Long Term THC Elicits Distinct Changes in Adolescent Brain Dopamine Signaling

长期使用 THC 会引起青少年大脑多巴胺信号的明显变化

基本信息

批准号：
10222631
负责人：
Bertha K Madras
金额：
$ 55.54万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10222631
关键词：
Acute Adolescence Adolescent Adolescent Behavior Adolescent marijuana use Adult Adverse effects Affect Age Agonist Animals Anxiety Attenuated Behavior Behavioral Biological Biological Assay Brain Brain region Cognition Complex Corpus striatum structure DCC gene Development Dopamine Dopamine D2 Receptor Dopamine Receptor Dynorphins Euphoria Female Fluorescence Resonance Energy Transfer Future Gene Expression High Prevalence Human Hypersensitivity Impaired cognition In Situ Laboratories Link Marijuana Measures Mediator of activation protein Mental Depression Methods Microscopy Molecular Monkeys Neurobehavioral Manifestations Neurons Nucleus Accumbens Pathway interactions Peptides Pharmaceutical Preparations Pharmacology Pilot Projects Population Predisposition Prefrontal Cortex Primates Proteins Psychoses Psychotropic Drugs Rattus Regulation Relaxation Research Resolution Rewards Risk Rodent Schizophrenia Sex Differences Signal Transduction Substance Use Disorder THC exposure Testing Three-Dimensional Imaging addiction age difference behavioral response cohort density designer receptors exclusively activated by designer drugs dopamine D5 receptor dopamine transporter gender difference hedonic in vitro testing insight male marijuana use marijuana use disorder marijuana user new technology novel preference protein expression psychiatric symptom response sex vulnerable adolescent

项目摘要

Adolescents are more susceptible to developing a marijuana use disorder and adverse cognitive and psychiatric symptoms. Females are more vulnerable to marijuana-induced anxiety. In animals as in humans, THC (the main psychoactive constituent of marijuana) can elicit both positive (reward) and negative effects (anxiety). Our research has revealed two novel mechanisms that conceivably contribute to adolescent and female responses to marijuana. (1) We discovered a dopamine D1-D2 receptor heteromer complex in nucleus accumbens which in pilot studies, engenders anxiogenic or rewarding effects, depending on its functional activity: (a) Adolescent nucleus accumbens (NAc) expressed lower density of the D1-D2 heteromer, and disruption of its bimolecular association enhanced reward more in adolescents than adults. (b) D1-D2 heteromer density was higher in female NAc and activation promoted higher anxiogenic effects in female rather than male rats. This novel discovery of a unique molecular entity linked to rewarding or anxiogenic effects, provides exciting leads to investigate the relevance of D1-D2 heteromer to THC-induced behavior in adolescents or females. (2) We discovered that repeated THC administration to adolescent rats increased dcc gene expression subsequently in their mature prefrontal cortex. Implicated in schizophrenia, DCC protein guides the development of prefrontal cortical dopamine circuitry, specifically during adolescence. To pursue these leads: Aim 1 will quantify age- and sex-dependent expression of D1-D2 heteromer and whether modulation of heteromer activity is reflected in rewarding or aversive behaviors. Aim 2 will measure THC effects on D1-D2 heteromer expression, on behaviors, on plausible downstream mediators of behaviors, as a function of age and sex, and whether modulation of D1-D2 heteromer activity affects THC-induced behaviors. Aim 3 will manipulate D1-D2 heteromer expressing neurons in NAc and consequences to THC-induced behaviors. Aim 4 will determine if THC alters DCC expression in adolescent primate prefrontal cortex and dopamine prefrontal cortex circuitry. These novel biological substrates of THC will yield insights into heightened THC (or marijuana) reward in adolescents, or increased anxiety in females, and a possible mechanism by which adolescent marijuana use can elevate the risk for psychosis and cognitive impairment. Conceivably, novel targets for medications development may emerge from these newly identified biological substrates.

