{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T13:43:08Z","timestamp":1770903788031,"version":"3.50.1"},"reference-count":113,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T00:00:00Z","timestamp":1760572800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Basic neuroscience has identified dopamine and corticotropin-releasing hormone (CRH) systems and amygdala circuits as key contributors to drug and alcohol reward, craving, and relapse. However, directly targeting these systems has had no impact on the treatment of addictive disorders. CRH receptor 1 (CRHR1) and dopamine receptor D1 are both modulators of amygdala function. The intercalating cell masses (ITC) regulate intra-amygdala signal flow and are highly enriched in CRHR1 and D1. To date, interactions between these systems have not been extensively examined. We tested these interactions using a combination of <jats:italic>in vivo<\/jats:italic> pharmacology, genetic targeting and behavioral studies in rodents.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The impact of CRHR1 activation on D1 was demonstrated using i. c.v. injection of either CRH (2\u00a0\u03bcg\/\u03bcL) or stressin I (4 \u03bcg\/2\u00a0\u03bcL) in na\u00efve rats followed by D1 receptor autoradiography. We then injected stressin I (0.01 \u03bcg\/0.5\u00a0\u03bcL) and stressin I in combination with the D1 antagonist SCH23390 (120 ng\/0.5\u00a0\u03bcL) site-specifically into the ITC and tested animals in the Elevated-Plus-Maze (EPM), followed by saturated D1 receptor autoradiography. Alcohol dependence was also induced in rats and D1<jats:sup>Cre<\/jats:sup>-Crhr1<jats:sup>\u2212\/\u2212<\/jats:sup> knockout mice <jats:italic>via<\/jats:italic> cyclic intermittent alcohol vapor exposure. Following abstinence, rats were used for D1 expression analysis (<jats:italic>in situ<\/jats:italic> hybridization, D1 autoradiography) and assessment of morphological changes using Golgi-impregnation. In addition, abstinent D1<jats:sup>Cre<\/jats:sup>-Crhr1<jats:sup>\u2212\/\u2212<\/jats:sup> mice were analyzed for alcohol drinking and stress-related alcohol drinking (Two-Bottle-Free-Choice, Forced Swim Stress-induced drinking). Double-immunofluorescence immunostainings were performed for D1 and CRHR1 in the amygdala of <jats:italic>Crhr1<\/jats:italic>-GFP reporter mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Pharmacological activation of CRHR1 by i. c.v. injection of CRH or stressin I increased D1 binding sites exclusively in the amygdala, but not in extra-amygdala brain regions. Site-specific CRHR1 activation in the amygdala\/ITC was associated with increased anxiety-like behavior that was prevented by co-treatment with SCH23390. In dependent D1<jats:sup>Cre<\/jats:sup>-Crhr1<jats:sup>\u2212\/\u2212<\/jats:sup> mice, the D1-CRHR1 interaction appears to be critically involved in maladaptive stress coping and increased relapse propensity. Our immunohistochemical findings also suggest the D1-CRHR1 interaction is dependent on co-localized receptors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings suggest D1-CRHR1 interactions within the ITC of the amygdala in response to stress, alcohol behavior, and the development of dependence, thereby providing a novel mechanism that may be targetable by therapeutic polypharmacological interference.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1677510","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T05:33:10Z","timestamp":1760592790000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Reducing stress and alcohol-related behaviors by targeting D1-CRHR1 receptor interactions in the amygdala"],"prefix":"10.3389","volume":"16","author":[{"given":"Laura","family":"Broccoli","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rick E.","family":"Bernardi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Giannone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anika","family":"Hoppe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kay","family":"Jungling","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dasiel O.","family":"Borroto-Escuela","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberto","family":"Rimondini-Giorgini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miguel","family":"P\u00e9rez de la Mora","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oliver","family":"von Bohlen und Halbach","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kjell","family":"Fuxe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans-Christian","family":"Pape","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan M.","family":"Deussing","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rainer","family":"Spanagel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolfgang H.","family":"Sommer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anita C.","family":"Hansson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1038\/nn.2499","article-title":"Synaptic correlates of fear extinction in the amygdala","volume":"13","author":"Amano","year":"2010","journal-title":"Nat. Neurosci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"109151","DOI":"10.1016\/j.celrep.2021.109151","article-title":"Apical intercalated cell cluster: a distinct sensory regulator in the amygdala","volume":"35","author":"Asede","year":"2021","journal-title":"Cell Rep."