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Such drug\u2010induced neuroadaptations may constitute an initial cellular mechanism eventually leading to compulsive drug\u2010seeking behavior. To evaluate the impact of GABA<jats:sub>B<\/jats:sub> receptors on addiction\u2010related persistent neuroplasticity, we tested the ability of orthosteric agonist baclofen and two positive allosteric modulators (PAMs) of GABA<jats:sub>B<\/jats:sub> receptors to suppress neuroadaptations in the ventral tegmental area (VTA) and reward\u2010related behaviors induced by ethanol and cocaine. A novel compound (S)\u20101\u2010(5\u2010fluoro\u20102,3\u2010dihydro\u20101H\u2010inden\u20102\u2010yl)\u20104\u2010methyl\u20106,7,8,9\u2010tetrahydro\u2010[1,2,4]triazolo[4,3\u2010a]quinazolin\u20105(4H)\u2010one (ORM\u201027669) was found to be a GABA<jats:sub>B<\/jats:sub> PAM of low efficacy as agonist, whereas the reference compound (R,S)\u20105,7\u2010di\u2010tert\u2010butyl\u20103\u2010hydroxy\u20103\u2010trifluoromethyl\u20103H\u2010benzofuran\u20102\u2010one (rac\u2010BHFF) had a different allosteric profile being a more potent PAM in the calcium\u2010based assay and an agonist, coupled with potent PAM activity, in the [<jats:sup>35<\/jats:sup>S] GTP\u03b3S binding assay in rat and human recombinant receptors. Using autoradiography, the high\u2010efficacy rac\u2010BHFF and the low\u2010efficacy ORM\u201027669 potentiated the effects of baclofen on [<jats:sup>35<\/jats:sup>S] GTP\u03b3S binding with identical brain regional distribution. Treatment of mice with baclofen, rac\u2010BHFF, or ORM\u201027669 failed to induce glutamate receptor neuroplasticity in the VTA DA neurons. Pretreatment with rac\u2010BHFF at non\u2010sedative doses effectively reversed both ethanol\u2010 and cocaine\u2010induced plasticity and attenuated cocaine i.v. self\u2010administration and ethanol drinking. Pretreatment with ORM\u201027669 only reversed ethanol\u2010induced neuroplasticity and attenuated ethanol drinking but had no effects on cocaine\u2010induced neuroplasticity or self\u2010administration. These findings encourage further investigation of GABA<jats:sub>B<\/jats:sub> receptor PAMs with different efficacies in addiction models to develop novel treatment strategies for drug addiction.<\/jats:p>","DOI":"10.1111\/adb.12688","type":"journal-article","created":{"date-parts":[[2018,11,13]],"date-time":"2018-11-13T10:49:49Z","timestamp":1542106189000},"page":"1191-1203","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["GABA<sub>B<\/sub> receptor positive allosteric modulators with different efficacies affect neuroadaptation to and self\u2010administration of alcohol and cocaine"],"prefix":"10.1111","volume":"24","author":[{"given":"Elena","family":"de Miguel","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine University of Helsinki  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