{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:20:23Z","timestamp":1785406823640,"version":"3.56.0"},"posted":{"date-parts":[[2025,11,28]]},"group-title":"Pharmacology and Toxicology","reference-count":69,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["DP1DA058385"],"award-info":[{"award-number":["DP1DA058385"]}],"id":[{"id":"https:\/\/ror.org\/00fq5cm18","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000102","name":"Health Resources and Services Administration","doi-asserted-by":"crossref","award":["D34HP45723"],"award-info":[{"award-number":["D34HP45723"]}],"id":[{"id":"10.13039\/100000102","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Loma Linda University School of Pharmacy"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Rationale<\/jats:title>\n                  <jats:p>Dopamine D4 receptors (D4Rs) have been implicated in the pathophysiology of attention-deficit\/hyperactivity disorder (ADHD), yet their precise role and therapeutic relevance remain underexplored. Highly selective D4R compounds may provide a valuable tool to elucidate D4R function and assess their potential as non-stimulant ADHD treatments.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>This study examined the behavioral effects of two novel D4R drugs, namely, FMJ-01-38 (high-efficacy partial agonist) and FMJ-01-54 (full antagonist) in adolescent spontaneously hypertensive (SHR\/NCrl) rats, a validated ADHD model, and Wistar controls.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Rats received intraperitoneal FMJ-01-38 or FMJ-01-54 (5\u201310 mg\/kg) or vehicle prior to behavioral assays assessing locomotor activity (open field tests), recognition memory (novel object preference), attention and working memory (Y-maze test), and impulsivity (delay discounting task).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>FMJ-01-38 dose-dependently reduced locomotor hyperactivity and improved spontaneous alternation behavior in SHR\/NCrl; at 5 mg\/kg it enhanced novel-object preference and decreased impulsive choice and action, indicating attenuation of ADHD-like symptoms and cognitive enhancement. FMJ-01-54 produced similar improvements in Y-maze and novel-object performance without altering locomotor activity or impulsivity of SHR\/NCrl, suggesting selective cognitive improvement. In Wistar rats, FMJ-01-38 increased novel-object preference only at the 5 mg\/kg dose, while FMJ-01-54 treatment did not produce any significant behavioral effects.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>These findings demonstrate that D4R modulation, through either partial agonism or antagonism, differentially ameliorates ADHD-related behaviors. Both FMJ-01-38 and FMJ-01-54 produced minimal effects in control animals, suggesting pathology-specific efficacy and highlighting D4R ligands as promising non-stimulant therapeutic candidates for ADHD.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.11.26.690786","type":"posted-content","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T13:20:17Z","timestamp":1764336017000},"source":"Crossref","is-referenced-by-count":0,"title":["Novel Dopamine 4 Receptor Ligands Differentially Ameliorate ADHD-like Behaviors in Spontaneously Hypertensive Rats"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2046-522X","authenticated-orcid":false,"given":"Ike C.","family":"de la Pe\u00f1a","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Andino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Amis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad A.","family":"Alkhatib","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1845-9373","authenticated-orcid":false,"given":"Thomas M.","family":"Keck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1907-431X","authenticated-orcid":false,"given":"Comfort A.","family":"Boateng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025112910351603000_2025.11.26.690786v1.1","doi-asserted-by":"publisher","DOI":"10.26434\/chemrxiv-2024-0z6jk-v2"},{"key":"2025112910351603000_2025.11.26.690786v1.2","doi-asserted-by":"publisher","DOI":"10.3109\/15622975.2011.595822"},{"key":"2025112910351603000_2025.11.26.690786v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2009.01.018"},{"key":"2025112910351603000_2025.11.26.690786v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1301164"},{"key":"2025112910351603000_2025.11.26.690786v1.5","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.3c00734"},{"key":"2025112910351603000_2025.11.26.690786v1.6","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1417.007"},{"key":"2025112910351603000_2025.11.26.690786v1.7","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0308292101"},{"key":"2025112910351603000_2025.11.26.690786v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbb.2005.08.002"},{"key":"2025112910351603000_2025.11.26.690786v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1301244"},{"key":"2025112910351603000_2025.11.26.690786v1.10","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-023-06347-1"},{"key":"2025112910351603000_2025.11.26.690786v1.11","doi-asserted-by":"publisher","DOI":"10.1007\/s40263-013-0130-6"},{"key":"2025112910351603000_2025.11.26.690786v1.12","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci15090913"},{"key":"2025112910351603000_2025.11.26.690786v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2015.05.012"},{"key":"2025112910351603000_2025.11.26.690786v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2015.05.012"},{"key":"2025112910351603000_2025.11.26.690786v1.15","doi-asserted-by":"publisher","DOI":"10.1007\/s10519-017-9861-3"},{"key":"2025112910351603000_2025.11.26.690786v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2015.07.044"},{"key":"2025112910351603000_2025.11.26.690786v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2020.173826"},{"key":"2025112910351603000_2025.11.26.690786v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2010.07.037"},{"key":"2025112910351603000_2025.11.26.690786v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2011.11.001"},{"key":"2025112910351603000_2025.11.26.690786v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2018.02.001"},{"key":"2025112910351603000_2025.11.26.690786v1.21","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-024-00495-0"},{"key":"2025112910351603000_2025.11.26.690786v1.22","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.1014678"},{"key":"2025112910351603000_2025.11.26.690786v1.23","doi-asserted-by":"crossref","unstructured":"Forrest, J. , Chen, W. , and Jagadheesan, K. 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