The effects of HIV-1 regulatory TAT protein expression on brain reward function, response to psychostimulants and delay-dependent memory in mice.
Depression and psychostimulant abuse are common comorbidities among humans with immunodeficiency virus (HIV) disease. The HIV regulatory protein TAT is one of multiple HIV-related proteins associated with HIV-induced neurotoxicity. TAT-induced dysfunction of dopamine and serotonin systems in corticolimbic brain areas may result in impaired reward function, thus, contributing to depressive symptoms and psychostimulant abuse. Transgenic mice with doxycycline-induced TAT protein expression in the brain (TAT+, TAT- control) show neuropathology resembling brain abnormalities in HIV+ humans. We evaluated brain reward function in response to TAT expression, nicotine and methamphetamine administration in TAT+ and TAT- mice using the intracranial self-stimulation procedure. We evaluated the brain dopamine and serotonin systems with high-performance liquid chromatography. The effects of TAT expression on delay-dependent working memory in TAT+ and TAT- mice using the operant delayed nonmatch-to-position task were also assessed. During doxycycline administration, reward thresholds were elevated by 20% in TAT+ mice compared with TAT- mice. After the termination of doxycycline treatment, thresholds of TAT+ mice remained significantly higher than those of TAT- mice and this was associated with changes in mesolimbic serotonin and dopamine levels. TAT+ mice showed a greater methamphetamine-induced threshold lowering compared with TAT- mice. TAT expression did not alter delay-dependent working memory. These results indicate that TAT expression in mice leads to reward deficits, a core symptom of depression, and a greater sensitivity to methamphetamine-induced reward enhancement. Our findings suggest that the TAT protein may contribute to increased depressive-like symptoms and continued methamphetamine use in HIV-positive individuals.
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA; Queensland Brain Institute, The University of Queensland, St. Lucia, Qld, Australia.
James P
JP
Kesby
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
Athina
A
Markou
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA. Electronic address: ssemenova@ucsd.edu.
Svetlana
S
Semenova
D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D015696:Gene Products, tat / Q000096:biosynthesis* / Q000235:genetics; D015497:HIV-1; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology*; D012201:Reward; D013997:Time Factors
D000697:Central Nervous System Stimulants; D015696:Gene Products, tat
Anhedonia; Cognition; Dopamine; Methamphetamine; Serotonin