},{"key":"B3","doi-asserted-by":"publisher","first-page":"9098","DOI":"10.1523\/JNEUROSCI.1176-22.2022","article-title":"Amygdala intercalated cells: gate keepers and conveyors of internal state to the circuits of emotion","volume":"42","author":"Asede","year":"2022","journal-title":"J. Neurosci."},{"key":"B4","doi-asserted-by":"crossref","first-page":"2926","DOI":"10.1523\/JNEUROSCI.22-07-02926.2002","article-title":"Reduction of stress-induced behavior by antagonism of corticotropin-releasing hormone 2 (CRH2) receptors in lateral septum or CRH1 receptors in amygdala","volume":"22","author":"Bakshi","year":"2002","journal-title":"J. Neurosci."},{"key":"B5","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1038\/74263","article-title":"Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress","volume":"24","author":"Bale","year":"2000","journal-title":"Nat. Genet."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1829","DOI":"10.1097\/01.alc.0000149977.95306.3a","article-title":"Increased ethanol drinking after repeated chronic ethanol exposure and withdrawal experience in C57BL\/6 mice","volume":"28","author":"Becker","year":"2004","journal-title":"Alcohol Clin. Exp. Res."},{"key":"B7","doi-asserted-by":"publisher","first-page":"774","DOI":"10.1093\/ntr\/ntt274","article-title":"Transcriptional regulation of L-type calcium channel subtypes Cav1.2 and Cav1.3 by nicotine and their potential role in nicotine sensitization","volume":"16","author":"Bernardi","year":"2014","journal-title":"Nicotine Tob. Res."},{"key":"B8","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.drugalcdep.2015.08.016","article-title":"Sex differences in dopamine binding and modafinil conditioned place preference in mice","volume":"155","author":"Bernardi","year":"2015","journal-title":"Drug Alcohol Depend."},{"key":"B9","doi-asserted-by":"publisher","first-page":"221","DOI":"10.3389\/fnbeh.2017.00221","article-title":"Dissociable role of corticotropin releasing hormone receptor subtype 1 on dopaminergic and D1 dopaminoceptive neurons in cocaine seeking behavior","volume":"11","author":"Bernardi","year":"2017","journal-title":"Front. Behav. Neurosci."},{"key":"B10","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1016\/j.bbrc.2010.09.110","article-title":"Dopamine D2 and 5-hydroxytryptamine 5-HT(\u2082A) receptors assemble into functionally interacting heteromers","volume":"401","author":"Borroto-Escuela","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B11","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1016\/j.bbrc.2013.10.067","article-title":"Dynamic modulation of FGFR1-5-HT1A heteroreceptor complexes. Agonist treatment enhances participation of FGFR1 and 5-HT1A homodimers and recruitment of beta-arrestin2","volume":"441","author":"Borroto-Escuela","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B12","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1111\/j.1527-3458.2001.tb00207.x","article-title":"SCH 23390: the first selective dopamine D1-like receptor antagonist","volume":"7","author":"Bourne","year":"2001","journal-title":"CNS Drug Rev."},{"key":"B13","article-title":"Cross-talk of the corticotropin releasing hormone receptor subtype 1 with the dopamine system: functional evidence on emotional responses to stress and alcohol dependence","author":"Broccoli","year":"2016"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1821","DOI":"10.1007\/s00213-018-4908-6","article-title":"Targeted overexpression of CRH receptor subtype 1 in central amygdala neurons: effect on alcohol-seeking behavior","volume":"235","author":"Broccoli","year":"2018","journal-title":"Psychopharmacol. Berl."},{"key":"B15","doi-asserted-by":"publisher","first-page":"e8528","DOI":"10.1371\/journal.pone.0008528","article-title":"CRF1-R activation of the dynorphin\/kappa opioid system in the mouse basolateral amygdala mediates anxiety-like behavior","volume":"4","author":"Bruchas","year":"2009","journal-title":"PLoS One"},{"key":"B16","doi-asserted-by":"publisher","first-page":"5131","DOI":"10.1523\/JNEUROSCI.6100-10.2011","article-title":"Different fear states engage distinct networks within the intercalated cell clusters of the amygdala","volume":"31","author":"Busti","year":"2011","journal-title":"J. Neurosci."