青少年更容易患有大麻使用障碍和不利的认知和精神病症状。女性更容易受到大麻引起的焦虑的影响。在动物中人类，THC（大麻的主要精神活性成分）可以引起积极（奖励）和负面影响（焦虑）。我们的研究揭示了两个新的机制，可以想象对青少年和女性对大麻的反应。（1）我们发现了多巴胺D1-D2受体伏隔核中的异构体复合物，在试点研究中，引起焦虑或奖励效果，取决于其功能活性：（a）伏隔核（NAC）表达较低 D1-D2异构体的密度以及其双重分子关联的破坏增强了奖励青少年比成年人。（b）雌性NAC中D1-D2异构体密度较高，激活促进了女性而不是雄性大鼠的焦虑作用较高。这本小说发现了独特的分子与奖励或焦虑作用相关的实体，为研究的相关性提供了令人兴奋的潜在客户 D1-D2异构体与青少年或女性的THC诱导的行为。（2）我们发现重复对青少年大鼠的THC给药随后在其成熟中增加了DCC基因表达前额叶皮层。 DCC蛋白与精神分裂症有关，指导前额叶皮质的发展多巴胺电路，特别是在青春期。追求这些线索：AIM 1将量化年龄和年龄 D1-D2异构体的性别依赖性表达以及是否反映异构体活性的调节在奖励或厌恶行为方面。 AIM 2将测量THC对D1-D2异构体表达的影响，对行为，在行为的合理下游调解人上，作为年龄和性别的函数，以及是否是否 D1-D2异构体活性的调节会影响THC诱导的行为。 AIM 3将操纵D1-D2 在NAC中表达神经元的异构体以及对THC诱导的行为的后果。目标4意志确定THC在青少年灵长类动物前额叶皮层和多巴胺前额叶中是否改变了DCC的表达皮层电路。这些新型THC的新生物底物将产生对THC增强的见解（或大麻）在青少年中的奖励或女性焦虑的增加，以及一种可能的机制青春期使用可以提高精神病和认知障碍的风险。可以想象，新颖药物开发的靶标可能会从这些新确定的生物底物中出现。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Endocannabinoid System and Exogenous Cannabinoids in Depression and Anxiety: A Review.

DOI：
10.3390/brainsci13020325
发表时间：
2023-02-14
期刊：
BRAIN SCIENCES
影响因子：
3.3
作者：
Hasbi, Ahmed;Madras, Bertha K. K.;George, Susan R. R.
通讯作者：
George, Susan R. R.

Sex Differences in Dopamine Receptors and Relevance to Neuropsychiatric Disorders.

DOI：
10.3390/brainsci11091199
发表时间：
2021-09-11
期刊：
Brain sciences
影响因子：
3.3
作者：
Williams OOF;Coppolino M;George SR;Perreault ML
通讯作者：
Perreault ML

Tinkering with THC-to-CBD ratios in Marijuana.

调整大麻中 THC 与 CBD 的比例。

DOI：
10.1038/s41386-018-0217-3
发表时间：
2019
期刊：
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
影响因子：
0
作者：
Madras,BerthaK
通讯作者：
Madras,BerthaK

Psychiatry and the Opioid Overdose Crisis.

DOI：
10.1176/appi.focus.20190003
发表时间：
2019-04-01
期刊：
Focus (American Psychiatric Publishing)
影响因子：
0
作者：
Madras, Bertha K;Connery, Hilary
通讯作者：
Connery, Hilary

Δ9-Tetrahydrocannabinol does not upregulate an aversive dopamine receptor mechanism in adolescent brain unlike in adults.

DOI：
10.1016/j.crneur.2023.100107
发表时间：
2023
期刊：
Current research in neurobiology
影响因子：
0
作者：
Di Raddo, Marie-Eve;Milenkovic, Marija;Sivasubramanian, Meenalochani;Hasbi, Ahmed;Bergman, Jack;Withey, Sarah;Madras, Bertha K;George, Susan R
通讯作者：
George, Susan R