Long Term THC Elicits Distinct Changes in Adolescent Brain Dopamine Signaling

青少年更容易患上大麻使用障碍和不良认知障碍 精神症状。女性更容易受到大麻引起的焦虑的影响。在动物中，如在 人类的THC(大麻的主要精神活性成分)可以引起积极的(奖励)和 负面影响(焦虑)。我们的研究揭示了两种可以想见的新机制 青少年和女性对大麻的反应。(1)我们发现了一种多巴胺D1-D2受体 伏隔核中的异构体复合体，在初步研究中，它会产生焦虑或奖励 影响，取决于其功能活性：(A)青少年伏核(NAC)表达较低 D_1-D_2异构体的密度和它的双分子缔合的破坏在更多的情况下增加了奖励 青少年多于成年人。(2)雌性NAC的D1D2异构体密度较高，激活程度较高 雌性大鼠比雄性大鼠具有更高的焦虑效应。这一独特分子的新发现 与奖励或焦虑效应有关的实体，提供了令人兴奋的线索来调查 D1-D2异构体对青少年或女性的THC诱导行为。(2)我们发现重复的 成年大鼠给药后DCC基因表达增强 前额叶皮质。与精神分裂症有关的DCC蛋白引导前额叶皮质的发育 多巴胺回路，特别是在青春期。为了追踪这些线索：目标1将量化年龄--以及 D_1-D_2异构体的性别依赖性表达及其是否反映了异构体活性的调节 在奖励或厌恶的行为中。AIM 2将测量THC对d1-d2异构体表达的影响 行为，基于行为的合理下游中介，作为年龄和性别的函数，以及是否 D1-D2异构体活性的调节会影响THC的诱导行为。目标3将操纵d1-d2 NAC内异构体表达神经元及其对THC诱导行为的影响。目标4将 确定THC是否改变青少年灵长类前额叶皮质和多巴胺前额叶DCC的表达 大脑皮层回路。这些新的THC生物底物将对提高THC(或 大麻)对青少年的奖励，或增加女性的焦虑，以及一种可能的机制，通过 青少年使用大麻会增加患精神病和认知障碍的风险。可想而知，新奇 药物开发的靶点可能来自这些新发现的生物底物。

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.