{"doi":"10.17615/m6xp-kb38","title":"Control of serotonergic function in medial prefrontal cortex by serotonin-2A receptors through a glutamate-dependent mechanism","abstract":"We examined the in vivo effects of the hallucinogen 4-iodo-2,5-dimethoxyamphetamine (DOI). DOI suppressed the firing rate of 7 of 12 dorsal raphe (DR) serotonergic (5-HT) neurons and partially inhibited the rest (ED5O = 20 μg/kg, i.v.), an effect reversed by M100907 (5-HT2A antagonist) and picrotoxinin (GABAA antagonist). DOI (1 mg/kg, s.c.) reduced the 5-HT release in medial prefrontal cortex (mPFC) to 33 ± 8% of baseline, an effect also antagonized by M100907. However, the local application of DOI in the mPFC increased 5-HT release (164 ± 6% at 100 μM), an effect antagonized by tetrodotoxin, M100907, and BAY × 3702 (5-HT1A agonist) but not by SB 242084 (5-HT2C antagonist). The 5-HT increase was also reversed by NBQX (AMPA-KA antagonist) and 1S,3S-ACPD (mGluR 2/3 agonist) but not by MK-801 (NMDA antagonist). AMPA mimicked the 5-HT elevation produced by DOI. Likewise, the electrical-chemical stimulation of thalamocortical afferents and the local inhibition of glutamate uptake increased the 5-HT release through AMPA receptors. DOI application in mPFC increased the firing rate of a subgroup of 5-HT neurons (5 of 10), indicating an enhanced output of pyramidal neurons. Dual-label fluorescence confocal microscopic studies demonstrated colocalization of 5-HT1A and 5-HT2A receptors on individual cortical pyramidal neurons. Thus, DOI reduces the activity of ascending 5-HT neurons through a DR-based action and enhances serotonergic and glutamatergic transmission in mPFC through 5-HT2A and AMPA receptors. Because pyramidal neurons coexpress 5-HT1A and 5-HT2A receptors, DOI disrupts the balance between excitatory and inhibitory inputs and leads to an increased activity that may mediate its hallucinogenic action.","journal":"UNC Libraries","year":2020,"id":85765,"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":20,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9613,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":438901,"name":"R. Martin-Ruiz","orcid":null,"position":1,"is_corresponding":false},{"id":438902,"name":"D.A. Shapiro","orcid":null,"position":2,"is_corresponding":false},{"id":438023,"name":"Pau Celada","orcid":"0000-0002-3893-9000","position":3,"is_corresponding":false},{"id":396552,"name":"B.L. Roth","orcid":null,"position":4,"is_corresponding":false},{"id":438024,"name":"M. Victoria Puig","orcid":"0000-0002-1490-4153","position":5,"is_corresponding":false},{"id":438025,"name":"Guadalupe Mengod","orcid":"0000-0001-7223-7873","position":6,"is_corresponding":false},{"id":438900,"name":"F. Artigas","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T21:58:16.217017Z","pmid":null,"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":[]}