Mechanisms Underlying TAAR1-induced Wakefulness and REM Sleep Suppression

TAAR1 诱导觉醒和快速眼动睡眠抑制的机制

• 批准号: 10170448
• 负责人: Thomas S Kilduff
• 金额: $ 64.58万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170448
• 关键词: Address; Agonist; Amines; Amygdaloid structure; Anti-Anxiety Agents; Antidepressive Agents; Antipsychotic Agents; Arousal; Attenuated; Biological Psychiatry; Brain region; Cataplexy; Cells; Clinical Trials; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Dose; Electroencephalography; Frequencies; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Glutamates; Hour; Human; Knock-out; Knockout Mice; Laboratories; LacZ Genes; Mediating; Midbrain structure; Mus; Narcolepsy; Neurobiology; Neurons; Nucleus solitarius; Paper; Parkinson Disease; Pathway interactions; Pharmacology; Phenotype; Physiology; Preoptic Areas; Property; Psychoses; Publications; REM Sleep; Rattus; Regulation; Rodent; Schizophrenia; Seizures; Signal Transduction; Sleep; Spinal; System; Technology; Testing; Therapeutic; Ventral Tegmental Area; Wakefulness; Wild Type Mouse; awake; base; cell type; dopaminergic neuron; dorsal raphe nucleus; efficacy evaluation; in vitro activity; in vivo; mRNA Expression; microendoscopy; mouse model; neural circuit; neurochemistry; neuromechanism; neuropsychiatry; nonhuman primate; novel; novel therapeutics; overexpression; psychostimulant; receptor

PROJECT SUMMARY Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor involved in the regulation of dopaminergic, serotonergic and glutamatergic activity. TAAR1 agonists have anxiolytic, antidepressant-, and antipsychotic-like properties in both rodent and non-human primates; TAAR1 agonists are in clinical trials for schizophrenia and Parkinson’s disease psychosis. We have previously shown that TAAR1 agonists are wake- promoting in mice, rats and, most recently, non-human primates, characterized the sleep/wake phenotype of Taar1 knockout (KO) and overexpressing (OE) mice, and evaluated the effects of TAAR1 agonists on sleep/wake in wildtype (WT), KO and OE mice. We also showed that two different TAAR1 agonists suppressed REM sleep and reduced cataplexy in mouse models of narcolepsy, precisely the properties desirable in a narcolepsy therapeutic. Having established TAAR1 agonists as potential novel treatments for narcolepsy, we will now investigate the underlying in vivo neurobiology. In Taar1-LacZ mice, we will determine whether TAAR1 is expressed in monoaminergic, glutamatergic or other cell types and use the RNAscope technology to determine endogenous Taar1 mRNA expression in WT and KO mice and rats. Since TAAR1 negatively regulates dopaminergic (DA) neuronal activity in vitro, we will test the hypothesis that TAAR1 partial agonism promotes wakefulness by modulating DA arousal systems. To address this hypothesis, we will assess neuronal activity in the ventral tegmental area and dorsal raphe nuclei of DAT-ires-Cre mice using in vivo Ca2+ microendoscopy, and determine whether pretreatment with DA D1- and D2-receptor antagonists attenuates TAAR1-mediated wake-promotion. Since serotonergic neurons are wake-active and REM-inactive and TAAR1 negatively regulates serotonergic neuronal activity in vitro, we will also test the hypothesis that TAAR1 partial agonism promotes wakefulness by modulating serotonergic arousal systems. We will determine whether TAAR1 partial agonists modulate the activity of DRN serotonergic neurons using in vivo Ca2+ microendoscopy in Fev-Cre mice and assess whether blockade of serotonergic signaling attenuates the wake-promoting effects of TAAR1 partial agonists. We have found that TAAR1 deletion elevates high-frequency gamma EEG activity, suggesting that TAAR1 modulates cortical function. To determine whether TAAR1-mediated elevation of gamma activity is conserved across species and specific to TAAR1, we will investigate basal sleep/wake physiology and conduct quantitative EEG analyses in Taar1 KO and OE rats and Taar2-9 KO mice. Together, these Aims will begin to establish the neural circuitry and mechanisms that underlie the efficacy of TAAR1 agonists.

项目总结