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Here, we used a newly established animal procedure called optogenetic intracranial self\u2010stimulation (ICSS) (oICSS) to re\u2010examine the abuse potential of cannabinoids in mice. A specific adeno\u2010associated viral vector carrying a channelrhodopsin gene was microinjected into the ventral tegmental area (VTA) to express light\u2010sensitive channelrhodopsin in dopamine (DA) neurons of transgenic dopamine transporter (DAT)\u2010Cre mice. Optogenetic stimulation of VTA DA neurons was highly reinforcing and produced a classical \u201csigmoidal\u201d\u2010shaped stimulation\u2013response curve dependent upon the laser pulse frequency. Systemic administration of cocaine dose\u2010dependently enhanced oICSS and shifted stimulation\u2013response curves upward, in a way similar to previously observed effects of cocaine on electrical ICSS. In contrast, \u0394\n                    <jats:sup>9<\/jats:sup>\n                    \u2010tetrahydrocannabinol (\u0394\n                    <jats:sup>9<\/jats:sup>\n                    \u2010THC), but not cannabidiol, dose\u2010dependently decreased oICSS responding and shifted oICSS curves downward. WIN55,212\u20102 and ACEA, two synthetic cannabinoids often used in laboratory settings, also produced dose\u2010dependent reductions in oICSS. We then examined several new synthetic cannabinoids, which are used recreationally. XLR\u201011 produced a cocaine\u2010like increase, AM\u20102201 produced a \u0394\n                    <jats:sup>9<\/jats:sup>\n                    \u2010THC\u2010like reduction, while 5F\u2010AMB had no effect on oICSS responding. Immunohistochemistry and RNAscope\n                    <jats:italic>in situ<\/jats:italic>\n                    hybridization assays indicated that CB\n                    <jats:sub>1<\/jats:sub>\n                    Rs are expressed mainly in VTA GABA and glutamate neurons, while CB\n                    <jats:sub>2<\/jats:sub>\n                    Rs are expressed mainly in VTA DA neurons. Together, these findings suggest that most cannabinoids are not reward enhancing, but rather reward attenuating or aversive in mice. Activation of CB\n                    <jats:sub>1<\/jats:sub>\n                    R and\/or CB\n                    <jats:sub>2<\/jats:sub>\n                    R in different populations of neurons in the brain may underlie the observed actions.\n                  <\/jats:p>","DOI":"10.1111\/adb.13005","type":"journal-article","created":{"date-parts":[[2021,2,6]],"date-time":"2021-02-06T11:27:04Z","timestamp":1612610824000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Optogenetic brain\u2010stimulation reward: A new procedure to re\u2010evaluate the rewarding\n                    <i>versus<\/i>\n                    aversive effects of cannabinoids in dopamine transporter\u2010Cre mice"],"prefix":"10.1111","volume":"26","author":[{"given":"Bree A.","family":"Humburg","sequence":"first","affiliation":[{"name":"Addiction Biology Unit, Molecular Targets and Medications Discovery, Intramural Research Program National Institute on Drug Abuse  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1843-227X","authenticated-orcid":false,"given":"Chloe J.","family":"Jordan","sequence":"additional","affiliation":[{"name":"Addiction Biology Unit, Molecular Targets and Medications Discovery, Intramural Research Program National Institute on Drug Abuse  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai\u2010Ying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Addiction Biology Unit, Molecular Targets and Medications Discovery, Intramural Research Program National Institute on Drug Abuse  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Shen","sequence":"additional","affiliation":[{"name":"Synaptic Plasticity Section, Intramural Research Program National Institute on Drug Abuse  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Han","sequence":"additional","affiliation":[{"name":"Addiction Biology Unit, Molecular Targets and Medications Discovery, Intramural Research Program National Institute on Drug Abuse  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo\u2010Hua","family":"Bi","sequence":"additional","affiliation":[{"name":"Addiction Biology Unit, Molecular Targets and Medications Discovery, Intramural Research Program National Institute on Drug Abuse  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Briana","family":"Hempel","sequence":"additional","affiliation":[{"name":"Addiction Biology Unit, Molecular Targets and Medications Discovery, Intramural Research Program National Institute on Drug Abuse  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewa","family":"Galaj","sequence":"additional","affiliation":[{"name":"Addiction Biology Unit, Molecular Targets and Medications Discovery, Intramural Research Program National Institute on Drug Abuse  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael H.","family":"Baumann","sequence":"additional","affiliation":[{"name":"Designer Drug Research Unit, Intramural Research Program National Institute on Drug Abuse  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6482-8104","authenticated-orcid":false,"given":"Zheng\u2010Xiong","family":"Xi","sequence":"additional","affiliation":[{"name":"Addiction Biology Unit, Molecular Targets and Medications Discovery, Intramural Research Program National Institute on Drug Abuse  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,2,3]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1542\/pir.2018-0347"},{"key":"e_1_2_8_3_1","unstructured":"National Institute on Drug Abuse.What is the scope of marijuana use in the United States?https:\/\/www.drugabuse.gov\/publications\/research\u2010reports\/marijuana\/what\u2010scope\u2010marijuana\u2010use\u2010in\u2010united\u2010states. 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