Cellular basis of amphetamine-induced hallucinations

描述（由申请人提供）： 幻觉是对不存在的刺激的感知。 在人类中，高剂量的安非他明可以引发幻觉，以及偏执型精神病发作，这与精神分裂症几乎无法区分。 虽然安非他明如何在大脑中起作用的药理学已经有了一些详细的了解，但其精神作用背后的电生理机制还不清楚。 该实验室最近发现，单次高剂量的安非他明会在无脊椎动物模型系统中引起明显的幻觉，海洋软体动物Tritonia Diomedea。 在分离的大脑准备中，安非他明引起动物的高阈值逃避游泳运动程序的反复自发爆发。 这种效应可以追溯到通常触发游泳的中央传入神经元中的动作电位的自发爆发。 因为这些神经元在这个准备中与皮肤断开连接，动物的大脑对感知到的皮肤刺激产生了复杂的反应，而这种刺激并不存在--也就是说，它正在经历一种躯体幻觉 该项目有三个具体目标。 第一个目标将集中在生物物理机制，安非他明诱导平台电位的传入神经元的属性，使他们兴奋，从而容易爆发成自发的活动爆发。 第二个目标是确定在安非他明存在的情况下，在传入神经元群体的成员中观察到的爆炸性放电扩散是否是由于增强的化学或电突触连接。 第三个目标将探讨安非他明的重复使用是否会随着时间的推移而导致其作用的敏感化。 我们的研究结果应促进发展，改善药物治疗安非他明过量和成瘾。 它们还可能与治疗其他滥用药物以及精神分裂症等疾病引起的幻觉有关。

DESCRIPTION (provided by applicant): Hallucinations are perceptions of stimuli that are not really there. In humans, high doses of amphetamine can trigger hallucinations, as well as paranoid psychotic episodes that are virtually indistinguishable from those of schizophrenia. While the pharmacology of how amphetamine acts in the brain is known in some detail, the electrophysiological mechanisms underlying its psychotogenic effects are not yet understood. This laboratory recently found that single, high doses of amphetamine elicit apparent hallucinations in an invertebrate model system, the marine mollusk Tritonia Diomedea. In isolated brain preparations, amphetamine caused repeated, spontaneous eruptions of the animal's high-threshold escape swim motor program. This effect was traced to spontaneous bursts of action potentials in the centrally-located afferent neurons that normally trigger the swim. Because these neurons are disconnected from the skin in this preparation, the animal's brain is generating a complex response to a perceived skin stimulus that isn't really there -- i.e., it is experiencing a somatic hallucination. The project has three specific aims. The first aim will focus on the biophysical mechanism by which amphetamine induces plateau potential properties in the afferent neurons, rendering them bistable and thus prone to erupt into spontaneous bursts of activity. The second aim will determine whether the explosive spread of firing observed among the members of the afferent neuron population in the presence of amphetamine is due to enhanced chemical or electrical synaptic connections. The third aim will explore whether repeated amphetamine leads to sensitization of its effects over time. Our results should facilitate the development of improved pharmacotherapy for treating amphetamine overdose and addiction. They may also have relevance for the treatment of hallucinations caused by other drugs of abuse as well as by diseases such as schizophrenia.