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Yohimbine as a pharmacological probe for alcohol research: a systematic review of rodent and human studies

Abstract

Alcohol use disorder (AUD) is a significant public health concern, contributing to a myriad of social, psychological, and physiological issues. Despite substantial efforts within the alcohol research field, promising preclinical findings have failed to translate to clinical use, highlighting the necessity to develop safe and effective pharmacological probes with the ability to be used in preclinical and clinical research. Yohimbine, an α2 adrenergic receptor antagonist, is a well-validated pharmacological tool that has been widely employed in alcohol studies to evaluate noradrenergic activation. This scoping systematic review examines published literature in rodent and human studies involving the use of yohimbine relevant to alcohol research. We conducted a systematic literature review of MEDLINE, Embase, Web of Science Core Collection, CINAHL, PsycInfo, and Cochrane Central Register of Controlled Trials to identify: (1) Experimental Characteristics and Methodology, (2) Sex Differences, (3) Neurochemical Systems and Brain Regions, and (4) Discussion of Applications for Medication Development. Sixty-seven (62 preclinical and 5 clinical) studies were identified meeting the stated criteria, comprising extensive evidence supporting the use of yohimbine as a safe, titratable pharmacological agent for translational alcohol research. Support for the use of yohimbine as a fully translational tool, however, is hindered by limited available findings from human laboratory studies, as well as a dearth of studies examining sex differences in yohimbine’s mechanistic actions. Additional consideration should be given to further translational modeling, ideally allowing for parallel preclinical and clinical assessment of yohimbine, methodological assessment of neurochemical systems and brain regions.

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Fig. 1: PRISMA Flowchart.
Fig. 2: Yohimbine doses administered in animal studies.

References

  1. Grant BF, Goldstein RB, Saha TD, Chou SP, Jung J, Zhang H, et al. Epidemiology of DSM-5 alcohol use disorder: results from the national epidemiologic survey on alcohol and related conditions III. JAMA Psychiatry. 2015;72:757–66. https://doi.org/10.1001/jamapsychiatry.2015.0584.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Koob G, Kreek MJ. Stress, dysregulation of drug reward pathways, and the transition to drug dependence. Am J Psychiatry. 2007;164:1149–59. https://doi.org/10.1176/appi.ajp.2007.05030503.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Sinha R. How does stress lead to risk of alcohol relapse? Alcohol Res. 2012;34:432–40.

    PubMed  PubMed Central  Google Scholar 

  4. Spierling SR, Zorrilla EP. Don’t stress about CRF: assessing the translational failures of CRF(1)antagonists. Psychopharmacol (Berl). 2017;234:1467–81. https://doi.org/10.1007/s00213-017-4556-2.

    CAS  Article  Google Scholar 

  5. Haass-Koffler CL, Swift RM, Leggio L. Noradrenergic targets for the treatment of alcohol use disorder. Psychopharmacol (Berl). 2018;235:1625–34. https://doi.org/10.1007/s00213-018-4843-6.

    CAS  Article  Google Scholar 

  6. Skelly MJ, Chappell AE, Carter E, Weiner JL. Adolescent social isolation increases anxiety-like behavior and ethanol intake and impairs fear extinction in adulthood: Possible role of disrupted noradrenergic signaling. Neuropharmacology. 2015;97:149–59. https://doi.org/10.1016/j.neuropharm.2015.05.025.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Kenna GA, Haass-Koffler CL, Zywiak WH, Edwards SM, Brickley MB, Swift RM, et al. Role of the α1 blocker doxazosin in alcoholism: a proof-of-concept randomized controlled trial. Addict Biol. 2016;21:904–14. https://doi.org/10.1111/adb.12275.

    CAS  Article  PubMed  Google Scholar 

  8. McCall JG, Al-Hasani R, Siuda ER, Hong DY, Norris AJ, Ford CP, et al. CRH engagement of the locus coeruleus noradrenergic system mediates stress-induced anxiety. Neuron. 2015;87:605–20. https://doi.org/10.1016/j.neuron.2015.07.002.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Szabadi E. Functional neuroanatomy of the central noradrenergic system. J Psychopharmacol. 2013;27:659–93. https://doi.org/10.1177/0269881113490326.