},{"key":"B17","doi-asserted-by":"publisher","first-page":"3441","DOI":"10.1046\/j.1460-9568.1999.00763.x","article-title":"Spontaneous and evoked activity of intercalated amygdala neurons","volume":"11","author":"Collins","year":"1999","journal-title":"Eur. J. Neurosci."},{"key":"B18","doi-asserted-by":"publisher","first-page":"20016","DOI":"10.1073\/pnas.0908789106","article-title":"CRF system recruitment mediates dark side of compulsive eating","volume":"106","author":"Cottone","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B19","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.neulet.2004.11.079","article-title":"Anxiolytic effects of intra-amygdaloid injection of the D1 antagonist SCH23390 in the rat","volume":"377","author":"De La Mora","year":"2005","journal-title":"Neurosci. Lett."},{"key":"B20","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1038\/s41593-018-0151-z","article-title":"Chronic CRH depletion from GABAergic, long-range projection neurons in the extended amygdala reduces dopamine release and increases anxiety","volume":"21","author":"Dedic","year":"2018","journal-title":"Nat. Neurosci."},{"key":"B21","doi-asserted-by":"publisher","first-page":"3896","DOI":"10.1210\/endo.137.9.8756563","article-title":"Cloning and characterization of human urocortin","volume":"137","author":"Donaldson","year":"1996","journal-title":"Endocrinology"},{"key":"B22","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/0306-4522(86)90010-2","article-title":"Autoradiographic distribution of the D1 agonist [3H]SKF 38393, in the rat brain and spinal cord. Comparison with the distribution of D2 dopamine receptors","volume":"19","author":"Dubois","year":"1986","journal-title":"Neuroscience"},{"key":"B23","doi-asserted-by":"publisher","first-page":"966","DOI":"10.1016\/j.neuron.2014.04.042","article-title":"Amygdala microcircuits controlling learned fear","volume":"82","author":"Duvarci","year":"2014","journal-title":"Neuron"},{"key":"B24","doi-asserted-by":"publisher","first-page":"752","DOI":"10.1111\/acer.12686","article-title":"Chronic intermittent ethanol exposure in mice leads to an up-regulation of CRH\/CRHR1 signaling","volume":"39","author":"Eisenhardt","year":"2015","journal-title":"Alcohol Clin. Exp. Res."},{"key":"B25","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1124\/mol.104.003624","article-title":"Evidence for negative binding cooperativity within CCR5-CCR2b heterodimers","volume":"67","author":"El-Asmar","year":"2005","journal-title":"Mol. Pharmacol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1016\/s0006-8993(00)03234-0","article-title":"Prolonged fear responses in mice lacking dopamine D1 receptor","volume":"892","author":"El-Ghundi","year":"2001","journal-title":"Brain Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1016\/j.neuroscience.2005.10.062","article-title":"Effects of environmental and pharmacological stressors on c-fos and corticotropin-releasing factor mRNA in rat brain: relationship to the reinstatement of alcohol seeking","volume":"138","author":"Funk","year":"2006","journal-title":"Neuroscience"},{"key":"B29","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1016\/s0306-4522(03)00148-9","article-title":"The dopamine D1 receptor-rich main and paracapsular intercalated nerve cell groups of the rat amygdala: relationship to the dopamine innervation","volume":"119","author":"Fuxe","year":"2003","journal-title":"Neuroscience"},{"key":"B30","volume-title":"Holm-Bonferroni sequencial correction: an EXCEL calculator-ver, 1.2","author":"Gaetano","year":"2013"},{"key":"B31","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1016\/S2215-0366(18)30337-7","article-title":"The global burden of disease attributable to alcohol and drug use in 195 countries and territories, 1990\u20132016: a systematic analysis for the Global Burden of Disease Study 2016","volume":"5","year":"2018","journal-title":"Lancet Psychiatry"},{"key":"B32","doi-asserted-by":"publisher","first-page":"2718","DOI":"10.1523\/JNEUROSCI.4985-06.2007","article-title":"3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl-imidazo [1,2-b]pyridazine: a novel brain-penetrant, orally available corticotropin-releasing factor receptor 1 antagonist with efficacy in animal models of alcoholism","volume":"27","author":"Gehlert","year":"2007","journal-title":"J. Neurosci."},{"key":"B33","doi-asserted-by":"publisher","first-page":"2113","DOI":"10.1111\/j.1530-0277.2009.01051.x","article-title":"Operant behavior and alcohol levels in blood and brain of alcohol-dependent rats","volume":"33","author":"Gilpin","year":"2009","journal-title":"Alcohol Clin. Exp. Res."