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While much experimental evidence from psychostimulants supports this hypothesis, it has been challenged for opioid reinforcement. Here, we monitor genetically encoded DA and calcium indicators as well as cFos in mice to reveal that heroin activates DA neurons located in the medial part of the VTA, preferentially projecting to the medial shell of the nucleus accumbens (NAc). Chemogenetic and optogenetic manipulations of VTA DA or GABA neurons establish a causal link to heroin reinforcement. Inhibition of DA neurons blocked heroin self-administration, while heroin inhibited optogenetic self-stimulation of DA neurons. Likewise, heroin occluded the self-inhibition of VTA GABA neurons. Together, these experiments support a model of disinhibition of a subset of VTA DA neurons in opioid reinforcement.<\/jats:p>","DOI":"10.7554\/elife.39945","type":"journal-article","created":{"date-parts":[[2018,10,29]],"date-time":"2018-10-29T20:22:00Z","timestamp":1540844520000},"source":"Crossref","is-referenced-by-count":183,"title":["Dopamine neurons projecting to medial shell of the nucleus accumbens drive heroin reinforcement"],"prefix":"10.7554","volume":"7","author":[{"given":"Julie","family":"Corre","sequence":"first","affiliation":[{"name":"Department of Basic Neurosciences, Medical Faculty, University of Geneva, Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruud","family":"van Zessen","sequence":"additional","affiliation":[{"name":"Department of Basic Neurosciences, Medical Faculty, University of Geneva, Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5915-5627","authenticated-orcid":true,"given":"Micha\u00ebl","family":"Loureiro","sequence":"additional","affiliation":[{"name":"Department of Basic Neurosciences, Medical Faculty, University of Geneva, Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tommaso","family":"Patriarchi","sequence":"additional","affiliation":[{"name":"School of Medicine, Department of Biochemistry and Molecular Medicine, University of California Davis, California, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7012-6926","authenticated-orcid":true,"given":"Lin","family":"Tian","sequence":"additional","affiliation":[{"name":"School of Medicine, Department of Biochemistry and Molecular Medicine, University of California Davis, California, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Pascoli","sequence":"additional","affiliation":[{"name":"Department of Basic Neurosciences, Medical Faculty, University of Geneva, Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7917-4596","authenticated-orcid":true,"given":"Christian","family":"L\u00fcscher","sequence":"additional","affiliation":[{"name":"Department of Basic Neurosciences, Medical Faculty, University of Geneva, Geneva, Switzerland"},{"name":"Service of Neurology, University of Geneva Hospital, Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2018,10,30]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1007\/s002130000634","article-title":"The effects of excitotoxic lesions of the nucleus accumbens core or shell regions on intravenous heroin self-administration in rats","volume":"153","author":"Alderson","year":"2001","journal-title":"Psychopharmacology"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"8821","DOI":"10.1523\/JNEUROSCI.2225-08.2008","article-title":"Preferential enhancement of dopamine transmission within the nucleus accumbens shell by cocaine is attributable to a direct increase in phasic dopamine release events","volume":"28","author":"Aragona","year":"2008","journal-title":"Journal of Neuroscience"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1038\/nrn3104","article-title":"Opiate versus psychostimulant addiction: the differences do matter","volume":"12","author":"Badiani","year":"2011","journal-title":"Nature Reviews Neuroscience"},{"key":"bib4","doi-asserted-by":"publisher","DOI":"10.1101\/280537","article-title":"Neuronal signature of social novelty exploration in the VTA: implication for autism spectrum disorder","volume":"280537","author":"Bariselli","year":"2018","journal-title":"bioRxiv"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1037\/0735-7044.106.2.351","article-title":"A single brain stem substrate mediates the motivational effects of both opiates and food in nondeprived rats but not in deprived rats","volume":"106","author":"Bechara","year":"1992","journal-title":"Behavioral Neuroscience"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1016\/j.cell.2015.07.015","article-title":"Circuit architecture of VTA dopamine neurons revealed by systematic Input-Output mapping","volume":"162","author":"Beier","year":"2015","journal-title":"Cell"},{"key":"bib7","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/S0022-3565(25)20689-9","article-title":"Effects of cocaine and related drugs in nonhuman primates. 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