    CAS  Article  PubMed  Google Scholar 

  10. Bremner JD, Krystal JH, Southwick SM, Charney DS. Noradrenergic mechanisms in stress and anxiety: I. Preclinical studies. Synapse. 1996;23:28–38.

    CAS  Article  Google Scholar 

  11. Bremner JD, Krystal JH, Southwick SM, Charney DS. Noradrenergic mechanisms in stress and anxiety: II. Clinical studies. Synapse. 1996;23:39–51.

    CAS  Article  Google Scholar 

  12. Haass-Koffler CL, Bartlett SE. Stress and addiction: contribution of the corticotropin releasing factor (CRF) system in neuroplasticity. Front Mol Neurosci. 2012;5:91 https://doi.org/10.3389/fnmol.2012.00091.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Simms JA, Haass-Koffler CL, Bito-Onon J, Li R, Bartlett SE. Mifepristone in the central nucleus of the amygdala reduces yohimbine stress-induced reinstatement of ethanol-seeking. Neuropsychopharmacology. 2012;37:906–18. https://doi.org/10.1038/npp.2011.268.

    CAS  Article  PubMed  Google Scholar 

  14. Marinelli PW, Funk D, Juzytsch W, Harding S, Rice KC, Shaham Y, et al. The CRF1 receptor antagonist antalarmin attenuates yohimbine-induced increases in operant alcohol self-administration and reinstatement of alcohol seeking in rats. Psychopharmacol (Berl). 2007;195:345–55. https://doi.org/10.1007/s00213-007-0905-x.

    CAS  Article  Google Scholar 

  15. Bertholomey ML, Verplaetse TL, Czachowski CL. Alterations in ethanol seeking and self-administration following yohimbine in selectively bred alcohol-preferring (P) and high alcohol drinking (HAD-2) rats. Behav Brain Res. 2013;238:252–8. https://doi.org/10.1016/j.bbr.2012.10.030.

    CAS  Article  PubMed  Google Scholar 

  16. Funk D, Coen K, Tamadon S, Li Z, Loughlin A, Lê AD. Effects of prazosin and doxazosin on yohimbine-induced reinstatement of alcohol seeking in rats. Psychopharmacol (Berl). 2016;233:2197–207. https://doi.org/10.1007/s00213-016-4273-2.

    CAS  Article  Google Scholar 

  17. McDougle CJ, Krystal JH, Price LH, Heninger GR, Charney DS. Noradrenergic response to acute ethanol administration in healthy subjects: comparison with intravenous yohimbine. Psychopharmacol (Berl). 1995;118:127–35. https://doi.org/10.1007/bf02245830.

    CAS  Article  Google Scholar 

  18. Umhau JC, Schwandt ML, Usala J, Geyer C, Singley E, George DT, et al. Pharmacologically induced alcohol craving in treatment seeking alcoholics correlates with alcoholism severity, but is insensitive to acamprosate. Neuropsychopharmacol: Off Publ Am Coll Neuropsychopharmacol. 2011;36:1178–86. https://doi.org/10.1038/npp.2010.253.

    CAS  Article  Google Scholar 

  19. Guizzetti M, Davies DL, Egli M, Finn DA, Molina P, Regunathan S, et al. Sex and the lab: an alcohol-focused commentary on the NIH initiative to balance sex in cell and animal studies. Alcohol Clin Exp Res. 2016;40:1182–91. https://doi.org/10.1111/acer.13072.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Moningka H, Lichenstein S, Worhunsky PD, DeVito EE, Scheinost D, Yip SW. Can neuroimaging help combat the opioid epidemic? A systematic review of clinical and pharmacological challenge fMRI studies with recommendations for future research. Neuropsychopharmacology. 2019;44:259–73. https://doi.org/10.1038/s41386-018-0232-4.

    Article  PubMed  Google Scholar 

  21. Verplaetse TL, Cosgrove KP, Tanabe J, McKee SA. Sex/gender differences in brain function and structure in alcohol use: A narrative review of neuroimaging findings over the last 10 years. J Neurosci Res. 2021;99:309–23. https://doi.org/10.1002/jnr.24625.

