ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Neuropharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1691165
Methamphetamine and neuroHIV suppress astrocytic potassium channel function in the medial prefrontal cortex via different mechanisms
Provisionally accepted
- Rush University Department of Microbial Pathogens and Immunity, Chicago, United States
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Methamphetamine (Meth) is a highly addictive psychostimulant that disrupts neuronal function in the medial prefrontal cortex (mPFC), inducing Meth use disorders (MUD). MUD is often complicated by HIV-associated neurocognitive disorders (HAND, a.k.a. neuroAIDS/neuroHIV), and vice versa. MUD and neuroHIV also disrupt astrocytes, altering their role in supporting normal neuron function. The mechanism(s) underlying Meth and neuroHIV's impact on astrocytes and astrocyte-neuron interplay remains unknown. To define that, we assessed the activity of cortical astrocyte K+ channels that regulate extracellular K+ homeostasis ([K+]e), and substantially neuronal excitability in the brain. HIV-1 transgenic (Tg) rats, a rodent model of neuroHIV with combined antiretroviral therapy (cART) that have no active HIV-1 replication but expression of viral proteins, were given daily repeated Meth administrations. Saline-pretreated non-Tg rats served as control. We then conducted electrophysiological assessment in mPFC astrocytes after acute Meth (20, 100μM in bath) or daily repeated Meth administrations (5mg/kg/day s.c. for 5 days) followed by a 3-day withdrawal. We found that both Meth and neuroHIV suppressed the activity of astrocytic K+ channels, regardless of subtypes. The maximum reduction occurred in response to combined Meth/neuroHIV, showing exacerbated astrocyte dysfunction. Blocking the trace amine-associated receptor 1 (TAAR1)/G protein-coupled signaling pathway abolished Meth-induced, but not neuroHIV-induced, suppression of K2P, Kv, and Kir channel activity. Collectively, these findings demonstrate that Meth and neuroHIV inhibit astrocyte function, which could exacerbate mPFC neuronal dysfunction in MUD and/or neuroHIV. They also suggest that Meth-and neuroHIV-induced astrocytic K+ channel function was mediated by TAAR1-and/or chemokine receptor-coupled signaling pathways.
Keywords: astrocyte, Methamphetamine (METH), NeuroHIV, medial prefrontal cortex (mPFC), K+ channel, Electrophysiology, Trace amine-associated receptor 1 (TAAR1)
Received: 22 Aug 2025; Accepted: 15 Oct 2025.
Copyright: © 2025 Chen, Cassoday, Mamede, Al-Harthi and HU. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: XIU-TI HU, xiu-ti_hu@rush.edu
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