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的认知和行为障碍。 精神症状。女性更容易受到大麻引起的焦虑。在动物中， 人类，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新的机制， 青少年和女性对大麻的反应。(1)我们发现多巴胺D1-D2受体 在初步研究中，丘脑核中的异聚体复合物引起焦虑或奖励 影响，取决于其功能活动：（a）青少年丘脑核（NAc）表达较低， D1-D2异聚体的密度，以及其双分子缔合的破坏， 青少年比成年人。(b)D1-D2异聚体密度在女性NAc中较高，激活促进 雌性大鼠的焦虑效应高于雄性大鼠。这种新发现的独特分子 实体链接到奖励或焦虑的影响，提供了令人兴奋的线索，调查的相关性， D1-D2异聚体对THC诱导的青少年或女性行为的影响。(2)我们发现， 对青春期大鼠给予THC，随后在其成熟期增加了dcc基因的表达。 前额皮质与精神分裂症有关，DCC蛋白指导前额叶皮层的发育 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- D1-D2异聚体的性别依赖性表达以及是否反映了异聚体活性的调节 奖励或厌恶的行为。目的2将测量THC对D1-D2异聚体表达的影响， 行为，对行为的合理下游介质，作为年龄和性别的函数，以及是否 D1-D2异聚体活性的调节影响THC诱导的行为。目标3将操纵D1-D2 NAc中表达异聚体的神经元和THC诱导行为的后果。目标4将 确定THC是否改变青少年灵长类前额叶皮层和多巴胺前额叶皮层中DCC的表达 皮层回路THC的这些新的生物底物将产生对提高THC（或 大麻）奖励在青少年，或增加焦虑的女性，和一个可能的机制， 青少年吸食大麻会增加精神病和认知障碍的风险。可以想象，小说 药物开发的靶点可能来自这些新鉴定的生物底物。

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.