权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Endogenous Cannabinoid Control of Reward Substrates

奖励底物的内源性大麻素控制

基本信息

批准号：
10754671
负责人：
Joseph F Cheer
金额：
$ 5.32万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10754671
关键词：
2-arachidonylglycerol Adult Animals Behavior Control Behavioral Brain CCL4 gene CNR1 gene Cell Nucleus Cell membrane Cells Clinical Crisis Intervention Cues Data Disease Disease remission Disinhibition Dissection Dopamine Educational process of instructing Endocannabinoids Environment Enzymes Ethology Funding GTP-Binding Proteins Genetic Globus Pallidus Harm Reduction In Vitro Infrastructure Knowledge Learning Link Maps Mediating Membrane Messenger RNA Methodology Midbrain structure Motivation Mus Negative Reinforcements Neuromodulator Nucleus Accumbens Organism Outcome Output Pathway interactions Pattern Pharmaceutical Preparations Population Populations at Risk Positive Reinforcements Probability Process Production Punishment Relapse Rewards Role Signal Transduction Site Stimulus Technology Testing Therapeutic Time Training Transgenic Mice Transgenic Model Ventral Tegmental Area Work addiction behavior influence dopaminergic neuron drug craving drug withdrawal endocannabinoid signaling endogenous cannabinoid system expectation experience experimental study insight lipoprotein lipase motivated behavior motivational processes mouse model neural neurobiological mechanism optogenetics pharmacologic postsynaptic receptor receptor expression recruit superior colliculus Corpora quadrigemina theories tool treatment strategy

项目摘要

PROJECT SUMMARY One of the primary functions of the brain is to calculate the most adaptive action for the organism to make under a given set of environmental conditions. This process requires learning which features in the environment predict ethological relevance and subsequently deciding which actions to take, given the probable outcome of those actions. Hence, neural substrates for reward prediction must interact with those controlling behavioral output. The neuromodulator dopamine is a critical component of this interaction. Dopaminergic neurons in the midbrain are excited by rewards not predicted by the current environment. However, when stimuli reliably predict reward, they decrease activity time locked to the reward and shift to the environmental predictors themselves. Therefore, dopamine is thought of as a teaching signal that broadcasts stimuli-related reward predictions. Data from the previous funding cycles showed that endocannabinoids in the ventral tegmentum sculpt cue-induced surges in dopamine release in the nucleus accumbens during reward seeking. We hypothesized, but never unambiguously demonstrated, that this arises from release of the endocannabinoid 2AG from dopamine neurons themselves, which lessens their level of inhibition. This disinhibition mechanism is highly conserved as we found that it occurs during the pursuit of apetitive rewards but also during the avoidance of punishment. However, the precise excitatory input to the ventral tegmentum responsible for the on-demand release of 2AG from dopamine neurons is not known. Here, we propose experiments to further elucidate the role of endocannabinoid signaling in encoding of reward-related cues and its role in motivation. First, we will assess, using genetic dissection approaches, whether 2AG is indeed released from dopamine neurons for their activity to conform to reward prediction theories and whether it can causally influence behavior (aim 1). Next, we will determine which CB1 receptor-expressing afferents to dopamine neurons in the VTA are responsible for the disinhibitory actions of 2AG during cue-driven reward seeking. We will provide further mechanistic insight to these questions by studying the excitatory afferents that give rise to 2AG-dependent dopamine neuron disinhibition during the pursuit of rewards (aim 2). Thus, we will isolate the different components necessary for endocannabinoid signaling to modulate motivational processes using a methodologically-integrated approach, as specific genetic control of 2AG production and CB1 receptor expression will allow explicit tests of current hypotheses of endocannabinoid modulation of motivated behavior. The present proposal makes use of tools not yet applied to these questions to generate new insights on therapeutic strategies for the treatment of motivational disorders such as maladaptive drug seeking.

项目总结

项目成果

期刊论文数量（53）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Contributions of nucleus accumbens dopamine to cognitive flexibility.

DOI：
10.1111/ejn.14152
发表时间：
2019-08
期刊：
The European journal of neuroscience
影响因子：
0
作者：
Radke AK;Kocharian A;Covey DP;Lovinger DM;Cheer JF;Mateo Y;Holmes A
通讯作者：
Holmes A

Olanzapine treatment of adolescent rats alters adult reward behaviour and nucleus accumbens function.

DOI：
10.1017/s1461145712001642
发表时间：
2013-08
期刊：
The international journal of neuropsychopharmacology
影响因子：
0
作者：
Vinish M;Elnabawi A;Milstein JA;Burke JS;Kallevang JK;Turek KC;Lansink CS;Merchenthaler I;Bailey AM;Kolb B;Cheer JF;Frost DO
通讯作者：
Frost DO

Methamphetamine-induced dopamine terminal deficits in the nucleus accumbens are exacerbated by reward-associated cues and attenuated by CB1 receptor antagonism.