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

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 Ca homeostasis of NAcc neurons.

RESULTS

We provide evidence that Tat triggers a Ca 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 (IP) receptor-mediated Ca release from endoplasmic reticulum, followed by Ca and Na influx via transient receptor potential canonical channels. The influx of cations depolarizes the membrane promoting additional Ca entry through voltage-gated P/Q-type Ca 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 IP-generating mechanisms are concomitantly initiated. When tested here, cocaine produced a dose-dependent potentiation of the effect of Tat on cytosolic Ca.

CONCLUSION

We describe for the first time a HIV-1 Tat-triggered Ca 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.