title: Imaging dopaminergic dysfunction as a surrogate marker of neuropathology in a small-animal model of HIV.
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.
authors.forename: Dianne E
authors.initials: DE
authors.lastname: Lee
authors.forename: William C
authors.initials: WC
authors.lastname: Reid
authors.forename: Wael G
authors.initials: WG
authors.lastname: Ibrahim
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Peterson
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Lentz
authors.forename: Dragan
authors.initials: D
authors.lastname: Maric
authors.forename: Peter L
authors.initials: PL
authors.lastname: Choyke
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Jagoda
authors.forename: Dima A
authors.initials: DA
authors.lastname: Hammoud
mesh_terms: D000818:Animals; D001549:Benzamides / Q000493:pharmacokinetics*; D015415:Biomarkers / Q000032:analysis; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D004195:Disease Models, Animal; D015658:HIV Infections / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D049268:Positron-Emission Tomography / Q000379:methods; D011759:Pyrrolidines / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D051381:Rats; D055647:Rats, Transgenic; D017448:Receptors, Dopamine D2 / Q000032:analysis; D050637:Receptors, Dopamine D3 / Q000032:analysis
chemical_list: D001549:Benzamides; D015415:Biomarkers; C094948:N-((1-allyl-2-pyrrolidinyl)methyl)-5-(3-fluoropropyl)-2,3-dimethoxybenzamide; D011759:Pyrrolidines; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3