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.