Δ-Tetrahydrocannabinol Increases Dopamine D1-D2 Receptor Heteromer and Elicits Phenotypic Reprogramming in Adult Primate Striatal Neurons

• Published in: iScience 2020-01, Vol.23 (1), p.100794-100794, Article 100794
• Main Authors: Hasbi, Ahmed, Madras, Bertha K., Bergman, Jack, Kohut, Stephen, Lin, Zhicheng, Withey, Sarah L., George, Susan R.
• Format: Article
• Language: English
• Subjects: Cellular Neuroscience; Drugs; Neuroscience
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2019.100794

Long-term cannabis users manifest deficits in dopaminergic functions, reflecting Δ9-tetrahydrocannabinol (THC)-induced neuroadaptive dysfunctional dopamine signaling, similar to those observed upon dopamine D1-D2 heteromer activation. The molecular mechanisms remain largely unknown. We show evolutionary and regional differences in D1-D2 heteromer abundance in mammalian striatum. Importantly, chronic THC increased the number of D1-D2 heteromer-expressing neurons, and the number of heteromers within individual neurons in adult monkey striatum. The majority of these neurons displayed a phenotype co-expressing the characteristic markers of both striatonigral and striatopallidal neurons. Furthermore, THC increased D1-D2-linked calcium signaling markers (pCaMKIIα, pThr75-DARPP-32, BDNF/pTrkB) and inhibited cyclic AMP signaling (pThr34-DARPP-32, pERK1/2, pS845-GluA1, pGSK3). Cannabidiol attenuated most but not all of these THC-induced neuroadaptations. Targeted pathway analyses linked these changes to neurological and psychological disorders. These data underline the importance of the D1-D2 receptor heteromer in cannabis use-related disorders, with THC-induced changes likely responsible for the reported adverse effects observed in heavy long-term users. [Display omitted] •Dopamine D1 and D2 receptors form complexes in the striatum of mammalian species•Evolutionary differences in D1-D2 expression: human > primate > rat > mouse•Chronic THC increased D1-D2-expressing neuron numbers in nonhuman primate striatum•Chronic THC altered primate striatal neuron phenotype and signaling reversed by CBD Drugs; Neuroscience; Cellular Neuroscience