},{"key":"B34","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1111\/j.1476-5381.2011.01631.x","article-title":"Insights into mechanisms of corticotropin-releasing hormone receptor signal transduction","volume":"166","author":"Grammatopoulos","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1007\/s00213-008-1324-3","article-title":"Repeated cycles of chronic intermittent ethanol exposure in mice increases voluntary ethanol drinking and ethanol concentrations in the nucleus accumbens","volume":"201","author":"Griffin","year":"2009","journal-title":"Psychopharmacol. Berl."},{"key":"B36","doi-asserted-by":"publisher","first-page":"732","DOI":"10.1111\/j.1749-6632.1999.tb09312.x","article-title":"A functional role for dopamine transmission in the amygdala during conditioned fear","volume":"877","author":"Guarraci","year":"1999","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"B37","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1038\/s41586-021-03593-1","article-title":"Intercalated amygdala clusters orchestrate a switch in fear state","volume":"594","author":"Hagihara","year":"2021","journal-title":"Nature"},{"key":"B38","doi-asserted-by":"publisher","first-page":"6535","DOI":"10.1523\/JNEUROSCI.4773-08.2009","article-title":"Chronic cocaine enhances corticotropin-releasing factor-dependent potentiation of excitatory transmission in ventral tegmental area dopamine neurons","volume":"29","author":"Hahn","year":"2009","journal-title":"J. Neurosci."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1099","DOI":"10.1111\/ejn.16157","article-title":"65 years of research on dopamine\u2019s role in classical fear conditioning and extinction: a systematic review","volume":"59","author":"Hamati","year":"2024","journal-title":"EJN"},{"key":"B40","doi-asserted-by":"publisher","first-page":"15236","DOI":"10.1073\/pnas.0604419103","article-title":"Variation at the rat Crhr1 locus and sensitivity to relapse into alcohol seeking induced by environmental stress","volume":"103","author":"Hansson","year":"","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B41","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1111\/j.1365-2826.2005.01390.x","article-title":"Corticosterone actions on the hippocampal brain-derived neurotrophic factor expression are mediated by exon IV promoter","volume":"18","author":"Hansson","year":"","journal-title":"J. Neuroendocrinol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.neubiorev.2018.09.010","article-title":"Dopamine and opioid systems adaptation in alcoholism revisited: convergent evidence from positron emission tomography and postmortem studies","volume":"106","author":"Hansson","year":"2019","journal-title":"Neurosci. Biobehav Rev."},{"key":"B43","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1016\/j.tins.2007.06.006","article-title":"A key role for corticotropin-releasing factor in alcohol dependence","volume":"30","author":"Heilig","year":"2007","journal-title":"Trends Neurosci."},{"key":"B44","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1016\/j.neubiorev.2009.11.018","article-title":"Translating the neuroscience of alcoholism into clinical treatments: from blocking the buzz to curing the blues","volume":"35","author":"Heilig","year":"2010","journal-title":"Neurosci. Biobehav Rev."},{"key":"B45","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1038\/nrn3110","article-title":"Pharmacogenetic approaches to the treatment of alcohol addiction","volume":"12","author":"Heilig","year":"2011","journal-title":"Nat. Rev. Neurosci."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1644","DOI":"10.1038\/nn.3869","article-title":"Encoding of fear learning and memory in distributed neuronal circuits","volume":"17","author":"Herry","year":"2014","journal-title":"Nat. Neurosci."},{"key":"B47","doi-asserted-by":"publisher","first-page":"18091","DOI":"10.1074\/jbc.M107731200","article-title":"Coaggregation, cointernalization, and codesensitization of adenosine A2A receptors and dopamine D2 receptors","volume":"277","author":"Hillion","year":"2002","journal-title":"J. Biol. Chem."},{"key":"B48","doi-asserted-by":"publisher","first-page":"3024","DOI":"10.1073\/pnas.1506012113","article-title":"Convergent evidence from alcohol-dependent humans and rats for a hyperdopaminergic state in protracted abstinence","volume":"113","author":"Hirth","year":"2016","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B49","first-page":"65","article-title":"A simple sequential rejective method procedure","author":"Holm","year":"1979","journal-title":"Scand. J. Stat."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1088","DOI":"10.1046\/j.1471-4159.1999.0721088.x","article-title":"Dopaminergic innervation of the amygdala is highly responsive to stress","volume":"72","author":"Inglis","year":"1999","journal-title":"J. Neurochem."