TY - JOUR T1 - HIV-1 Tat and morphine differentially disrupt pyramidal cell structure and function and spatial learning in hippocampal area CA1: Continuous versus interrupted morphine exposure JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0547-20.2021 SP - ENEURO.0547-20.2021 AU - William D. Marks AU - Jason J. Paris AU - Aaron J. Barbour AU - Jean Moon AU - Valerie J. Carpenter AU - Virginia D. McLane AU - Arianna R.S. Lark AU - Sara R. Nass AU - Jingli Zhang AU - Viktor Yarotskyy AU - A. Rory McQuiston AU - Pamela E. Knapp AU - Kurt F. Hauser Y1 - 2021/03/26 UR - http://www.eneuro.org/content/early/2021/03/26/ENEURO.0547-20.2021.abstract N2 - About half the people infected with HIV have neurocognitive deficits that often include memory impairment and hippocampal deficits, which can be exacerbated by opioid abuse. To explore the effects of opioids and HIV on hippocampal CA1 pyramidal neuron structure and function, we induced HIV-1 Tat expression in transgenic mice for 14 d and co-administered time-release morphine or vehicle subcutaneous implants during the final 5 d (days 9-14) to establish steady-state morphine levels. Morphine was withheld from some ex vivo slices during recordings to begin to assess the initial pharmacokinetic consequences of opioid withdrawal. Tat expression reduced hippocampal CA1 pyramidal neuronal excitability at lower stimulating currents. Pyramidal cell firing rates were unaffected by continuous morphine exposure. Behaviorally, exposure to Tat or high dosages of morphine impaired spatial memory. Exposure to Tat and steady-state levels of morphine appeared to have largely independent effects on pyramidal neuron structure and function, a response that is distinct from other vulnerable brain regions such as the striatum. By contrast, acutely withholding morphine (from morphine-tolerant ex vivo slices) revealed unique and selective neuroadaptive shifts in CA1 pyramidal neuronal excitability and dendritic plasticity, including some interactions with Tat. Collectively, the results show that opioid-HIV interactions in hippocampal area CA1 are more nuanced than previously assumed, and appear to vary depending on the outcome assessed and on the pharmacokinetics of morphine exposure.Significance StatementHIV-1 transgenic mice were co-exposed to Tat and morphine to explore opioid-HIV interactions in hippocampal area CA1. Spatial memory was impaired by both Tat and morphine. Tat expression reduced the firing rate of hippocampal CA1 pyramidal neurons at lower stimulating currents irrespective of morphine exposure. Exposure to Tat and steady-state levels of morphine acted in a largely independent manner to alter pyramidal neuron structure, function, and associated behavior. This makes CA1 distinct from other regions such as the striatum. Alternatively, withholding morphine (from morphine-tolerant ex vivo slices) revealed unique, but subtle, neuroadaptive shifts in pyramidal neuronal excitability and dendritic plasticity, suggesting that opioid-HIV interactions in the hippocampus are markedly influenced by the pharmacokinetics of opioid exposure. ER -