Cellular basis of amphetamine-induced hallucinations

描述(由申请人提供)：幻觉是对并不真实存在的刺激的感知。在人类身上，高剂量的苯丙胺会引发幻觉，以及与精神分裂症几乎无法区分的偏执型精神病发作。虽然安非他明如何在大脑中发挥作用的药理学已经有了一些详细的了解，但其潜在的心理作用的电生理机制还不清楚。 该实验室最近发现，单次、高剂量的苯丙胺在无脊椎动物模型系统--海洋软体动物Tritonia Diomedea--中会引起明显的幻觉。在孤立的大脑准备中，苯丙胺导致动物高门槛逃逸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枢传入神经元中自发爆发的动作电位。因为在这种准备过程中，这些神经元与皮肤断开了联系，动物的大脑对感知到的皮肤刺激产生了复杂的反应，而这种刺激并不是真的在那里--即它正在经历一种躯体幻觉。 该项目有三个具体目标。第一个目标将集中于苯丙胺在传入神经元中诱导平台电位特性的生物物理机制，使其成为双稳态，从而容易爆发为自发的活动爆发。第二个目的将确定在苯丙胺存在的情况下观察到的传入神经元群体成员之间的爆炸性放电扩散是由于化学或电突触连接的增强。第三个目标将探索随着时间的推移，反复使用苯丙胺是否会导致其影响的敏感化。我们的结果将有助于开发治疗苯丙胺过量和成瘾的改进药物疗法。它们也可能与其他药物滥用以及精神分裂症等疾病引起的幻觉的治疗有关。

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.