title: Combination of methamphetamine and HIV-1 gp120 causes distinct long-term alterations of behavior, gene expression, and injury in the central nervous system.
abstract: Methamphetamine (METH) abuse is frequent in individuals infected with human immunodeficiency virus type-1 (HIV-1) and is suspected to aggravate HIV-associated neurocognitive disorders (HAND). METH is a psychostimulant that compromises several neurotransmitter systems and HIV proteins trigger neuronal injury but the combined effects of viral infection and METH abuse are incompletely understood. In this study we treated transgenic mice expressing the HIV envelope protein gp120 in the brain (HIV-1 gp120tg) at 3-4 months of age with an escalating-dose, multiple-binge METH regimen. The long-term effects were analyzed after 6-7 months of drug abstinence employing behavioral tests and analysis of neuropathology, electrophysiology and gene expression. Behavioral testing showed that both HIV-1 gp120tg and WT animals treated with METH displayed impaired learning and memory. Neuropathological analysis revealed that METH similar to HIV-1 gp120 caused a significant loss of neuronal dendrites and pre-synaptic terminals in hippocampus and cerebral cortex of WT animals. Electrophysiological studies in hippocampal slices showed that METH exposed HIV-1 gp120tg animals displayed reduced post-tetanic potentiation, whereas both gp120 expression and METH lead to reduced long-term potentiation. A quantitative reverse transcription-polymerase chain reaction array showed that gp120 expression, METH and their combination each caused a significant dysregulation of specific components of GABAergic and glutamatergic neurotransmission systems, providing a possible mechanism for synaptic dysfunction and behavioral impairment. In conclusion, both HIV-1 gp120 and METH caused lasting behavioral impairment in association with neuropathology and altered gene expression. However, combined METH exposure and HIV-1 gp120 expression resulted in the most pronounced, long lasting pre- and post-synaptic alterations coinciding with impaired learning and memory.
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: mhoefer@sanfordburnham.org.
authors.forename: Melanie M
authors.initials: MM
authors.lastname: Hoefer
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: asanchez@sanfordburnham.org.
authors.forename: Ana B
authors.initials: AB
authors.lastname: Sanchez
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: rmaung@sanfordburnham.org.
authors.forename: Ricky
authors.initials: R
authors.lastname: Maung
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: cderozieres@sanfordburnham.org.
authors.forename: Cyrus M
authors.initials: CM
authors.lastname: de Rozieres
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: cata6498@pacificu.edu.
authors.forename: Irene C
authors.initials: IC
authors.lastname: Catalan
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: cari.j.cox78@gmail.com.
authors.forename: Cari C
authors.initials: CC
authors.lastname: Dowling
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: vthaney@sanfordburnham.org.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Thaney
authors.affiliation: Del E. Webb Center for Neuroscience & Aging Research, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: pina-crespo@sanfordburnham.org.
authors.forename: Juan
authors.initials: J
authors.lastname: Piña-Crespo
authors.affiliation: Del E. Webb Center for Neuroscience & Aging Research, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: dzhang@sanfordburnham.org.
authors.forename: Dongxian
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, 10550 North Torrey Pines Road, MB6, La Jolla, CA 92037, USA. Electronic address: aroberts@scripps.edu.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Roberts
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA; Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA. Electronic address: mkaul@sanfordburnham.org.
authors.forename: Marcus
authors.initials: M
authors.lastname: Kaul
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000473:pathology* / Q000821:virology; D000697:Central Nervous System Stimulants / Q000009:adverse effects; D015699:HIV Envelope Protein gp120; D015658:HIV Infections / Q000150:complications*; D015497:HIV-1; D007150:Immunohistochemistry; D008694:Methamphetamine / Q000009:adverse effects*; D051379:Mice; D008822:Mice, Transgenic; D018408:Patch-Clamp Techniques; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019966:Substance-Related Disorders / Q000150:complications*; D059467:Transcriptome / Q000187:drug effects
chemical_list: D000697:Central Nervous System Stimulants; D015699:HIV Envelope Protein gp120; C514793:gp120 protein, Human immunodeficiency virus 1; D008694:Methamphetamine
keywords: Behavior; Electrophysiology; Gene expression; HIV-1 gp120; Methamphetamine; NeuroAIDS; Neuropathology; Transgenic animal model