O'Daly Owen Gareth, Joyce Daniel, Stephan Klaas Enno, Murray Robin McGregor, Shergill Sukhwinder S
Cognition, Schizophrenia and Imaging Lab, Department of Psychosis Studies, Institute of Psychiatry, King’s College London, England. o.o’
Arch Gen Psychiatry. 2011 Jun;68(6):545-54. doi: 10.1001/archgenpsychiatry.2011.3. Epub 2011 Feb 7.
Recent work suggests that the amphetamine sensitization model of schizophrenia can safely be induced in healthy volunteers and is associated both with behavioral and dopaminergic hypersensitivity to amphetamine. However, the effects of a sensitization on brain function remain unclear.
To assess the impact of a sensitizing dosage regimen of dextroamphetamine on human cortical functioning and cognition.
Randomized, double-blind, parallel-groups design using pharmacological functional magnetic resonance imaging.
The neuroimaging research unit at the Institute of Psychiatry, King's College London, London, England.
Healthy male volunteers (n = 22).
Dextroamphetamine (20 mg) or placebo administration at 4 testing sessions, using a dosage regimen shown to induce sensitization (ie, 3 doses administered with a 48-hour interdose interval and a final dose after a 2-week washout period).
Sensitization was characterized by enhanced subjective response to the drug, changes in behavioral performance (reaction time and accuracy), and functional magnetic resonance imaging measurements of brain activity during an N-back working memory task.
Sensitization was associated with more rapid responding during the performance of an intermediate-load working memory challenge. During a high-load cognitive challenge, sensitization did not produce performance deficits, but functional magnetic resonance imaging showed hyperactivity of the dorsolateral prefrontal cortex and aberrant recruitment of the superior temporal gyrus, caudate nucleus, and thalamus. Furthermore, the change in striatal activity was negatively correlated with the enhanced subjective effects of the drug, whereas prefrontal hyperactivity was positively correlated with sensitized measures of alertness.
These transient load-dependent abnormalities of frontal and temporal activity induced by amphetamine sensitization support neuroimaging findings in schizophrenic patients, implying that amphetamine sensitization may help to bridge pathophysiological theories of schizophrenia that focus on pharmacological (dopaminergic) and cognitive mechanisms, respectively.
近期研究表明，精神分裂症的苯丙胺致敏模型可在健康志愿者中安全诱导，且与对苯丙胺的行为及多巴胺能超敏反应相关。然而，致敏对脑功能的影响仍不明确。
评估右旋苯丙胺致敏剂量方案对人类皮质功能和认知的影响。
采用药理功能磁共振成像的随机、双盲、平行组设计。
英国伦敦国王学院精神病学研究所的神经影像研究室。
健康男性志愿者（n = 22）。
在4次测试中给予右旋苯丙胺（20 mg）或安慰剂，采用已证明可诱导致敏的剂量方案（即3剂，给药间隔为48小时，在2周洗脱期后给予最后一剂）。
致敏的特征为对药物的主观反应增强、行为表现（反应时间和准确性）的变化，以及在N-back工作记忆任务期间脑活动的功能磁共振成像测量。
致敏与中等负荷工作记忆挑战执行过程中更快的反应相关。在高负荷认知挑战期间，致敏未导致表现缺陷，但功能磁共振成像显示背外侧前额叶皮质活动亢进，以及颞上回、尾状核和丘脑的异常募集。此外，纹状体活动的变化与药物增强的主观效应呈负相关，而前额叶活动亢进与致敏的警觉性测量呈正相关。
苯丙胺致敏诱导的这些短暂的负荷依赖性额叶和颞叶活动异常支持了精神分裂症患者的神经影像研究结果，这意味着苯丙胺致敏可能有助于弥合分别关注药理学（多巴胺能）和认知机制的精神分裂症病理生理理论。
