Δ9-Tetrahydrocannabinol does not upregulate an aversive dopamine receptor mechanism in adolescent brain unlike in adults.

Content Provider	Europe PMC
Author	Di Raddo, Marie-Eve Milenkovic, Marija Sivasubramanian, Meenalochani Hasbi, Ahmed Bergman, Jack Withey, Sarah Madras, Bertha K. George, Susan R.
Copyright Year	2023
Description	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. Highlights • Dopamine D1-D2 heteromer striatal expression increases with adolescent maturation. • Chronic THC upregulates D1-D2 heteromer in adult but not adolescent rat or monkey. • D1-D2 heteromer downstream signaling is activated by THC only in adult NAc. • THC-induced negative emotionality in adult rat correlates to striatal D1-D2 expression. • D1-D2 heteromer upregulation by THC is CB1R-dependent.
Related Links	https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC10663137&blobtype=pdf
Volume Number	5
DOI	10.1016/j.crneur.2023.100107
PubMed Central reference number	PMC10663137
PubMed reference number	38020805
Journal	Current Research in Neurobiology [Curr Res Neurobiol]
e-ISSN	2665945X
Language	English
Publisher	Elsevier
Publisher Date	2023-09-04
Access Restriction	Open
Rights License	This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). © 2023 Published by Elsevier B.V.
Subject Keyword	Dopamine Adolescent Cannabis Δ9-Tetrahydrocannabinol Addiction
Content Type	Text
Resource Type	Article
Subject	Bioengineering