    CAS  Article  PubMed  Google Scholar 

  22. Kezer CA, Simonetto DA, Shah VH. Sex differences in alcohol consumption and alcohol-associated liver disease. Mayo Clin Proc. 2021;96:1006–16. https://doi.org/10.1016/j.mayocp.2020.08.020.

    Article  PubMed  Google Scholar 

  23. Peltier MR, Verplaetse TL, Mineur YS, Petrakis IL, Cosgrove KP, Picciotto MR, et al. Sex differences in stress-related alcohol use. Neurobiol Stress. 2019;10:100149 https://doi.org/10.1016/j.ynstr.2019.100149.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Agabio R, Pisanu C, Gessa GL, Franconi F. Sex differences in alcohol use disorder. Curr Med Chem. 2017;24:2661–70. https://doi.org/10.2174/0929867323666161202092908.

    CAS  Article  PubMed  Google Scholar 

  25. Mulvey B, Bhatti DL, Gyawali S, Lake AM, Kriaucionis S, Ford CP, et al. Molecular and functional sex differences of noradrenergic neurons in the mouse locus coeruleus. Cell Rep. 2018;23:2225–35. https://doi.org/10.1016/j.celrep.2018.04.054.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Bangasser DA, Valentino RJ. Sex differences in molecular and cellular substrates of stress. Cell Mol Neurobiol. 2012;32:709–23. https://doi.org/10.1007/s10571-012-9824-4.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Flores-Bonilla A, Richardson HN. Sex differences in the neurobiology of alcohol use disorder. Alcohol Res. 2020;40:04. https://doi.org/10.35946/arcr.v40.2.04.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Pfefferbaum A, Rosenbloom M, Deshmukh A, Sullivan E. Sex differences in the effects of alcohol on brain structure. Am J Psychiatry. 2001;158:188–97. https://doi.org/10.1176/appi.ajp.158.2.188.

    CAS  Article  PubMed  Google Scholar 

  29. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700 https://doi.org/10.1136/bmj.b2700.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Bramer WM, Giustini D, de Jonge GB, Holland L, Bekhuis T. De-duplication of database search results for systematic reviews in EndNote. J Med Libr Assoc. 2016;104:240–3. https://doi.org/10.3163/1536-5050.104.3.014.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Krauth D, Woodruff TJ, Bero L. Instruments for assessing risk of bias and other methodological criteria of published animal studies: a systematic review. Environ Health Perspect. 2013;121:985–92. https://doi.org/10.1289/ehp.1206389.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Ciccocioppo R, Stopponi S, Economidou D, Kuriyama M, Kinoshita H, Heilig M, et al. Chronic treatment with novel brain-penetrating selective NOP receptor agonist MT-7716 reduces alcohol drinking and seeking in the rat. Neuropsychopharmacology. 2014;39:2601–10. https://doi.org/10.1038/npp.2014.113.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. Bertholomey ML, Nagarajan V, Torregrossa MM. Sex differences in reinstatement of alcohol seeking in response to cues and yohimbine in rats with and without a history of adolescent corticosterone exposure. Psychopharmacol (Berl). 2016;233:2277–87. https://doi.org/10.1007/s00213-016-4278-x.

    CAS  Article  Google Scholar 

  34. Bertholomey ML, Stone K, Lam TT, Bang S, Wu W, Nairn AC, et al. Phosphoproteomic analysis of the amygdala response to adolescent glucocorticoid exposure reveals G-Protein coupled receptor kinase 2 as a target for reducing motivation for alcohol. Proteomes. 2018;6. https://doi.org/10.3390/proteomes6040041.

  35. Bertholomey ML, Torregrossa MM. Gonadal hormones affect alcohol drinking, but not cue+yohimbine-induced alcohol seeking, in male and female rats. Physiol Behav. 2019;203:70–80. https://doi.org/10.1016/j.physbeh.2017.10.025.