},{"key":"B51","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1016\/j.biopsych.2012.08.021","article-title":"Contrasting effects of pretraining, posttraining, and pretesting infusions of corticotropin-releasing factor into the lateral amygdala: attenuation of fear memory formation but facilitation of its expression","volume":"73","author":"Isogawa","year":"2013","journal-title":"Biol. Psychiatry"},{"key":"B52","doi-asserted-by":"publisher","first-page":"2007","DOI":"10.1016\/j.neuroscience.2006.05.054","article-title":"The distribution of dopamine D1 receptor and mu-opioid receptor 1 receptor immunoreactivities in the amygdala and interstitial nucleus of the posterior limb of the anterior commissure: relationships to tyrosine hydroxylase and opioid peptide terminal systems","volume":"141","author":"Jacobsen","year":"2006","journal-title":"Neuroscience"},{"key":"B53","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1016\/j.neuron.2008.07.002","article-title":"Neuropeptide S-mediated control of fear expression and extinction: role of intercalated GABAergic neurons in the amygdala","volume":"59","author":"Jungling","year":"2008","journal-title":"Neuron"},{"key":"B54","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1002\/cne.21848","article-title":"Type 1 corticotropin-releasing factor receptor expression reported in BAC transgenic mice: implications for reconciling ligand-receptor mismatch in the central corticotropin-releasing factor system","volume":"511","author":"Justice","year":"2008","journal-title":"J. Comp. Neurol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"13856","DOI":"10.1523\/JNEUROSCI.4715-08.2008","article-title":"Dopamine enhances fast excitatory synaptic transmission in the extended amygdala by a CRF-R1-dependent process","volume":"28","author":"Kash","year":"2008","journal-title":"J. Neurosci."},{"key":"B56","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1038\/74271","article-title":"Deletion of crhr2 reveals an anxiolytic role for corticotropin-releasing hormone receptor-2","volume":"24","author":"Kishimoto","year":"2000","journal-title":"Nat. Genet."},{"key":"B57","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.neubiorev.2018.09.008","article-title":"Addiction and stress: an allostatic view","volume":"106","author":"Koob","year":"2019","journal-title":"Neurosci. Biobehav Rev."},{"key":"B58","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.1038\/npp.2014.306","article-title":"The corticotropin releasing hormone-1 (CRH1) receptor antagonist pexacerfont in alcohol dependence: a randomized controlled experimental medicine study","volume":"40","author":"Kwako","year":"2015","journal-title":"Neuropsychopharmacology"},{"key":"B59","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1016\/s0006-8993(98)00281-9","article-title":"Infusion of the dopamine D1 receptor antagonist SCH 23390 into the amygdala blocks fear expression in a potentiated startle paradigm","volume":"795","author":"Lamont","year":"1998","journal-title":"Brain Res."},{"key":"B60","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1146\/annurev.neuro.23.1.155","article-title":"Emotion circuits in the brain","volume":"23","author":"Ledoux","year":"2000","journal-title":"Annu. Rev. Neurosci."},{"key":"B61","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1177\/1073858416679936","article-title":"Amygdala circuits for fear memory: a key role for dopamine regulation","volume":"23","author":"Lee","year":"2017","journal-title":"Neuroscientist"},{"key":"B62","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.coph.2009.10.007","article-title":"Dimerization in GPCR mobility and signaling","volume":"10","author":"Lohse","year":"2010","journal-title":"Curr. Opin. Pharmacol."},{"key":"B63","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1007\/s00213-005-0026-3","article-title":"Effect of pattern and number of chronic ethanol exposures on subsequent voluntary ethanol intake in C57BL\/6J mice","volume":"181","author":"Lopez","year":"2005","journal-title":"Psychopharmacol. Berl."},{"key":"B64","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1007\/7854_2022_412","article-title":"Synaptic effects induced by alcohol","volume":"71","author":"Lovinger","year":"2023","journal-title":"Curr. Top. Behav. Neurosci."