Ruthie E Wittenberg, Sanghee Yun, Kechun Yang, Olivia K Swanson, Shannon L Wolfman, Lorianna M Colón, Amelia J Eisch, John A Dani
{"title":"自相矛盾的腹侧被盖区GABA信号驱动青少年尼古丁后吗啡奖励增强。","authors":"Ruthie E Wittenberg, Sanghee Yun, Kechun Yang, Olivia K Swanson, Shannon L Wolfman, Lorianna M Colón, Amelia J Eisch, John A Dani","doi":"10.1016/j.biopsych.2025.05.027","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>An important yet poorly understood risk factor for opioid use disorder is adolescent nicotine use. We investigated the neural mechanisms underlying this understudied interaction.</p><p><strong>Methods: </strong>Male and female adolescent mice received two-weeks of nicotine water (Adol Nic) or plain water (Adol Water). In adulthood, mice underwent three 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 and dopamine (DA) neuron morphine responses. Finally, VTA GABA neurons were chemogenetically inhibited during morphine CPP.</p><p><strong>Results: </strong>In adulthood, Adol Nic mice had greater morphine CPP, more morphine locomotor sensitization, and more choice-based morphine consumption vs. Adol Water mice. In contrast, adult mice given nicotine vs. water had similar morphine CPP measured a month later. Patch clamp analysis of VTA neurons from adult Adol Water mice showed canonical cell-type responses to bath-applied morphine: fewer action potentials in GABA neurons and more in DA neurons. Paradoxically, VTA GABA and DA neurons from adult Adol Nic mice did not show these morphine responses. In support of a causal relationship between GABA neuron firing and reward behavior, chemogenetic inhibition of VTA GABA neurons in Adol Water mice during pairing increased morphine CPP. In contrast, inhibition of VTA GABA neurons in Adol Nic mice brought morphine CPP down to control levels.</p><p><strong>Conclusions: </strong>These data indicate a circuitry adaptation by which adolescent nicotine intake promotes morphine reward later in life, showing that adolescent nicotine exposure alters reward circuitry well into adulthood.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.0000,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Paradoxical ventral tegmental area GABA signaling drives enhanced morphine reward after adolescent nicotine.\",\"authors\":\"Ruthie E Wittenberg, Sanghee Yun, Kechun Yang, Olivia K Swanson, Shannon L Wolfman, Lorianna M Colón, Amelia J Eisch, John A Dani\",\"doi\":\"10.1016/j.biopsych.2025.05.027\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>An important yet poorly understood risk factor for opioid use disorder is adolescent nicotine use. We investigated the neural mechanisms underlying this understudied interaction.</p><p><strong>Methods: </strong>Male and female adolescent mice received two-weeks of nicotine water (Adol Nic) or plain water (Adol Water). In adulthood, mice underwent three 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 and dopamine (DA) neuron morphine responses. Finally, VTA GABA neurons were chemogenetically inhibited during morphine CPP.</p><p><strong>Results: </strong>In adulthood, Adol Nic mice had greater morphine CPP, more morphine locomotor sensitization, and more choice-based morphine consumption vs. Adol Water mice. In contrast, adult mice given nicotine vs. water had similar morphine CPP measured a month later. Patch clamp analysis of VTA neurons from adult Adol Water mice showed canonical cell-type responses to bath-applied morphine: fewer action potentials in GABA neurons and more in DA neurons. Paradoxically, VTA GABA and DA neurons from adult Adol Nic mice did not show these morphine responses. In support of a causal relationship between GABA neuron firing and reward behavior, chemogenetic inhibition of VTA GABA neurons in Adol Water mice during pairing increased morphine CPP. In contrast, inhibition of VTA GABA neurons in Adol Nic mice brought morphine CPP down to control levels.</p><p><strong>Conclusions: </strong>These data indicate a circuitry adaptation by which adolescent nicotine intake promotes morphine reward later in life, showing that adolescent nicotine exposure alters reward circuitry well into adulthood.</p>\",\"PeriodicalId\":8918,\"journal\":{\"name\":\"Biological Psychiatry\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":9.0000,\"publicationDate\":\"2025-06-24\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biological Psychiatry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.biopsych.2025.05.027\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biological Psychiatry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.biopsych.2025.05.027","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
Paradoxical ventral tegmental area GABA signaling drives enhanced morphine reward after adolescent nicotine.
Background: An important yet poorly understood risk factor for opioid use disorder is adolescent nicotine use. We investigated the neural mechanisms underlying this understudied interaction.
Methods: Male and female adolescent mice received two-weeks of nicotine water (Adol Nic) or plain water (Adol Water). In adulthood, mice underwent three 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 and dopamine (DA) neuron morphine responses. Finally, VTA GABA neurons were chemogenetically inhibited during morphine CPP.
Results: In adulthood, Adol Nic mice had greater morphine CPP, more morphine locomotor sensitization, and more choice-based morphine consumption vs. Adol Water mice. In contrast, adult mice given nicotine vs. water had similar morphine CPP measured a month later. Patch clamp analysis of VTA neurons from adult Adol Water mice showed canonical cell-type responses to bath-applied morphine: fewer action potentials in GABA neurons and more in DA neurons. Paradoxically, VTA GABA and DA neurons from adult Adol Nic mice did not show these morphine responses. In support of a causal relationship between GABA neuron firing and reward behavior, chemogenetic inhibition of VTA GABA neurons in Adol Water mice during pairing increased morphine CPP. In contrast, inhibition of VTA GABA neurons in Adol Nic mice brought morphine CPP down to control levels.
Conclusions: These data indicate a circuitry adaptation by which adolescent nicotine intake promotes morphine reward later in life, showing that adolescent nicotine exposure alters reward circuitry well into adulthood.
期刊介绍:
Biological Psychiatry is an official journal of the Society of Biological Psychiatry and was established in 1969. It is the first journal in the Biological Psychiatry family, which also includes Biological Psychiatry: Cognitive Neuroscience and Neuroimaging and Biological Psychiatry: Global Open Science. The Society's main goal is to promote excellence in scientific research and education in the fields related to the nature, causes, mechanisms, and treatments of disorders pertaining to thought, emotion, and behavior. To fulfill this mission, Biological Psychiatry publishes peer-reviewed, rapid-publication articles that present new findings from original basic, translational, and clinical mechanistic research, ultimately advancing our understanding of psychiatric disorders and their treatment. The journal also encourages the submission of reviews and commentaries on current research and topics of interest.