biostudies-literatureWittenberg RENational Institute of Neurological Disorders and StrokeChernowitz Medical Research FoundationNIDA NIH HHSNational Institute of Diabetes and Digestive and Kidney DiseasesNIDDK NIH HHSNIMH NIH HHSNational Aeronautics and Space AdministrationNIAAA NIH HHSNational Institute of Mental HealthNINDS NIH HHSNational Institutes of HealthNational Institute on Drug Abuse467-478https://www.ebi.ac.uk/biostudies/studies/S-EPMC12445159biostudies-literatureUnknown99(6)<h4>Background</h4>An important yet poorly understood risk factor for opioid use disorder is adolescent nicotine use. We investigated the neural mechanisms underlying this understudied interaction.<h4>Methods</h4>Male and female adolescent mice received 2 weeks of nicotine water (Adol Nic) or plain water (Adol Water). In adulthood, mice underwent 3 morphine tests: conditioned place preference (CPP), locomotor sensitization, and two-bottle choice. Ex vivo ventral tegmental area (VTA) brain slices were assessed via patch clamp for GABA (gamma-aminobutyric acid) and dopamine (DA) neuron responses to morphine. Finally, VTA GABA neurons were chemogenetically inhibited during morphine CPP.<h4>Results</h4>In adulthood, Adol Nic mice showed greater morphine CPP, more choice-based morphine consumptBiological psychiatryParadoxical Ventral Tegmental Area GABA Signaling Drives Enhanced Morphine Reward After Adolescent Nicotine.PMC12445159F31 DA053111R37 DA053296R01 AA026267R01 NS088555R01 MH12997080NSSC21K0814R01 DK135871Swanson OKDani JAWolfman SLYang KYun SEisch AJColon LMWittenberg REfalseParadoxical Ventral Tegmental Area GABA Signaling Drives Enhanced Morphine Reward After Adolescent Nicotine.<h4>Background</h4>An important yet poorly understood risk factor for opioid use disorder is adolescent nicotine use. We investigated the neural mechanisms underlying this understudied interaction.<h4>Methods</h4>Male and female adolescent mice received 2 weeks of nicotine water (Adol Nic) or plain water (Adol Water). In adulthood, mice underwent 3 morphine tests: conditioned place preference (CPP), locomotor sensitization, and two-bottle choice. Ex vivo ventral tegmental area (VTA) brain slices were assessed via patch clamp for GABA (gamma-aminobutyric acid) and dopamine (DA) neuron responses to morphine. Finally, VTA GABA neurons were chemogenetically inhibited during morphine CPP.<h4>Results</h4>In adulthood, Adol Nic mice showed greater morphine CPP, more choice-based morphine consumpt2026-01-01T00:00:00Z2026 Mar2026-07-16T15:12:45.634Z2026-07-09T11:04:35.542ZS-EPMC124451594057127010.1016/j.biopsych.2025.05.027