},{"key":"B65","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1016\/j.neuroscience.2012.08.067","article-title":"Intercalated and paracapsular cell islands of the adult rat amygdala: a combined rapid-Golgi, ultrastructural, and immunohistochemical account","volume":"226","author":"Marcellino","year":"2012","journal-title":"Neuroscience"},{"key":"B66","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1016\/j.neuron.2005.10.029","article-title":"A specialized subclass of interneurons mediates dopaminergic facilitation of amygdala function","volume":"48","author":"Marowsky","year":"2005","journal-title":"Neuron"},{"key":"B67","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1002\/cne.902080409","article-title":"Cytoarchitecture of the central amygdaloid nucleus of the rat","volume":"208","author":"Mcdonald","year":"1982","journal-title":"J. Comp. Neurol."},{"key":"B68","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/0304-3940(85)90186-7","article-title":"Immunohistochemical identification of gamma-aminobutyric acid-containing neurons in the rat basolateral amygdala","volume":"53","author":"Mcdonald","year":"1985","journal-title":"Neurosci. Lett."},{"key":"B69","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/0306-4522(93)90156-a","article-title":"Localization of GABA-like immunoreactivity in the monkey amygdala","volume":"52","author":"Mcdonald","year":"1993","journal-title":"Neuroscience"},{"key":"B70","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/adb.12187","article-title":"Postdependent state in rats as a model for medication development in alcoholism","volume":"20","author":"Meinhardt","year":"2015","journal-title":"Addict. Biol."},{"key":"B71","doi-asserted-by":"publisher","first-page":"1259","DOI":"10.1038\/npp.2014.312","article-title":"The neurometabolic fingerprint of excessive alcohol drinking","volume":"40","author":"Meinhardt","year":"2015","journal-title":"Neuropsychopharmacology"},{"key":"B72","doi-asserted-by":"publisher","first-page":"3855","DOI":"10.1523\/JNEUROSCI.4957-05.2006","article-title":"Behavioral and anatomical interactions between dopamine and corticotropin-releasing factor in the rat","volume":"26","author":"Meloni","year":"2006","journal-title":"J. Neurosci."},{"key":"B73","doi-asserted-by":"publisher","first-page":"4758","DOI":"10.1523\/JNEUROSCI.18-12-04758.1998","article-title":"Aversive and appetitive events evoke the release of corticotropin-releasing hormone and bombesin-like peptides at te central nucleus of the amygdala","volume":"18","author":"Merali","year":"1998","journal-title":"J. Neurosci."},{"key":"B74","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1002\/cne.902470209","article-title":"The intercalated cells of the amygdala","volume":"247","author":"Millhouse","year":"1986","journal-title":"J. Comp. Neurol."},{"key":"B75","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1038\/npp.2011.297","article-title":"Brain-specific inactivation of the Crhr1 gene inhibits post-dependent and stress-induced alcohol intake, but does not affect relapse-like drinking","volume":"37","author":"Molander","year":"2012","journal-title":"Neuropsychopharmacology"},{"key":"B76","doi-asserted-by":"publisher","first-page":"858","DOI":"10.1016\/j.biopsych.2017.10.012","article-title":"Corticotropin-releasing factor type 1 receptor antagonists for stress-related disorders: time to call it quits?","volume":"82","author":"Murrough","year":"2017","journal-title":"Biol. Psychiatry"},{"key":"B77","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1093\/alcalc\/agp065","article-title":"Augmented stress-induced alcohol drinking and withdrawal in mice lacking functional natriuretic peptide-A receptors","volume":"45","author":"Mutschler","year":"2010","journal-title":"Alcohol Alcohol"},{"key":"B78","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1002\/cne.902660105","article-title":"Distribution of GABA-like immunoreactivity in the rat amygdaloid complex","volume":"266","author":"Nitecka","year":"1987","journal-title":"J. Comp. Neurol."},{"key":"B79","doi-asserted-by":"publisher","first-page":"1558","DOI":"10.1016\/S0140-6736(10)61462-6","article-title":"Drug harms in the UK: a multicriteria decision analysis","volume":"376","author":"Nutt","year":"2010","journal-title":"Lancet"},{"key":"B80","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1523\/JNEUROSCI.2666-07.2008","article-title":"Dopamine and corticotropin-releasing factor synergistically alter basolateral amygdala-to-medial prefrontal cortex synaptic transmission: functional switch after chronic cocaine administration","volume":"28","author":"Orozco-Cabal","year":"2008","journal-title":"J. Neurosci."