title: Adolescent HIV-1 transgenic rats: evidence for dopaminergic alterations in behavior and neurochemistry revealed by methamphetamine challenge.
abstract: Since the introduction of combination antiretroviral therapy (cART) in the mid-90s, the most severe forms of HIV-1-associated neurocognitive disorders (HAND) have diminished. However, milder forms of HAND remain prevalent. Basic and clinical studies implicate alterations in the dopaminergic (DAergic) system in HIV-1 infection. We used the Fischer 344 HIV-1 transgenic (HIV-1 Tg) rat, which expresses 7 of the 9 HIV-1 genes, to examine potential DAergic alterations. Animals were studied beginning at 35 days of age to assess early-onset DAergic alterations, well before any documented neurological symptoms or clinical signs of "wasting". At 48 hr intervals, animals were administered a single dose of methamphetamine (METH) (0, 0.5, 1, 2.5 and 5 mg/kg/ml s.c.) and tested for the auditory startle response (ASR) and prepulse inhibition (PPI), using an auditory prepulse [85 dB(A) broad-band noise stimulus] and an auditory startle stimulus [100 dB(A) broad-band noise stimulus] in a sound-attenuating chamber with a continuous 70 dB(A) white noise background. The protocol used a 5-min acclimation period, 6 startle trials, and 36 PPI trials [ISIs of 0, 8, 40, 80, 120, and 4000 ms, 6-trial blocks, Latin square design]. As the dose of METH increased, PPI of the startle response decreased. The HIV-1 Tg rats displayed a greater dose-dependency to the METH-induced disruption of PPI compared to non-transgenic controls. Western blot analysis of midbrain extracts revealed lower tyrosine hydroxylase (TH) protein levels and higher monoamine oxidase A (MAO-A) protein levels in HIV-1 Tg rats treated with METH compared to non-transgenic controls. Early-detected cognitive alterations in the preattentive process of sensorimotor gating may have significant predictive utility regarding the progression of DAergic alterations in HIV-1 infection.
authors.affiliation: Department of Psychology, 1512 Pendleton Street, University of South Carolina, Columbia, SC 29208, USA. moranl@email.sc.edu
authors.forename: Landhing M
authors.initials: LM
authors.lastname: Moran
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Aksenov
authors.forename: Rosemarie M
authors.initials: RM
authors.lastname: Booze
authors.forename: Katy M
authors.initials: KM
authors.lastname: Webb
authors.forename: Charles F
authors.initials: CF
authors.lastname: Mactutus
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D015153:Blotting, Western; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects*; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008694:Methamphetamine / Q000494:pharmacology*; D008995:Monoamine Oxidase / Q000378:metabolism; D011237:Predictive Value of Tests; D051381:Rats; D055647:Rats, Transgenic; D013216:Reflex, Startle / Q000187:drug effects*; D055139:Sensory Gating / Q000187:drug effects; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D000697:Central Nervous System Stimulants; D008694:Methamphetamine; D014446:Tyrosine 3-Monooxygenase; D008995:Monoamine Oxidase; D004298:Dopamine