Δ9-Tetrahydrocannabinol does not upregulate an aversive dopamine receptor mechanism in adolescent brain unlike in adults.
Marie-Eve Di Raddo, Marija Milenkovic, Meenalochani Sivasubramanian, Ahmed Hasbi, Jack Bergman, Sarah L Withey, Bertha K. Madras, Susan R George
Current Research in Neurobiology 2023 DOI: 10.1016/j.crneur.2023.100107 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Adolescent monkeys and adolescent or adult rats |
| Interventions | THC Cannabidiol |
| Topics | Addiction Cannabis |
| Keywords | Adolescent Dopamine Δ9-tetrahydrocannabinol |
| Key findings | Repeated THC upregulated striatal dopamine D1-D2 receptor heteromers and produced anxiety- and anhedonia-like behavior in adult rats but not adolescent rats or monkeys, whose heteromer levels remained unchanged. The authors propose an age-specific anxiogenic, anti-reward mechanism that is operant in adult striatum but deficient in adolescent striatum, potentially increasing adolescent sensitivity to THC reward and vulnerability to continued use. |
Abstract
Earlier age of cannabis usage poses higher risk of Cannabis Use Disorder and adverse consequences, such as addiction, anxiety, dysphoria, psychosis, largely attributed to its principal psychoactive component, Δ9-tetrahydrocannabinol (THC) and altered dopaminergic function. As dopamine D1-D2 receptor heteromer activation causes anxiety and anhedonia, this signaling complex was postulated to contribute to THC-induced affective symptoms. To investigate this, we administered THC repeatedly to adolescent monkeys and adolescent or adult rats. Drug-naïve adolescent rat had lower striatal densities of D1-D2 heteromer compared to adult rat. Repeated administration of THC to adolescent rat or adolescent monkey did not alter D1-D2 heteromer expression in nucleus accumbens or dorsal striatum but upregulated it in adult rat. Behaviourally, THC-treated adult, but not adolescent rat manifested anxiety and anhedonia-like behaviour, with elevated composite negative emotionality scores that correlated with striatal D1-D2 density. THC modified downstream markers of D1-D2 activation in adult, but not adolescent striatum. THC administered with cannabidiol did not alter D1-D2 expression. In adult rat, co-administration of CB1 receptor (CB1R) inverse agonist with THC attenuated D1-D2 upregulation, implicating cannabinoids in the regulation of striatal D1-D2 heteromer expression. THC exposure revealed an adaptable age-specific, anxiogenic, anti-reward mechanism operant in adult striatum but deficient in adolescent rat and monkey striatum that may confer increased sensitivity to THC reward in adolescence while limiting its negative effects, thus promoting continued use and increasing vulnerability to long-term adverse cannabis effects.
Comparable studies
Other preclinical and animal studies on cannabis for addiction, most cited first.
Citations in the library
Cited by 3
- Which Came First? Utility of Preclinical Models in Cracking the Chicken-or-Egg Relationship between Cannabis Use and Schizophrenia Current Addiction Reports February 27, 2026
- Age-Related Effects of Cannabis and Cannabinoids on Brain and Behavior. Cannabis and Cannabinoid Research April 2026
- Astrogliosis Occurs Selectively in Amygdala of Adolescent Primate and Rodent Following Daily Δ9-Tetrahydrocannabinol, Prevented by Cannabidiol Co-Treatment. Biological Psychiatry Global Open Science July 1, 2025
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and 13 more in the library