    CAS  Article  PubMed  Google Scholar 

  36. Broccoli L, Uhrig S, von Jonquieres G, Schönig K, Bartsch D, Justice NJ, et al. Targeted overexpression of CRH receptor subtype 1 in central amygdala neurons: effect on alcohol-seeking behavior. Psychopharmacol (Berl). 2018;235:1821–33. https://doi.org/10.1007/s00213-018-4908-6.

    CAS  Article  Google Scholar 

  37. Cippitelli A, Brunori G, Schoch J, Armishaw CJ, Wu J, Zaveri NT, et al. Differential regulation of alcohol taking and seeking by antagonism at α4β2 and α3β4 nAChRs. Psychopharmacol (Berl). 2018;235:1745–57. https://doi.org/10.1007/s00213-018-4883-y.

    CAS  Article  Google Scholar 

  38. Mao L, Abdel-Rahman AA. Synergistic behavioral interaction between ethanol and clonidine in rats: role of alpha-2 adrenoceptors. J Pharm Exp Ther. 1996;279:443–9.

    CAS  Google Scholar 

  39. Russ RD, Abdel-Rahman AA, Wooles WR. Ethanol exhibits alpha receptor blocking-like properties in anesthetized rats. Proc Soc Exp Biol Med. 1989;190:1–6. https://doi.org/10.3181/00379727-190-42821.

    CAS  Article  PubMed  Google Scholar 

  40. Aziz AM, Brothers S, Sartor G, Holm L, Heilig M, Wahlestedt C, et al. The nociceptin/orphanin FQ receptor agonist SR-8993 as a candidate therapeutic for alcohol use disorders: validation in rat models. Psychopharmacol (Berl). 2016;233:3553–63. https://doi.org/10.1007/s00213-016-4385-8.

    CAS  Article  Google Scholar 

  41. Cippitelli A, Damadzic R, Hansson AC, Singley E, Sommer WH, Eskay R, et al. Neuropeptide Y (NPY) suppresses yohimbine-induced reinstatement of alcohol seeking. Psychopharmacol (Berl). 2010;208:417–26. https://doi.org/10.1007/s00213-009-1741-y.

    CAS  Article  Google Scholar 

  42. Dzung Lê A, Funk D, Harding S, Juzytsch W, Fletcher PJ. The role of noradrenaline and 5-hydroxytryptamine in yohimbine-induced increases in alcohol-seeking in rats. Psychopharmacol (Berl) 2009;204:477–88. https://doi.org/10.1007/s00213-009-1481-z.

    CAS  Article  Google Scholar 

  43. Gass JT, Olive MF. Reinstatement of ethanol-seeking behavior following intravenous self-administration in Wistar rats. Alcohol Clin Exp Res. 2007;31:1441–5. https://doi.org/10.1111/j.1530-0277.2007.00480.x.

    CAS  Article  PubMed  Google Scholar 

  44. Lê AD, Harding S, Juzytsch W, Funk D, Shaham Y. Role of alpha-2 adrenoceptors in stress-induced reinstatement of alcohol seeking and alcohol self-administration in rats. Psychopharmacol (Berl). 2005;179:366–73. https://doi.org/10.1007/s00213-004-2036-y.

    CAS  Article  Google Scholar 

  45. Le AD, Funk D, Coen K, Li Z, Shaham Y. Role of corticotropin-releasing factor in the median raphe nucleus in yohimbine-induced reinstatement of alcohol seeking in rats. Addict Biol. 2013;18:448–51. https://doi.org/10.1111/j.1369-1600.2011.00374.x.

    CAS  Article  PubMed  Google Scholar 

  46. Parale MP, Kulkarni SK. Studies with alpha 2-adrenoceptor agonists and alcohol abstinence syndrome in rats. Psychopharmacol (Berl). 1986;88:237–9. https://doi.org/10.1007/bf00652247.

