Cognition, Schizophrenia and Imaging Laboratory, King's College London, London, UK Centre for Neuroimaging Sciences, King's College London, London, UK o.o'
Cognition, Schizophrenia and Imaging Laboratory, King's College London, London, UK.
J Psychopharmacol. 2014 Sep;28(9):857-65. doi: 10.1177/0269881114527360. Epub 2014 Mar 26.
Amphetamine sensitisation (AS) is an established animal model of the hypersensitivity to psychostimulants seen in patients with schizophrenia. AS also models the dysregulation of mesolimbic dopamine signalling which has been implicated in the development of psychotic symptoms. Recent data suggest that the enhanced excitability of mesolimbic dopamine neurons in AS is driven by a hyperactivity of hippocampal (subiculum) neurons, consistent with a strong association between hippocampal dysfunction and schizophrenia. While AS can be modelled in human volunteers, its functional consequences on dopaminoceptive brain regions (i.e. striatum and hippocampus) remains unclear. Here we describe the effects of a sensitising dosage pattern of dextroamphetamine on the neural correlates of motor sequence learning in healthy volunteers, within a randomised, double-blind, parallel-groups design. Behaviourally, sensitisation was characterised by enhanced subjective responses to amphetamine but did not change performance (i.e. learning rate) during an explicit sequence learning task. In contrast, functional magnetic resonance imaging (fMRI) measurements showed that repeated intermittent amphetamine exposure was associated with increased blood-oxygen-level dependent (BOLD) signal within the medial temporal lobe (MTL) (subiculum/entorhinal cortex) and midbrain, in the vicinity of the substantia nigra/ventral tegmental area (SN/VTA) during sequence encoding. Importantly, MTL hyperactivity correlated with the sensitisation of amphetamine-induced attentiveness. The MTL-midbrain hyperactivity reported here mirrors observations in sensitised rodents and is consistent with contemporary models of schizophrenia and behavioural sensitisation. These findings of meso-hippocampal hyperactivity during AS thus link pathophysiological concepts of dopamine dysregulation to cognitive models of psychosis.
安非他命敏化（AS）是一种已建立的动物模型，可模拟精神分裂症患者对精神兴奋剂的超敏反应。AS 还模拟了中脑边缘多巴胺信号的失调，这与精神病症状的发展有关。最近的数据表明，AS 中中脑边缘多巴胺神经元的兴奋性增强是由海马（下托）神经元的过度活跃驱动的，这与海马功能障碍与精神分裂症之间的强烈关联一致。虽然可以在人类志愿者中模拟 AS，但它对多巴胺能接受脑区（即纹状体和海马体）的功能后果仍不清楚。在这里，我们描述了在随机、双盲、平行组设计中，一种安非他命敏化剂量模式对健康志愿者运动序列学习的神经相关性的影响。行为上，敏化表现为对安非他命的主观反应增强，但在明确的序列学习任务中不会改变表现（即学习率）。相比之下，功能磁共振成像（fMRI）测量显示，反复间歇性安非他命暴露与中脑内侧颞叶（MTL）（下托/内嗅皮层）和中脑的血氧水平依赖（BOLD）信号增加有关，在序列编码期间，靠近黑质/腹侧被盖区（SN/VTA）。重要的是，MTL 过度活跃与安非他命诱导注意力的敏化相关。这里报告的 MTL-中脑过度活跃反映了敏化啮齿动物的观察结果，与精神分裂症和行为敏化的当代模型一致。因此，AS 期间中脑-海马体的这种过度活跃将多巴胺失调的病理生理概念与精神病的认知模型联系起来。
