{"id":"2b14d015-60b8-5bce-9e1b-34699226f9fb","stable_key":"6660bba2-4fa0-590a-bf52-9803a24bea9f:transporter-slc6a4","predicate":"decreases_in_recorded_experiment","statement":"Serotonin uptake inhibition was much weaker than dopamine and norepinephrine uptake inhibition in the tested human-transporter assays.","claim_class":"mechanistic","status":"source_recorded","evidence_grade":"ungraded","direction":"negative","is_public":true,"mechanism_event_id":"b4785541-91b3-5387-a200-acc6e8e99dca","mechanism_event_label":"Serotonin uptake inhibition was much weaker than dopamine and norepinephrine uptake inhibition in the tested human-transporter assays.","subject":{"id":"624e6a4b-f96d-5d12-8206-30d1e1715c26","slug":"modafinil","display_name":"Modafinil","entity_type_key":"drug"},"object":{"id":"314fd0ec-f711-542e-98bb-8ae1ba13114a","slug":"slc6a4","display_name":"Human serotonin transporter SERT / SLC6A4","entity_type_key":"protein"},"evidence_count":1,"mechanism_event":{"id":"b4785541-91b3-5387-a200-acc6e8e99dca","stable_key":"6660bba2-4fa0-590a-bf52-9803a24bea9f:transporter-slc6a4-event","event_type":"biochemical_relationship","label":"Serotonin uptake inhibition was much weaker than dopamine and norepinephrine uptake inhibition in the tested human-transporter assays.","description":"A rhesus-monkey PET study detected both DAT and NET occupancy after intravenous modafinil. In human-transporter cell assays, dopamine uptake was inhibited more potently than norepinephrine uptake; serotonin uptake inhibition was much weaker. The same work found no direct TAAR1 activation, but altered phenethylamine responses when TAAR1 was coexpressed with particular transporters. This distinguishes **direct receptor agonism from transporter-dependent modulation**. Monkey intravenous target engagement does not establish the contribution of human NET at oral therapeutic exposure. [Madras et al., 2006](https://pubmed.ncbi.nlm.nih.gov/16885432/)","status":"provisional","compartment":null,"participants":[{"entity":{"id":"624e6a4b-f96d-5d12-8206-30d1e1715c26","slug":"modafinil","display_name":"Modafinil","entity_type_key":"drug"},"role":"tested factor","stoichiometry":null,"state_label":"Modafinil concentration series","sequence_order":0,"notes":""},{"entity":{"id":"314fd0ec-f711-542e-98bb-8ae1ba13114a","slug":"slc6a4","display_name":"Human serotonin transporter SERT / SLC6A4","entity_type_key":"protein"},"role":"measured outcome","stoichiometry":null,"state_label":"decrease","sequence_order":1,"notes":""}]},"contexts":[{"dimension":"evidence_access","value_text":"Primary indexed abstract checked; full methods and figures not comprehensively reviewed.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_contrast","value_text":"{\"intervention\": \"Modafinil concentration series\", \"comparator\": \"Assay control\", \"endpoint\": \"Serotonin uptake inhibition was much weaker than dopamine and norepinephrine uptake inhibition in the tested human-transporter assays.\", \"effect_direction\": \"decrease\", \"combination\": \"single\", \"conditions\": []}","comparator":null,"unit":null,"notes":"Explicit extracted experimental comparison; source-derived draft.","entity":null},{"dimension":"experimental_model","value_text":"Human-transporter cell assays; monkey intravenous PET is a separate experiment, not proof of oral-human NET contribution.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"interpretation_status","value_text":"Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"Serotonin uptake inhibition was much weaker than dopamine and norepinephrine uptake inhibition in the tested human-transporter assays.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro. | 2006 | DOI 10.1124/jpet.106.106583 | PMID 16885432 | https://pubmed.ncbi.nlm.nih.gov/16885432/","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"source_locator","value_text":"Reviewed reference lines 85-85; exact primary location described in quoted passage where extracted.","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"562b19c4-9132-589d-a839-953f137f07f3","evidence_kind":"source_excerpt","locator":"Lines 85-85","start_line":85,"end_line":85,"excerpt":"A rhesus-monkey PET study detected both DAT and NET occupancy after intravenous modafinil. In human-transporter cell assays, dopamine uptake was inhibited more potently than norepinephrine uptake; serotonin uptake inhibition was much weaker. The same work found no direct TAAR1 activation, but altered phenethylamine responses when TAAR1 was coexpressed with particular transporters. This distinguishes **direct receptor agonism from transporter-dependent modulation**. Monkey intravenous target engagement does not establish the contribution of human NET at oral therapeutic exposure. [Madras et al., 2006](https://pubmed.ncbi.nlm.nih.gov/16885432/)","model_system":"Human-transporter cell assays; monkey intravenous PET is a separate experiment, not proof of oral-human NET contribution.","directness":"reported_statement","verification_status":"source_recorded","notes":"Exact excerpt of the retained AI-assisted reviewed reference; primary sources are cited in primary_references and access scope is retained. 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