Dataset Information

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

ABSTRACT: Long-term cannabis users manifest deficits in dopaminergic functions, reflecting ?⁹-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 (pCaMKII?, 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.

SUBMITTER: Hasbi A

PROVIDER: S-EPMC6971351 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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

Hasbi Ahmed A Madras Bertha K BK Bergman Jack J Kohut Stephen S Lin Zhicheng Z Withey Sarah L SL George Susan R SR

iScience 20191224 1

Long-term cannabis users manifest deficits in dopaminergic functions, reflecting Δ<sup>9</sup>-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 hete ...[more]

PMID: 31972514

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Project description:Many neurological disorders and diseases including drug addiction are associated with specific neuronal cell types in the brain. The striatum, a region that plays a critically important role in the development of addictive drug-related behavior, provides a good example of the cellular heterogeneity challenges associated with analyses of specific neuronal cell types. Such studies are needed to identify the adaptive changes in neuroproteomic signaling that occur in response to diseases such as addiction. The striatum contains two major cell types, D1 and D2 type dopaminoceptive medium spiny neurons (MSNs), whose cell bodies and processes are intermingled throughout this region. Since little is known about the proteomes of these two neuronal cell populations, we have begun to address this challenge by using fluorescence-activated nuclear sorting (FANS) to isolate nuclei-containing fractions from striatum from D1 and D2 "Translating Ribosome Affinity Purification" (TRAP) mice. This approach enabled us to devise and implement a robust and reproducible workflow for preparing samples from specific MSN cell types for mass spectrometry analyses. These analyses quantified at least 685 proteins in each of four biological replicates of 50 K sorted nuclei from two D1 mice/replicate and from each of four biological replicates of 50 K sorted nuclei from two D2 mice/replicate. Proteome analyses identified 87 proteins that were differentially expressed in D1 versus D2 MSN nuclei and principal component analysis (PCA) of these proteins separated the 8 biological replicates into specific cell types. Central network analysis of the 87 differentially expressed proteins identified Hnrnpd and Hnmpa2b1 in D1 and Cct2 and Cct7 in D2 as potential central interactors. This workflow can now be used to improve our understanding of many neurological diseases including characterizing the short and long-term impact of drugs of abuse on the proteomes of these two dopaminoceptive neuronal populations.

Project description:BackgroundDopamine receptors interact with other receptors to form heterooligomers. One such complex, the D1-D2 heteromer, demonstrated in cultured striatal neurons and rat striatum has been linked to drug addiction, Parkinson's disease, schizophrenia, depression and anhedonia.MethodsD1-D2 heteromer expression was evaluated using in situ proximity ligation assay, in parallel with cellular colocalization of D1 and D2 mRNA using in situ hybridization in 19 different key rat brain regions. Expression in higher species and changes in rat striatum after repeated cocaine administration were evaluated.ResultsDifferences in D1-D2 heteromer expression in striatal subregions are documented in higher species with nonhuman primate and human demonstrating higher density of heteromer-expressing neurons compared to rodents. All species had higher density of D1-D2 neurons in nucleus accumbens compared to dorsal striatum. Multiple other brain regions are identified where D1-D2 heteromer is expressed, prominently in cerebral cortical subregions including piriform, medial prefrontal, orbitofrontal and others; subcortical regions such as claustrum, amygdala and lateral habenula. Three categories of regions are identified: D1-D2 heteromer expressed despite little to no observed D1/D2 mRNA colocalization, likely representing heteromer on neuronal projections from other brain regions; D1-D2 heteromer originating locally with the density of neurons expressing heteromer matching neurons with colocalized D1/D2 mRNA; regions with both a local origin and targeted inputs projecting from other regions. Repeated cocaine administration significantly increased density of neurons expressing D1-D2 heteromer and D1/D2 mRNA colocalization in rat striatum, with changes in both direct and indirect pathway neurons.ConclusionThe dopamine D1-D2 heteromer is expressed in key brain cortical and subcortical regions of all species examined. Species differences in striatum revealed greater abundance in human>nonhuman-primate>rat>mouse, suggesting an evolutionary biologic role for the D1-D2 heteromer in higher CNS function. Its upregulation in rat striatum following cocaine points to regulatory significance with possible relevance for clinical disorders such as drug addiction. The dopamine D1-D2 receptor heteromer may represent a potential target for neuropsychiatric and neurodegenerative disorders, given its distribution in highly relevant brain regions.

Dataset Information

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

Publications

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

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