Abstract
The dopaminergic system is especially vulnerable to the effects of human immunodeficiency virus (HIV) infection, rendering dopaminergic deficits early surrogate markers of HIV-associated neuropathology. We quantified dopamine D2/3 receptors in young HIV-1 transgenic (Tg) (n = 6) and age-matched control rats (n = 7) and adult Tg (n = 5) and age-matched control rats (n = 5) using [18F]fallypride positron emission tomography (PET). Regional uptake was quantified as binding potential (BPND) using the two-tissue reference model with the cerebellum as the reference. Time-activity curves were generated for the ventral striatum, dorsal striatum, thalamus, and cerebellum. Whereas BPND values were significantly lower in the ventral striatum (p < .001) and dorsal striatum (p = .001) in the adult Tg rats compared to controls rats, they were significantly lower only in the dorsal striatum (p < .05) in the young rats. Tg rats had smaller striatal volumes on magnetic resonance imaging. We also found lower expression levels of tyrosine hydroxylase on immunohistochemistry in the Tg animals. Our findings suggest that progressive striatal D2/3 receptor deficits occur in Tg rats as they age and can be detected using small-animal PET imaging. The effectiveness of various approaches in preventing or halting this dopaminergic loss in the Tg rat can thus be measured preclinically using [18F]fallypride PET as a molecular imaging biomarker of HIV-associated neuropathology.
Highlights
The dopaminergic system is especially vulnerable to the effects of human immunodeficiency virus (HIV) infection, rendering dopaminergic deficits early surrogate markers of HIV-associated neuropathology
We evaluated the dopaminergic system in the Tg rat using in vivo positron emission tomography (PET) and [18F]fallypride, a fluorinated dopamine D2/3 receptor high-affinity antagonist
The staining appeared to be diffusely decreased in the Tg rats in comparison with age-matched controls in one of three young, one of three adult, and one of two older Tg animals, whereas it appeared to be more focally decreased in the rest of the Tg animals compared to their agematched controls
Summary
The young animal group consisted of six male Tg rats (3.0 6 0.4 months; 265 6 29 g) and seven male age-matched Fischer F344 control rats (3.0 6 0.2 months; 283 6 26 g). A series of sagittal T2-weighted MRIs were initially obtained in the center of the brain to allow for consistent positioning of the coronal T2-weighted images with respect to the genu of the corpus callosum. SV measurements were based on three slices from the coronal T2 experiment, positioned at approximately bregma 20.6 through 1.44 determined by comparing the coregistered T2 images to the Paxinos and Watson rat brain atlas.[16]. To prepare brain tissues for staining, rats were first anesthetized with isoflurane (3% with 700 cc/min O2) This was followed by transcardial perfusion using 100 mL of normal saline (pH 7.4) and 350 mL of freshly prepared and filtered (0.45 micron filter) 4% paraformaldehyde (pH 7.4).
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