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

Abstract

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.