regulation of normal cognitive functions and dysregulation has been reported in a number of neuropsychiatric disorders including anxiety disorders, schizophrenia and addictions. Investigating the role of GABA in both health and disease has been constrained by difficulties in measuring acute changes in synaptic GABA using neurochemical imaging. The aim of this study was to investigate whether acute increases in synaptic GABA are detectable in the living human brain using the inverse agonist GABA-benzodiazepine receptor (GABA-BZR) positron emission tomography (PET) tracer, [(11)C]Ro15-4513. We examined the effect of 15 mg oral tiagabine, which increases synaptic GABA by inhibiting the GAT1 GABA uptake transporter, on [(11)C]Ro15-4513 binding in 12 male participants using a paired, double blind, placebo-controlled protocol. Spectral analysis was used to examine synaptic α1 and extrasynaptic α5 GABA-BZR subtype availability in brain regions with high levels of [(11)C]Ro15-4513 binding. We also examined the test-retest reliability of α1 and a5-specific [(11)C]Ro15-4513 binding in a separate cohort of 4 participants using the same spectral analysis protocol. Tiagabine administration produced significant reductions in hippocampal, parahippocampal, amygdala and anterior cingulate synaptic α1 [(11)C]Ro15-4513 binding, and a trend significance reduction in the nucleus accumbens. These reductions were greater than test-retest reliability, indicating that they are not the result of chance observations. Our results suggest that acute increases in endogenous synaptic GABA are detectable in the living human brain using [(11)C]Ro15-4513 PET. These findings have potentially major implications for the investigation of GABA function in brain disorders and in the development of new treatments targeting this neurotransmitter system.
抑制性γ-氨基丁酸（GABA）神经递质系统与正常认知功能的调节相关，据报道，在包括焦虑症、精神分裂症和成瘾症在内的多种神经精神疾病中，该系统存在调节异常。由于使用神经化学成像测量突触GABA的急性变化存在困难，因此对GABA在健康和疾病中的作用的研究受到了限制。本研究的目的是使用反向激动剂GABA-苯二氮䓬受体（GABA-BZR）正电子发射断层扫描（PET）示踪剂[(11)C]Ro15-4513，研究在活体人脑中是否可检测到突触GABA的急性增加。我们采用配对、双盲、安慰剂对照方案，检测了15mg口服噻加宾对12名男性参与者[(11)C]Ro15-4513结合的影响，噻加宾通过抑制GAT1 GABA摄取转运体来增加突触GABA。光谱分析用于检查[(11)C]Ro15-4513结合水平高的脑区中突触α1和突触外α5 GABA-BZR亚型的可用性。我们还使用相同的光谱分析方案，在另一组4名参与者中检测了α1和a5特异性[(11)C]Ro15-4513结合的重测信度。给予噻加宾后，海马体、海马旁回、杏仁核和前扣带回突触α1 [(11)C]Ro15-4513结合显著降低，伏隔核有降低趋势。这些降低大于重测信度，表明它们不是偶然观察的结果。我们的结果表明，使用[(11)C]Ro15-4513 PET可在活体人脑中检测到内源性突触GABA的急性增加。这些发现对脑疾病中GABA功能的研究以及针对该神经递质系统的新治疗方法的开发可能具有重大意义。
