{"doi":"10.1126/scisignal.ady8676","title":"TNF-α signaling mediates the dopaminergic effects of methamphetamine by stimulating dopamine transporters and L-type Ca <sup>2+</sup> channels","abstract":"The highly addictive psychostimulant methamphetamine increases the release of dopamine in the brain’s reward circuitry, where it also promotes the release of cytokines, including TNF-α, that contribute to neuroinflammation associated with methamphetamine abuse. Here, we found a dynamic interplay between methamphetamine and TNF-α in facilitating dopamine transmission within the ventral tegmental area (VTA) in mice. In ex vivo mouse brain slices and dopaminergic neurons, methamphetamine or TNF-α treatment increased dopamine release, intracellular Ca 2+ concentrations, and the firing activity of VTA dopaminergic neurons. These effects depended on the activity of dopamine transporter (DAT) and L-type voltage-gated Ca 2+ channels. Pharmacological inhibition of either DAT or TNF-α signaling mitigated these effects, suggesting that methamphetamine-induced alterations in VTA dopaminergic neurons are partially TNF-α dependent. These results underscore the role of neuroimmune signaling in modulating the dopaminergic circuitry and may inform therapeutic strategies for addressing methamphetamine addiction and its associated neuroinflammatory disorders.","journal":"Science Signaling","year":2025,"id":537593,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9542,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"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":283986,"name":"Marcelo Febo","orcid":"0000-0001-8981-4163","position":1,"is_corresponding":false},{"id":339818,"name":"Adriaan W. Bruijnzeel","orcid":"0000-0001-8466-1970","position":2,"is_corresponding":false},{"id":348108,"name":"Leah Phan","orcid":"0000-0002-7840-3366","position":3,"is_corresponding":false},{"id":460884,"name":"Adithya Gopinath","orcid":"0000-0002-6674-2301","position":4,"is_corresponding":false},{"id":1072097,"name":"Jordan M. Seibold","orcid":"0000-0001-9365-6014","position":5,"is_corresponding":false},{"id":1047793,"name":"Emily Miller","orcid":"0000-0003-4102-9558","position":6,"is_corresponding":false},{"id":254880,"name":"Habibeh Khoshbouei","orcid":"0000-0002-1533-8771","position":7,"is_corresponding":false},{"id":1423392,"name":"Landon Lin","orcid":"0000-0002-5942-9317","position":0,"is_corresponding":true}],"reference_count":100,"raw_metadata":null,"created_at":"2026-07-19T02:52:12.997494Z","pmid":"41401255","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":[]}