Gene network of dopamine receptor type 2 (Drd2) in addiction

Authors

• L Guerri
• L Dobbs
• A Meyers
• A Badillo Martinez
• V Alvarez
• D Goldman

Abstract

Low availability of type-2 dopamine receptors (D2Rs) in the striatum has been observed in a wide range of conditions associated with impaired decision-making, such as addiction, obesity and ADHD. Two neuronal populations account for most of D2R expression in the striatum: Medium Spiny Neurons of the “indirect pathway” (iMSNs) and the projections (auto-receptors) of dopamine neurons from VTA. However, neither the causes, the functional consequences nor the cellular component of this downregulation are well understood. To study the downstream effects of D2R gene (Drd2) downregulation and its gene network, we purify the whole transcriptome of iMSNs in male and female mice with either WT (wt) or low (het) level of Drd2 expression. This is achieved by conditionally driving both the expression of the Translating Ribosome Affinity Purification (TRAP) system and a floxed Drd2, in iMSNs. RNAseq analysis of a subset of samples shows a strong enrichment of known iMSN markers in the TRAP positive fraction and corresponding depletion in the negative fraction. Further, the TRAP negative fraction shows enrichment of transcripts characteristic of other striatal neurons and glial cells, allowing for their study in parallel. Preliminary analysis of positive fractions in Drd2 wt and het shows the differential expression of interesting genes related to neurotransmitter regulation and signaling molecules among others. Comparison of the four groups: Drd2 wt and het in males and females, will allow us to identify the gene network that is affected by Drd2 downregulation in addiction. These groups will be further studied in the context of cocaine exposure and self-administration paradigm. A full set of samples from untreated mice are currently being sequenced. The results for the complete analysis will be delivered at poster presentation.

Scientific Focus Area: Neuroscience

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