Δ-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 D 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 (pCaM-KIIa, 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 userelated disorders, with THC-induced changes likely responsible for the reported adverse effects observed in heavy long-term users. INTRODUCTION Cannabis is the most widely consumed illicit substance globally, with use reaching more than 180 million people aged 15-64 years (United Nations Office on Drugs and Crimes, World Drug Report, 2013). In North America, the prevalence of cannabis use is higher than the global average, as the movement to medicalize, legalize, and normalize its use continues unabated in the United States and Canada. A number of deleterious effects linked to the use of cannabis have been described, with consequences related to early age of initiation, frequency, and duration of use (

NOX1/NADPH Oxidase Promotes Synaptic Facilitation Induced by Repeated D2Receptor Stimulation: Involvement in Behavioral Repetition

“…Our observation of CS-specific upregulation of Nox1 mRNA induced by repeated D 2 receptor stimulation suggested a heterogeneous response to D 2 receptor stimulation between striatal subregions. In support of this, various regional differences in the striatum have been reported, including gene expression patterns (Puighermanal et al, 2020), the proportion of iMSNs (Gangarossa et al, 2013), and distribution of heteromeric D 2 receptors (A 2A -D 2 receptor: He et al, 2016; D 1 -D 2 receptor: Hasbi et al, 2020). Additionally, recent evidence indicates the difference in D 2 receptor signaling in iMSNs between dorsal and ventral striatum (Marcott et al, 2018).…”

Differential receptor crosstalk in DRD1-DRD2 heterodimer upon phasic and tonic dopamine signals

“…It has been difficult to directly monitor the status of receptor activation, thus the activation patterns of DRD1, DRD2, and DRD1-DRD2 heterodimer at tonic and phasic dopamine signals can be only suspected by measuring their downstream signaling pathways (16,(54)(55)(56). As we developed multicolor dopamine receptor sensors, R-DRD1 and G-DRD2, which can specifically report the activation status of DRD1 and DRD2, the functional crosstalk in the DRD1-DRD2 heterodimer can be directly measured for the first time (Fig.…”

“…Recent studies proposed that drug addiction can be also related to the DRD1-DRD2 heterodimer (14,56,59,60). Comparing to the control group, cocaine addicted patients showed a significant increased population of the DRD1-DRD2 heterodimer in the striatum (60).…”

Dopamine Receptors: Is It Possible to Become a Therapeutic Target for Depression?

“…In rodents, more than 95% of the cells in NAc are MSNs, which receive excitatory input from four major brain regions, namely the PFC, hippocampus, basolateral amygdala, and the thalamus ( Sesack and Grace, 2010 ). Morphological evidence suggests that DA D1 and D2 receptors form complexes in the dorsal striatum and NAc of mammalian species (including mice, rats, non-human primates, and humans), and in all of these species, a higher number of MSNs expressing the D1-D2 heteromers was observed in the NAc than in the dorsal striatum (caudate and putamen) ( Hasbi et al, 2020a ).…”