Decreased striatal D2/3 receptors in HIV-1 transgenic rat seen with [18F]Fallypride-PET

Objectives HIV-Associated Neurocognitive Disorders encompass a spectrum of behavioral and cognitive deficits that occur long after the HIV virus gains entry into the brain. The dopaminergic system seems to be particularly sensitive to HIV associated damage. To investigate the selectivity of the dopaminergic neurons to HIV, we quantified dopamine D2/3 receptors in the transgenic HIV+ rat (Tg) using [18F]Fallypride PET. We corroborated our results with behavioral measures and with immunohistochemistry staining for tyrosine hydroxylase expression.

Methods Young Tg (n=6) and control rats (n=7) as well as adult Tg (n=5) and control rats (n=5) were imaged after the administration of [18F]fallypride (mean= 1.2 mCi/scan). Dynamic images were reconstructed using OSEM-2D algorithm. Regional [18F]Fallypride uptake was quantified as binding potential (BPND) using the 2T Reference Model with cerebellum as reference. Time activity curves were generated for volumes of interest (VOI) in the ventral striatum (VS), dorsal striatum (DS), thalamus (Th), and cerebellum.

Results In the adult rats, BPND values were significantly decreased in the VS (p<0.001) and DS (p=0.001), but not in the Th. In the young rats, BPND values were significantly decreased only in the DS (p<0.05) but not in the VS or Th. Tg rats performed worse than controls on the rotarod test. The expression level of tyrosine hydroxylase was lower in the Tg rat brain sections compared to controls.

Conclusions We found striatal but not extrastriatal D2/3 receptor deficits in the Tg rat, more prominent in older animals, suggesting progressive damage. This was supported by dopamine-associated motor deficits and reduction of striatal tyrosine hydroxylase expression. We propose using the combination of the Tg rat and [18F]fallypride PET in the preclinical evaluation of novel neuroprotective therapies in HIV.

Research Support This work was supported by the Center of Infectious Diseases Imaging, National Institutes of Health (Intramural Program).