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

Ahmed Hasbi; Bertha K Madras; Jack Bergman; Stephen Kohut; Zhicheng Lin; Sarah L Withey; Susan R George

doi:10.1016/j.isci.2019.100794

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

iScience. 2020 Jan 24;23(1):100794. doi: 10.1016/j.isci.2019.100794. Epub 2019 Dec 24.

Authors

Ahmed Hasbi¹, Bertha K Madras², Jack Bergman², Stephen Kohut², Zhicheng Lin², Sarah L Withey², Susan R George³

Affiliations

¹ Department of Pharmacology, University of Toronto, Toronto, ON, Canada.
² Department of Psychiatry, Harvard Medical School, Boston, MA, USA; McLean Hospital, Belmont, USA.
³ Department of Pharmacology, University of Toronto, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada. Electronic address: s.george@utoronto.ca.

Abstract

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.

Keywords: Cellular Neuroscience; Drugs; Neuroscience.

Grants and funding

R01 DA042178/DA/NIDA NIH HHS/United States