    CAS  Article  Google Scholar 

  47. Sequeira MK, Nelson BS, Fulenwider HD, King CE, Nennig SE, Bohannon JB, et al. The neurokinin-1 receptor mediates escalated alcohol intake induced by multiple drinking models. Neuropharmacology 2018;137:194–201. https://doi.org/10.1016/j.neuropharm.2018.05.005.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Williams KL, Nickel MM, Bielak JT. Baclofen blocks yohimbine-induced increases in ethanol-reinforced responding in rats. Pharm Biochem Behav. 2016;144:20–5. https://doi.org/10.1016/j.pbb.2016.02.010.

    CAS  Article  Google Scholar 

  49. Cippitelli A, Cannella N, Braconi S, Duranti A, Tontini A, Bilbao A, et al. Increase of brain endocannabinoid anandamide levels by FAAH inhibition and alcohol abuse behaviours in the rat. Psychopharmacol (Berl). 2008;198:449–60. https://doi.org/10.1007/s00213-008-1104-0.

    CAS  Article  Google Scholar 

  50. Funk D, Coen K, Lê AD. The role of kappa opioid receptors in stress-induced reinstatement of alcohol seeking in rats. Brain Behav. 2014;4:356–67. https://doi.org/10.1002/brb3.222.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Haack AK, Sheth C, Schwager AL, Sinclair MS, Tandon S, Taha SA. Lesions of the lateral habenula increase voluntary ethanol consumption and operant self-administration, block yohimbine-induced reinstatement of ethanol seeking, and attenuate ethanol-induced conditioned taste aversion. PLoS One. 2014;9:e92701 https://doi.org/10.1371/journal.pone.0092701.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. Haass-Koffler CL, Henry AT, Melkus G, Simms JA, Naemmuddin M, Nielsen CK, et al. Defining the role of corticotropin releasing factor binding protein in alcohol consumption. Transl Psychiatry 2016;6:e953 https://doi.org/10.1038/tp.2016.208.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. Nielsen CK, Simms JA, Bito-Onon JJ, Li R, Ananthan S, Bartlett SE. The delta opioid receptor antagonist, SoRI-9409, decreases yohimbine stress-induced reinstatement of ethanol-seeking. Addict Biol. 2012;17:224–34. https://doi.org/10.1111/j.1369-1600.2010.00295.x.

    CAS  Article  PubMed  Google Scholar 

  54. Richards JK, Simms JA, Steensland P, Taha SA, Borgland SL, Bonci A, et al. Inhibition of orexin-1/hypocretin-1 receptors inhibits yohimbine-induced reinstatement of ethanol and sucrose seeking in Long-Evans rats. Psychopharmacol (Berl). 2008;199:109–17. https://doi.org/10.1007/s00213-008-1136-5.

    CAS  Article  Google Scholar 

  55. Richards JK, Simms JA, Bartlett SE. Conditioned cues and yohimbine induce reinstatement of beer and near-beer seeking in Long-Evans rats. Addict Biol. 2009;14:144–51. https://doi.org/10.1111/j.1369-1600.2008.00139.x.

    CAS  Article  PubMed  Google Scholar 

  56. Sheth C, Furlong TM, Keefe KA, Taha SA. Lesion of the rostromedial tegmental nucleus increases voluntary ethanol consumption and accelerates extinction of ethanol-induced conditioned taste aversion. Psychopharmacol (Berl). 2016;233:3737–49. https://doi.org/10.1007/s00213-016-4406-7.

    CAS  Article  Google Scholar 

  57. Simms JA, Bito-Onon JJ, Chatterjee S, Bartlett SE. Long-Evans rats acquire operant self-administration of 20% ethanol without sucrose fading. Neuropsychopharmacology. 2010;35:1453–63. https://doi.org/10.1038/npp.2010.15.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. Simms JA, Richards JK, Mill D, Kanholm I, Holgate JY, Bartlett SE. Induction of multiple reinstatements of ethanol- and sucrose-seeking behavior in Long-Evans rats by the α-2 adrenoreceptor antagonist yohimbine. Psychopharmacol (Berl). 2011;218:101–10. https://doi.org/10.1007/s00213-011-2451-9.

