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Extinction Circuits Controlling Heroin Seeking

控制海洛因寻找的灭绝电路

基本信息

批准号：
9912742
负责人：
JAMIE PETERS
金额：
$ 34.99万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-15 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9912742
关键词：
Address Anatomy Animals Automobile Driving Behavior Behavioral Brain Brain region Cocaine Conditioned Reflex Cues Data Desire for food Efferent Pathways Exposure to Extinction (Psychology)Female Food Fright Genetic Recombination Globus Pallidus Heroin Hypothalamic structure Lateral Lead Learning Masks Medial Mediating Memory Motivation Neuroanatomy Neurons Nucleus Accumbens Opiate Addiction Output Pathway interactions Pharmaceutical Preparations Play Population Prefrontal Cortex Process Public Health Rabies Rattus Relapse Reporting Research Retrieval Rewards Rodent Rodent Model Role Self Administration Sex Differences Site Synapses System Techniques Testing Tracer United States Viral Viral Vector Work conditioned fear craving designer receptors exclusively activated by designer drugs experimental study feeding innovation insight male memory process memory retrieval mu opioid receptors neural circuit novel recruit technological innovation theories tool vector

项目摘要

Abstract Opiate addiction is a huge public health threat in the United States currently. There is a real need for new treatments that reduce relapse rates, and a major relapse trigger is exposure to conditioned drug cues. The conditioned response to seek drug is intimately tied to the memory retrieved by these reminder cues. However, repeated exposure to these cues in the absence of reward can lead to a diminished conditioned response to seek drug, through a process known as extinction. Extinction is thought to establish an opposing inhibitory memory that suppresses the conditioned response, and has been shown to recruit portions of the prefrontal cortex. In particular, the infralimbic (IL) subregion in rodents exerts this inhibitory control over downstream effectors that would otherwise drive the conditioned response. This is true for a number of conditioned behaviors, including conditioned cocaine seeking, food seeking, and fear. Preliminary data suggest that the inhibitory function of this region is masked, but not lost, after heroin self-administration. This may be due to a primary site of action of heroin at mu opioid receptors (MORs) in IL, as activation of IL-MORs elicits feeding and a general hyper-appetitive state (Baldo 2016). Preliminary data suggest that IL-MORs also regulate the motivation to seek heroin, and is consistent with a theory separate appetitive driver and limiter functions exist within the IL cortex. These opposing functions may be encoded by distinct neuronal ensembles within IL with distinct downstream targets. Two major efferent targets of IL that are known to regulate both food and drug seeking are the lateral hypothalamus (LH) and the nucleus accumbens shell (NAshell). We propose that IL neuronal ensembles projecting to the LH drive heroin seeking, whereas those projecting to the NAshell inhibit heroin seeking. Indeed, preliminary data show that chemogenetic activation of the IL to NAshell pathway reduces cue-induced reinstatement of heroin seeking, similar to our reported effects in cocaine-seeking animals (Augur et al. 2016). We will use a novel TRAP-DREADD system to tag and reactivate different functional neuronal ensembles in IL that drive versus inhibit heroin seeking, and we will identify their downstream efferent targets by retrograde tracing. We will also use pathway-specific chemogenetics to activate these different IL efferent pathways and establish their functional role in cue-induced heroin relapse. Finally, we will use a novel trans-synaptic "trans-DREADD" strategy to examine the second-order circuits controlling heroin seeking. These experiments will determine the specific functional neural circuitry of IL and its downstream effectors, and establish their role in driving vs limiting heroin seeking. Furthermore, this work will provide new insight into the specific neuroanatomy controlling heroin seeking and the extent to which these limiter circuits can be exploited to reduce relapse.

文摘