{"doi":"10.3389/fphar.2025.1691165","title":"Methamphetamine and neuroHIV suppress astrocytic potassium channel function in the medial prefrontal cortex via different mechanisms","abstract":"Introduction 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. Methods 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, 100 μM in bath) or daily repeated Meth administrations (5 mg/kg/day s.c. for 5 days) followed by a 3-day withdrawal. Results 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 K 2P , K v , and K ir channel activity. Discussion 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.","journal":"Frontiers in Pharmacology","year":2025,"id":583015,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9552,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1495309,"name":"Stefanie L. Cassoday","orcid":null,"position":1,"is_corresponding":false},{"id":666028,"name":"João I. Mamede","orcid":"0000-0002-6048-1876","position":2,"is_corresponding":false},{"id":450927,"name":"Lena Al‐Harthi","orcid":"0000-0003-3915-3904","position":3,"is_corresponding":false},{"id":530380,"name":"Xiu‐Ti Hu","orcid":"0000-0002-4463-2216","position":4,"is_corresponding":false},{"id":762177,"name":"Lihua Chen","orcid":"0000-0003-2195-7330","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T02:58:59.653747Z","pmid":"41368584","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}