{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T11:15:05Z","timestamp":1770462905049,"version":"3.49.0"},"posted":{"date-parts":[[2026,1,20]]},"group-title":"Neuroscience","reference-count":181,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T00:00:00Z","timestamp":1768867200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NIH\/NIDA","award":["DA038588"],"award-info":[{"award-number":["DA038588"]}]},{"name":"NIH\/NIDA","award":["DA052909"],"award-info":[{"award-number":["DA052909"]}]},{"name":"NIH\/NIMH","award":["MH078105"],"award-info":[{"award-number":["MH078105"]}]},{"name":"Emory National Primate Research Center (ENPRC) Base Grant","award":["ORIP\/OD P51OD011132"],"award-info":[{"award-number":["ORIP\/OD P51OD011132"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Early life adverse (ELA) experiences such as child maltreatment (MALT) are associated with physical and mental illness, including substance use disorders (SUDs), but underlying neurobiological mechanisms remain unclear. This study examined long-term effects of infant MALT on adult brain serotonin (5HT) and dopamine (DA) receptors in corticolimbic regions involved in reward and emotional control, using positron emission tomography (PET) imaging, a translational infant MALT macaque model of cocaine use disorder (CUD) risk and a COC self-administration (SA) paradigm. The study focused on regional serotonin 5HT\n                  <jats:sub>1A<\/jats:sub>\n                  , 5HT\n                  <jats:sub>2A<\/jats:sub>\n                  , and dopamine D\n                  <jats:sub>2<\/jats:sub>\n                  \/D\n                  <jats:sub>3<\/jats:sub>\n                  receptor availability (BP) differences between MALT and Control animals using PET, both at baseline (pre-COC SA) and following chronic COC SA (once they reached a total of 100 mg\/kg intake). We also examined whether levels of these neurochemical receptors predicted COC SA measures, including reinforcing effects and potency using fixed-ratio (FR) peak response rates and progressive-ratio (PR) peak breakpoint. Our findings showed long-term effects of infant MALT on 5HT, but not DA, receptors in corticolimbic circuits. Specifically, MALT animals showed lower 5HT\n                  <jats:sub>1A<\/jats:sub>\n                  BP in the anterior cingulate cortex (ACC), medial prefrontal cortex (mPFC), and hippocampus compared to Controls. A MALT by Sex interaction effect was detected in 5HT\n                  <jats:sub>2A<\/jats:sub>\n                  BP in the OFC, with lower levels in MALT than Control males, but not in females. In addition, upregulation of 5HT\n                  <jats:sub>1A<\/jats:sub>\n                  and 5HT\n                  <jats:sub>2A<\/jats:sub>\n                  receptors was detected following chronic COC SA in most PFC subregions, hippocampus, and NAcc, particularly in the Control group. These findings suggest long-term effects of ELA on adult 5HT, but not DA, receptors in corticolimbic regions involved in emotional and reward processes. We also found associations between PET baseline (pre-COC SA) receptor BP data and COC SA measures. In particular, a positive correlation between 5HT\n                  <jats:sub>1A<\/jats:sub>\n                  receptor BP in caudate and peak FR Response Rates, whereas amygdala 5HT\n                  <jats:sub>1A<\/jats:sub>\n                  receptor levels were positively correlated with peak PR breakpoint and negatively correlated with peak FR Response Rates. Overall, these findings suggest an important role of 5HT\n                  <jats:sub>1A<\/jats:sub>\n                  and 5HT\n                  <jats:sub>2A<\/jats:sub>\n                  PFC receptors in early COC-related changes in reward circuitry and of amygdala 5HT receptors on cocaine-maintained behaviors. The dynamic change of these 5HT\n                  <jats:sub>1A<\/jats:sub>\n                  and 5HT\n                  <jats:sub>2A<\/jats:sub>\n                  receptors following chronic COC exposure was blunted in animals with ELA. It would be important to understand the biological consequences of these dynamic changes in 5HT receptors and whether they are associated with other stages of the addiction cycle, for example COC relapse, which could inform future pharmacological interventions that target 5HT receptors for treatment of CUD.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Simple Summary<\/jats:title>\n                  <jats:p>\n                    We studied the long-term effects of early life adversity (ELA) on adult brain dopamine (DA) and serotonin (5HT) signaling in corticolimbic regions involved in emotional and reward regulation. We used specific PET radioligands that bind to the DA D2\/D3, 5HT\n                    <jats:sub>1A<\/jats:sub>\n                    and 5HT\n                    <jats:sub>2A<\/jats:sub>\n                    receptors, finding lower levels of 5HT, but not DA, receptors binding potential (BP) in animals that experienced ELA. We also found associations between PET receptor BP measures and reinforcing effects of cocaine in i.v. self-administration paradigms using fixed- and progressive-ratio reinforcement schedules. In addition, a strong upregulation of 5HT, but not DA, receptors was identified following chronic cocaine exposure in prefrontal cortex (PFC). Our findings suggest long-term effects of ELA on adult PFC 5HT\n                    <jats:sub>1A<\/jats:sub>\n                    and 5HT\n                    <jats:sub>2A<\/jats:sub>\n                    receptors. The findings also suggest an important role of 5HT\n                    <jats:sub>1A<\/jats:sub>\n                    and 5HT\n                    <jats:sub>2A<\/jats:sub>\n                    , more so than D2\/D3, receptors in early cocaine-related changes in reward circuitry. The early dynamic changes of these 5HT receptors could serve as biomarkers for cocaine use disorder (CUD) and inform future pharmacological interventions.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.01.18.700208","type":"posted-content","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T17:50:12Z","timestamp":1768931412000},"source":"Crossref","is-referenced-by-count":0,"title":["Long-term Effects of Early Life Adversity On Brain Dopamine and Serotonin Receptor Systems Involved In Cocaine Reinforcement In Adult Macaques: a Positron Emission Tomography Study"],"prefix":"10.64898","author":[{"given":"Jose H.","family":"Acevedo-Polo","sequence":"first","affiliation":[{"name":"Emory National Primate Research Center, Emory University, Atlanta, GA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erin R.","family":"Siebert","sequence":"additional","affiliation":[{"name":"Emory National Primate Research Center, Emory University, Atlanta, GA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Khan","sequence":"additional","affiliation":[{"name":"Emory National Primate Research Center, Emory University, Atlanta, GA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mia I.","family":"Rough","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience and the Center for Addiction Research, Wake Forest University School of Medicine, Winston-Salem, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ronald J.","family":"Voll","sequence":"additional","affiliation":[{"name":"Emory National Primate Research Center, Emory University, Atlanta, GA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lahu N.","family":"Chavan","sequence":"additional","affiliation":[{"name":"Emory National Primate Research Center, Emory University, Atlanta, GA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark M.","family":"Goodman","sequence":"additional","affiliation":[{"name":"Emory National Primate Research Center, Emory University, Atlanta, GA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathon A.","family":"Nye","sequence":"additional","affiliation":[{"name":"Emory National Primate Research Center, Emory University, Atlanta, GA, USA"},{"name":"Medical University of South Carolina, Charleston, SC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael A.","family":"Nader","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience and the Center for Addiction Research, Wake Forest University School of Medicine, Winston-Salem, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. 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