Drugs of Abuse: Neuronal Survival and Signaling

滥用药物：神经元存活和信号传导

• 批准号: 6665381
• 负责人: KRISTA L MOULDER
• 金额: $ 1.36万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6665381
• 关键词: behavioral /social science research tag; biological signal transduction; brain electrical activity; calcium flux; cell death; drug abuse; electrophysiology; ethanol; excitatory aminoacid; gamma aminobutyrate; glutamate receptor; glutamate transporter; hippocampus; immunocytochemistry; insulinlike growth factor; laboratory rat; membrane channels; neuropharmacology; neurotoxicology; neurotransmitter transport; postdoctoral investigator; potassium; single cell analysis; synapses; synaptogenesis; voltage /patch clamp

DESCRIPTION (provided by applicant): The broadest objective of the proposed research is to characterize the changes in synaptic signaling that accompany increases and decrease in electrical activity. Chronic exposure to drugs of abuse such as ethanol, barbiturates, and benzodiazepines causes a downregulation in electrical activity, which ultimately leads to neuronal death. The goal of Aim 1 is to determine whether this decrease in neuronal activity results in reduced neurotransmitter release because of drug effects on Ca2+ currents, or in enhanced neurotransmitter release through initiation of homeostatic mechanisms. Such changes in synaptic signaling could either lessen or intensify the effects of drugs of abuse on neuronal survival. The goal of Aim 2 is to determine the effects on synaptic signaling caused by mimicking increased electrical activity with K+ depolarization. Preliminary data indicate that depolarization curtails development of glutamatergic synapses, while leaving inhibitory currents intact. Experiments will be conducted to distinguish whether a presynaptic and a postsynaptic mechanism accounts for this effect of K+ on excitatory currents. Both Aim 1 and Aim 2 will utilize whole-cell, patch-clamp techniques in a hippocampal microculture paradigm, which will facilitate examination of synaptic electrophysiology.

描述（由申请人提供）： 拟议研究的最广泛目标是表征伴随电活动增加和减少的突触信号的变化。长期暴露于滥用药物如乙醇、巴比妥类药物和苯二氮卓类药物会导致电活动下调，最终导致神经元死亡。目的1的目的是确定这种神经元活动的减少是否会导致神经递质释放减少，因为药物对Ca2+电流的影响，或通过启动稳态机制增强神经递质释放。突触信号的这种变化可能会减轻或加强滥用药物对神经元存活的影响。目的2的目标是确定通过模拟K+去极化增加的电活动对突触信号传导的影响。初步的数据表明，去极化缩短了突触的发育，同时保持抑制电流的完整。将进行实验以区分是否突触前和突触后机制解释K+对兴奋性电流的这种作用。目标1和目标2都将在海马微培养范例中利用全细胞膜片钳技术，这将有助于检查突触电生理学。