},{"key":"B81","doi-asserted-by":"publisher","first-page":"1077","DOI":"10.1016\/0306-4522(93)90050-p","article-title":"The intercalated cell masses project to the central and medial nuclei of the amygdala in cats","volume":"57","author":"Pare","year":"1993","journal-title":"Neuroscience"},{"key":"B27","volume-title":"The mouse brain in stereotaxic coordinates","author":"Paxinos","year":"2007"},{"key":"B82","volume-title":"The rat brain in stereotaxic coordinates","author":"Paxinos","year":"1998"},{"key":"B83","doi-asserted-by":"publisher","first-page":"1903","DOI":"10.1126\/science.1202107","article-title":"Glutamatergic and dopaminergic neurons mediate anxiogenic and anxiolytic effects of CRHR1","volume":"333","author":"Refojo","year":"2011","journal-title":"Science"},{"key":"B84","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1016\/j.neuron.2007.12.029","article-title":"CRF facilitates calcium release from intracellular stores in midbrain dopamine neurons","volume":"57","author":"Riegel","year":"2008","journal-title":"Neuron"},{"key":"B85","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1096\/fj.01-0593com","article-title":"Long-lasting increase in voluntary ethanol consumption and transcriptional regulation in the rat brain after intermittent exposure to alcohol","volume":"16","author":"Rimondini","year":"2002","journal-title":"FASEB J."},{"key":"B86","doi-asserted-by":"publisher","first-page":"4737","DOI":"10.1021\/jm0202122","article-title":"Potent and long-acting corticotropin releasing factor (CRF) receptor 2 selective peptide competitive antagonists","volume":"45","author":"Rivier","year":"2002","journal-title":"J. Med. Chem."},{"key":"B87","doi-asserted-by":"publisher","first-page":"1668","DOI":"10.1021\/jm0613875","article-title":"Stressin1-A, a potent corticotropin releasing factor receptor 1 (CRF1)-selective peptide agonist","volume":"50","author":"Rivier","year":"2007","journal-title":"J. Med. Chem."},{"key":"B88","doi-asserted-by":"publisher","first-page":"a039339","DOI":"10.1101\/cshperspect.a039339","article-title":"The role of the central amygdala in alcohol dependence","volume":"11","author":"Roberto","year":"2021","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"B90","doi-asserted-by":"publisher","first-page":"10575","DOI":"10.1523\/JNEUROSCI.19-23-10575.1999","article-title":"An inhibitory interface gates impulse traffic between the input and output stations of the amygdala","volume":"19","author":"Royer","year":"1999","journal-title":"J. Neurosci."},{"key":"B91","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/j.neuron.2016.11.034","article-title":"A central amygdala CRF circuit facilitates learning about weak threats","volume":"93","author":"Sanford","year":"2017","journal-title":"Neuron"},{"key":"B92","doi-asserted-by":"publisher","first-page":"1601","DOI":"10.1111\/j.1471-4159.1985.tb07233.x","article-title":"Binding of [3H]SCH23390 in rat brain: regional distribution and effects of assay conditions and GTP suggest interactions at a D1-like dopamine receptor","volume":"45","author":"Schulz","year":"1985","journal-title":"J. Neurochem."},{"key":"B93","doi-asserted-by":"publisher","first-page":"2818","DOI":"10.1038\/npp.2016.61","article-title":"The CRF1 antagonist verucerfont in anxious alcohol-dependent women: translation of neuroendocrine, but not of anti-craving effects","volume":"41","author":"Schwandt","year":"2016","journal-title":"Neuropsychopharmacology"},{"key":"B94","doi-asserted-by":"publisher","first-page":"2795","DOI":"10.1038\/npp.2016.94","article-title":"Lost in translation: CRF1 receptor antagonists and addiction treatment","volume":"41","author":"Shaham","year":"2016","journal-title":"Neuropsychopharmacology"},{"key":"B95","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1126\/science.1069836","article-title":"Enhanced and delayed stress-induced alcohol drinking in mice lacking functional CRH1 receptors","volume":"296","author":"Sillaber","year":"2002","journal-title":"Science"},{"key":"B96","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1111\/adb.12024","article-title":"Intermittent access ethanol consumption dysregulates CRF function in the hypothalamus and is attenuated by the CRF-R1 antagonist, CP-376395","volume":"19","author":"Simms","year":"2014","journal-title":"Addict. Biol."},{"key":"B97","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1016\/s0196-9781(01)00384-9","article-title":"The role of CRH in behavioral responses to stress","volume":"22","author":"Smagin","year":"2001","journal-title":"Peptides"},{"key":"B98","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.biopsych.2007.01.010","article-title":"Upregulation of voluntary alcohol intake, behavioral sensitivity to stress, and amygdala crhr1 expression following a history of dependence","volume":"63","author":"Sommer","year":"2008","journal-title":"Biol. Psychiatry"},{"key":"B99","doi-asserted-by":"publisher","first-page":"87","DOI":"10.3389\/fnint.2014.00087","article-title":"Dopamine systems adaptation during acquisition and consolidation of a skill","volume":"8","author":"Sommer","year":"2014","journal-title":"Front. Integr. Neurosci."