Cellular basis of amphetamine-induced hallucinations

安非他明引起幻觉的细胞基础

• 批准号: 6599462
• 负责人: William Frost
• 金额: $ 15.6万
• 依托单位: ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6599462
• 关键词: Mollusca; action potentials; afferent nerve; amphetamines; behavioral habituation /sensitization; biophysics; brain electrical activity; cell biology; drug abuse; electrical measurement; electrophysiology; hallucinations; neurons; paranoid psychosis; sensory mechanism; synapses

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.

描述（由申请人提供）：幻觉是对刺激的看法，这些刺激实际上并非如此。 在人类中，高剂量的苯丙胺可以引发幻觉，以及与精神分裂症几乎没有区别的偏执型精神病发作。 虽然尚不清楚其精神遗传作用的基于的电生理机制，但尚不清楚苯丙胺如何在大脑中起作用的药理学。 该实验室最近发现，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）中引起了明显的幻觉。 在孤立的大脑制剂中，苯丙胺引起了该动物高阈值逃生游泳运动计划的反复自发喷发。 这种效果可追溯到通常触发游泳的中央分级传入神经元中的自发动作电位。 由于这些神经元在这种制剂中与皮肤断开了连接，因此动物的大脑对感知到的皮肤刺激产生了复杂的反应，而皮肤刺激实际上并不存在 - 即，它正在经历躯体幻觉。 该项目具有三个特定的目标。 第一个目的将集中在生物物理机制上，通过这种机制，苯丙胺在传入神经元中诱导平稳的潜在特性，使它们可养成，因此容易爆发为自发的活性爆发。 第二个目的将决定在苯丙胺存在下观察到的传入神经元种群中观察到的爆炸性扩散是否是由于化学或电突触连接增强所致。 第三个目标将探索重复的苯丙胺是否会导致其影响随着时间的推移敏感。 我们的结果应促进改善药物治疗苯丙胺过量和成瘾的药物疗法。 它们也可能与其他滥用药物以及精神分裂症等疾病引起的幻觉有关。