title: Effects of HIV/TAT protein expression and chronic selegiline treatment on spatial memory, reversal learning and neurotransmitter levels in mice.
abstract: Neurotoxic viral protein TAT may contribute to deficits in dopaminergic and cognitive function in individuals infected with human immunodeficiency virus. Transgenic mice with brain-specific doxycycline-induced TAT expression (TAT+, TAT- control) show impaired cognition. However, previously reported TAT-induced deficits in reversal learning may be compromised by initial learning deficits. We investigated the effects of TAT expression on memory retention/recall and reversal learning, and neurotransmitter function. We also investigated if TAT-induced effects can be reversed by improving dopamine function with selegiline, a monoamine oxidase inhibitor. Mice were tested in the Barnes maze and TAT expression was induced after the task acquisition. Selegiline treatment continued throughout behavioral testing. Dopamine, serotonin and glutamate tissue levels in the prefrontal/orbitofrontal cortex, hippocampus and caudate putamen were measured using high performance liquid chromatography. Neither TAT expression nor selegiline altered memory retention. On day 2 of reversal learning testing, TAT+ mice made fewer errors and used more efficient search strategies than TAT- mice. TAT expression decreased dopamine turnover in the caudate putamen, increased serotonin turnover in the hippocampus and tended to increase the conversion of glutamate to glutamine in all regions. Selegiline decreased dopamine and serotonin metabolism in all regions and increased glutamate levels in the caudate putamen. In the absence of impaired learning, TAT expression does not impair spatial memory retention/recall, and actually facilitates reversal learning. Selegiline-induced increases in dopamine metabolism did not affect cognitive function. These findings suggest that TAT-induced alterations in glutamate signaling, but not alterations in monoamine metabolism, may underlie the facilitation of reversal learning.
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, USA; Queensland Brain Institute, The University of Queensland, St. Lucia, Qld, Australia.
authors.forename: James P
authors.initials: JP
authors.lastname: Kesby
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
authors.forename: Athina
authors.initials: A
authors.lastname: Markou
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, USA. Electronic address: ssemenova@ucsd.edu.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Semenova
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D015870:Gene Expression; D015696:Gene Products, tat / Q000235:genetics / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006678:HIV; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D011939:Mental Recall / Q000187:drug effects / Q000502:physiology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D012193:Reversal Learning / Q000187:drug effects / Q000502:physiology*; D012642:Selegiline / Q000494:pharmacology*; D012701:Serotonin / Q000378:metabolism; D065852:Spatial Memory / Q000187:drug effects / Q000502:physiology*
chemical_list: D015696:Gene Products, tat; D008996:Monoamine Oxidase Inhibitors; D005973:Glutamine; D012642:Selegiline; D012701:Serotonin; D018698:Glutamic Acid; D004298:Dopamine
keywords: AIDS; Barnes maze; Dopamine; Glutamate; Prefrontal cortex; l-Deprenyl