# Long Term THC Elicits Distinct Changes in Adolescent Brain Dopamine Signaling

> **NIH NIH R01** · MCLEAN HOSPITAL · 2020 · $561,653

## Abstract

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.

## Key facts

- **NIH application ID:** 9979805
- **Project number:** 5R01DA042178-04
- **Recipient organization:** MCLEAN HOSPITAL
- **Principal Investigator:** Bertha K Madras
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $561,653
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979805

## Citation

> US National Institutes of Health, RePORTER application 9979805, Long Term THC Elicits Distinct Changes in Adolescent Brain Dopamine Signaling (5R01DA042178-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9979805. Licensed CC0.

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