},{"key":"B100","doi-asserted-by":"publisher","first-page":"247","DOI":"10.31887\/DCNS.2017.19.3\/rspanagel","article-title":"Animal models of addiction","volume":"19","author":"Spanagel","year":"2017","journal-title":"Dialogues Clin. Neurosci."},{"key":"B101","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1093\/alcalc\/34.2.231","article-title":"Long-term alcohol self-administration with repeated alcohol deprivation phases: an animal model of alcoholism?","volume":"34","author":"Spanagel","year":"1999","journal-title":"Alcohol Alcohol"},{"key":"B102","doi-asserted-by":"publisher","first-page":"e13419","DOI":"10.1111\/adb.13419","article-title":"The ReCoDe addiction research consortium: losing and regaining control over drug intake-findings and future perspectives","volume":"29","author":"Spanagel","year":"2024","journal-title":"Addict. Biol."},{"key":"B103","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1002\/cne.10905","article-title":"Green fluorescent protein expression and colocalization with calretinin, parvalbumin, and somatostatin in the GAD67-GFP knock-in mouse","volume":"467","author":"Tamamaki","year":"2003","journal-title":"J. Comp. Neurol."},{"key":"B104","doi-asserted-by":"publisher","first-page":"3950","DOI":"10.1038\/sj.emboj.7600387","article-title":"Receptor activity-independent recruitment of betaarrestin2 reveals specific signalling modes","volume":"23","author":"Terrillon","year":"2004","journal-title":"EMBO J."},{"key":"B105","doi-asserted-by":"publisher","first-page":"111310","DOI":"10.1016\/j.pnpbp.2025.111310","article-title":"Fear conditioning: insights into learning, memory and extinction and its relevance to clinical disorders","volume":"138","author":"Trent","year":"2025","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"B106","doi-asserted-by":"publisher","first-page":"1058","DOI":"10.1038\/npp.2016.266","article-title":"Differential roles for L-Type calcium channel subtypes in alcohol dependence","volume":"42","author":"Uhrig","year":"2017","journal-title":"Neuropsychopharmacology"},{"key":"B107","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/s0741-8329(03)00020-x","article-title":"Antagonism of corticotropin-releasing factor attenuates the enhanced responsiveness to stress observed during protracted ethanol abstinence","volume":"29","author":"Valdez","year":"2003","journal-title":"Alcohol"},{"key":"B108","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1016\/j.biopsych.2005.08.025","article-title":"Regional- and age-dependent reduction in trkB receptor expression in the hippocampus is associated with altered spine morphologies","volume":"59","author":"Von Bohlen Und Halbach","year":"2006","journal-title":"Biol. Psychiatry"},{"key":"B109","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1101\/lm.808608","article-title":"Selective and protracted effect of nifedipine on fear memory extinction correlates with induced stress response","volume":"15","author":"Waltereit","year":"2008","journal-title":"Learn Mem."},{"key":"B110","doi-asserted-by":"publisher","first-page":"2157","DOI":"10.1113\/jphysiol.2007.150078","article-title":"Corticotropin-releasing factor increases mouse ventral tegmental area dopamine neuron firing through a protein kinase C-dependent enhancement of Ih","volume":"586","author":"Wanat","year":"2008","journal-title":"J. Physiol."},{"key":"B111","doi-asserted-by":"publisher","first-page":"e17047","DOI":"10.1371\/journal.pone.0017047","article-title":"Convergent processing of both positive and negative motivational signals by the VTA dopamine neuronal populations","volume":"6","author":"Wang","year":"2011","journal-title":"PLoS One"},{"key":"B112","volume-title":"Global status report on alcohol and health","year":"2018"},{"key":"B113","doi-asserted-by":"publisher","first-page":"1041929","DOI":"10.3389\/fnbeh.2022.1041929","article-title":"Dopaminergic circuits underlying associative aversive learning","volume":"16","author":"Zafiri","year":"2022","journal-title":"Front. Behav. Neurosci."},{"key":"B114","doi-asserted-by":"publisher","first-page":"eabj9019","DOI":"10.1126\/sciadv.abj9019","article-title":"Opposite effects of stress on effortful motivation in high and low anxiety are mediated by CRHR1 in the VTA","volume":"8","author":"Zalachoras","year":"2022","journal-title":"Sci. Adv."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1677510\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T05:33:13Z","timestamp":1760592793000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1677510\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,16]]},"references-count":113,"alternative-id":["10.3389\/fphar.2025.1677510"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1677510","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,16]]},"article-number":"1677510"}}