BDNF in the Reward Circuit for DBS-Induced Opioid Extinction

DBS 引起的阿片类药物灭绝的奖赏回路中的 BDNF

• 批准号: 10629686
• 负责人: Jennifer Luz Barreto Estrada
• 金额: $ 14.9万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629686
• 关键词: Amygdaloid structure; Animal Model; Animals; Area; Attenuated; Behavioral; Biological; Brain; Brain Diseases; Brain region; Brain-Derived Neurotrophic Factor; COVID-19 pandemic; Cessation of life; Cholera Toxin; Clinic; Clozapine; Cues; Data; Deep Brain Stimulation; Dorsal; Drug Modelings; Electric Stimulation; Extinction; Frequencies; Future; Genetic; Genetic Techniques; Glutamates; Grant; Hippocampus; Human; Impairment; Implanted Electrodes; Injections; Knowledge; Location; Measures; Medial; Memory; Mental disorders; Molecular; Morphine; Movement Disorders; Neurons; Neurosurgical Procedures; Neurotrophic Tyrosine Kinase Receptor Type 2; Nucleus Accumbens; Opiate Addiction; Opioid; Overdose; Oxides; Persons; Pharmaceutical Preparations; Pharmacological Treatment; Phase; Physiologic pulse; Pilot Projects; Population; Prefrontal Cortex; Principal Investigator; Procedures; Process; Rattus; Refractory; Relapse; Reporting; Research; Research Personnel; Research Project Grants; Resistance; Rewards; Rodent; Rodent Model; Role; Substance Use Disorder; Time; Ventral Striatum; addiction; antagonist; cocaine overdose; conditioned place preference; cost estimate; designer receptors exclusively activated by designer drugs; drug seeking behavior; drug testing; experimental study; genetic approach; genetic manipulation; immunoreactivity; insight; learning extinction; nervous system disorder; opioid use disorder; pharmacologic; prevent; programs; reduce symptoms; retrograde transport; sobriety; suicidal morbidity; tool

Abstract/Summary Deep brain stimulation (DBS) is a neurosurgical procedure that is used to treat neurologic and psychiatric disorders. Recent research in both animals and humans has shown that DBS may be an effective procedure for refractory addiction. We previously propose to use DBS as treatment for drug-seeking behaviors in a rat animal model, and found that high frequency DBS (HF-DBS) of the ventral striatum/nucleus accumbens (VS/NAc) impaired extinction of morphine-induced conditioned place preference (CPP), whereas low frequency DBS (LF-DBS) enhanced extinction memory (reducing drug seeking behavior). Interestingly, we also found that LF-DBS significatively shortens the persistency of the drug (LF-DBS~10 days vs sham-DBS~40 days). At the molecular level, we found that DBS-treated animals increased BDNF expression in the hippocampus (HPC). However, drug reinstatement was not significatively prevented in LF-DBS- treated animals when stimulation was applied only during extinction sessions. In this transition between the SCORE-SuRE grant cycle, we propose to further advance the knowledge in drug- seeking behavior, and in the underlying DBS’ mechanisms of action, by using pharmacological and chemogenetic approaches. Therefore, in the present study, Aim 1a-c will determine whether LF-DBS applied during extinction, in addition to provide electrical stimulation in the phase of drug reinstatement prevents drug seeking in a higher percentage of animals. Also, BDNF expression will be measured in the HPC, as well as in other brain regions, i.e., amygdala, VS/NAc, and medial prefrontal cortex (mPFC). Aim 2a will use a pharmacological approach by infusing BDNF and TrkB antagonist (ANA-12) in the VS/NAc to determine their effects in extinction of morphine CPP. Since glutamatergic neurons in the HPC encompass a subpopulation of neurons expressing BDNF, the approach in Aim 2b is to use the chemogenetic tool, known as designer receptors exclusively activated by designer drugs (DREADDs) to activate HPC glutamatergic neurons in the presence of ANA-12, to prevent extinction of morphine CPP. Activation of DREADDs will be done with clozapine N-oxide (CNO). Aim 2c will inactivate HPC-NAc glutamatergic/BDNFergic projections that will prevent the beneficial effects of LF-DBS. Our study represents a circuit-based approach to better understand the action mechanisms of drug- seeking and extinction. Because rodent models of drug extinction resemble exposure-based therapies in humans, it is possible that targeted electrical stimulation and the DBS-increased expression of pro-extinction molecules might represent an effective future approach to reduce the symptoms of addiction and opioid use disorders (OUD).

抽象/总结