HIV Tat excites D1 receptor-like expressing neurons from rat nucleus accumbens

Drug Alcohol Depend. 2017 Sep 1;178:7-14. doi: 10.1016/j.drugalcdep.2017.04.015. Epub 2017 Jun 8.


Background: HIV-1 infection and drug abuse are frequently co-morbid and their association greatly increases the severity of HIV-1-induced neuropathology. While nucleus accumbens (NAcc) function is severely perturbed by drugs of abuse, little is known about how HIV-1 infection affects NAcc.

Methods: We used calcium and voltage imaging to investigate the effect of HIV-1 trans-activator of transcription (Tat) on rat NAcc. Based on previous neuronal studies, we hypothesized that Tat modulates intracellular Ca2+ homeostasis of NAcc neurons.

Results: We provide evidence that Tat triggers a Ca2+ signaling cascade in NAcc medium spiny neurons (MSN) expressing D1-like dopamine receptors leading to neuronal depolarization. Firstly, Tat induced inositol 1,4,5-trisphsophate (IP3) receptor-mediated Ca2+ release from endoplasmic reticulum, followed by Ca2+ and Na+ influx via transient receptor potential canonical channels. The influx of cations depolarizes the membrane promoting additional Ca2+ entry through voltage-gated P/Q-type Ca2+ channels and opening of tetrodotoxin-sensitive Na+ channels. By activating this mechanism, Tat elicits a feed-forward depolarization increasing the excitability of D1-phosphatidylinositol-linked NAcc MSN. We previously found that cocaine targets NAcc neurons directly (independent of the inhibition of dopamine transporter) only when IP3-generating mechanisms are concomitantly initiated. When tested here, cocaine produced a dose-dependent potentiation of the effect of Tat on cytosolic Ca2+.

Conclusion: We describe for the first time a HIV-1 Tat-triggered Ca2+ signaling in MSN of NAcc involving TRPC and depolarization and a potentiation of the effect of Tat by cocaine, which may be relevant for the reward axis in cocaine-abusing HIV-1-positive patients.

Keywords: Calcium imaging; Calcium influx; Depolarization; Intracellular calcium mobilization; Medium spiny neurons; TRPC.

MeSH terms

  • Animals
  • Calcium / metabolism
  • Cells, Cultured
  • Cocaine / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Female
  • Male
  • Neurons / metabolism
  • Neurons / physiology*
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / physiology*
  • Rats
  • Receptors, Dopamine D1 / metabolism*
  • Signal Transduction / physiology
  • Sodium / metabolism
  • tat Gene Products, Human Immunodeficiency Virus / pharmacology
  • tat Gene Products, Human Immunodeficiency Virus / physiology*


  • Receptors, Dopamine D1
  • tat Gene Products, Human Immunodeficiency Virus
  • Sodium
  • Cocaine
  • Calcium