Abstract
The striatum is especially vulnerable to HIV-1 infection, with medium spiny neurons (MSNs) exhibiting marked synaptodendritic damage that can be exacerbated by opioid use disorder. Despite known structural defects in MSNs co-exposed to HIV-1 Tat and opioids, the pathophysiological sequelae of sustained HIV-1 exposure and acute comorbid effects of opioids on dopamine D1 and D2 receptor-expressing (D1 and D2) MSNs are unknown. To address this question, Drd1-tdTomato- or Drd2-eGFP-expressing reporter and conditional HIV-1 Tat transgenic mice were interbred. MSNs in ex vivo slices from male mice were assessed by whole-cell patch-clamp electrophysiology and filled with biocytin to explore the functional and structural effects of progressive Tat and acute morphine exposure. Although the excitability of both D1 and D2 MSNs increased following 48 h of Tat exposure, D1 MSN firing rates decreased below control (Tat−) levels following 2 weeks and 1 month of Tat exposure but returned to control levels after 2 months. D2 neurons continued to display Tat-dependent increases in excitability at 2 weeks, but also returned to control levels following 1 and 2 months of Tat induction. Acute morphine exposure increased D1 MSN excitability irrespective of the duration of Tat exposure, while D2 MSNs were variably affected. That D1 and D2 MSN excitability would return to control levels was unexpected since both subpopulations displayed significant synaptodendritic degeneration and pathologic phospho-tau-Thr205 accumulation following 2 months of Tat induction. Thus, despite frank morphologic damage, D1 and D2 MSNs uniquely adapt to sustained Tat and acute morphine insults.
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This work was supported by Grant Nos. R01 DA045588 (KFH), R01 MH107507 (ARM), R01 DA034231 (PEK & KFH), K02 DA027374 (KFH), and F32 DA053163 (SRN) from the National Institutes of Health, and the pilot grant project for the P30 Center Grant on Drug Abuse Research (VY) funded via the NIH NIDA P30 grant P30 DA033934 (PI: Dr. W.L. Dewey).
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ARSL, LKS, KFH, PEK: Conceived and designed the study. ARM, WDM: Developed physiological methodology and stimulus paradigms. ARSL, LKS, SRN, MGM, MO, TMI: Performed the experiments and data acquisition. ARSL, LKS, MGM, MO, VY: Participated in the analysis, and interpretation. ARSL, SRN, MGM, MO and KFH: Wrote original manuscript. KFH, PEK, ARM, SRN: Provided funding support. All authors participated in proofing, revising, and approving of the final version of the manuscript.
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Lark, A.R.S., Silva, L.K., Nass, S.R. et al. Progressive Degeneration and Adaptive Excitability in Dopamine D1 and D2 Receptor-Expressing Striatal Neurons Exposed to HIV-1 Tat and Morphine. Cell Mol Neurobiol 43, 1105–1127 (2023). https://doi.org/10.1007/s10571-022-01232-5
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DOI: https://doi.org/10.1007/s10571-022-01232-5