    CAS  Article  Google Scholar 

  59. Tabbara RI, Rahbarnia A, Lê AD, Fletcher PJ. The pharmacological stressor yohimbine, but not U50,488, increases responding for conditioned reinforcers paired with ethanol or sucrose. Psychopharmacol (Berl). 2020;237:3689–702. https://doi.org/10.1007/s00213-020-05647-0.

    CAS  Article  Google Scholar 

  60. Williams KL, Harding KM. Repeated alcohol extinction sessions in conjunction with MK-801, but not yohimbine or propranolol, reduces subsequent alcohol cue-induced responding in rats. Pharm Biochem Behav. 2014;116:16–24. https://doi.org/10.1016/j.pbb.2013.11.020.

    CAS  Article  Google Scholar 

  61. Koechling UM, Smith BR, Amit Z. Differential effects of catecholamine antagonists on ethanol-induced excitation in mice. Psychopharmacol (Berl). 1990;102:234–8. https://doi.org/10.1007/bf02245927.

    CAS  Article  Google Scholar 

  62. Koechling UM, Amit Z. Effects of CA antagonists on ethanol-induced excitation in habituated and nonhabituated mice: interaction with stress factors? Pharm Biochem Behav. 1993;44:791–6. https://doi.org/10.1016/0091-3057(93)90007-g.

    CAS  Article  Google Scholar 

  63. Liljequist S, Berggren U, Engel J. The effect of catecholamine receptor antagonists on ethanol-induced locomotor stimulation. J Neural Transm. 1981;50:57–67. https://doi.org/10.1007/bf01254914.

    CAS  Article  PubMed  Google Scholar 

  64. Carlsson ML, Engberg G. Ethanol behaves as an NMDA antagonist with respect to locomotor stimulation in monoamine-depleted mice. J Neural Transm Gen Sect. 1992;87:155–60. https://doi.org/10.1007/bf01245017.

    CAS  Article  PubMed  Google Scholar 

  65. Edwards F, Schabinsky VV, Jackson DM, Starmer GA, Jenkins O. Involvement of catecholamines in acute tolerance to ethanol in mice. Psychopharmacol (Berl). 1983;79:246–50. https://doi.org/10.1007/bf00427821.

    CAS  Article  Google Scholar 

  66. Bachtell RK, Tsivkovskaia NO, Ryabinin AE. Alcohol-induced c-Fos expression in the Edinger-Westphal nucleus: pharmacological and signal transduction mechanisms. J Pharm Exp Ther. 2002;302:516–24. https://doi.org/10.1124/jpet.102.036046.

    CAS  Article  Google Scholar 

  67. Funk D, Li Z, Coen K, Lê AD. Effects of pharmacological stressors on c-fos and CRF mRNA in mouse brain: relationship to alcohol seeking. Neurosci Lett 2008;444:254–8. https://doi.org/10.1016/j.neulet.2008.08.043.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. King CE, Becker HC. Oxytocin attenuates stress-induced reinstatement of alcohol seeking behavior in male and female mice. Psychopharmacol (Berl). 2019;236:2613–22. https://doi.org/10.1007/s00213-019-05233-z.

    CAS  Article  Google Scholar 

  69. Ayanwuyi LO, Stopponi S, Ubaldi M, Cippitelli A, Nasuti C, Damadzic R, et al. Neurokinin 1 receptor blockade in the medial amygdala attenuates alcohol drinking in rats with innate anxiety but not in Wistar rats. Br J Pharmacol. 2015;172:5136–46. https://doi.org/10.1111/bph.13280.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. Borruto AM, Fotio Y, Stopponi S, Petrella M, De Carlo S, Domi A, et al. NOP receptor antagonism attenuates reinstatement of alcohol-seeking through modulation of the mesolimbic circuitry in male and female alcohol-preferring rats. Neuropsychopharmacology. 2021;46:2121–31. https://doi.org/10.1038/s41386-021-01096-1.

    CAS  Article  PubMed  Google Scholar 

  71. Fotio Y, Borruto AM, Benvenuti F, Demopulos G, Gaitanaris G, Roberto M, et al. Activation of peroxisome proliferator-activated receptor γ reduces alcohol drinking and seeking by modulating multiple mesocorticolimbic regions in rats. Neuropsychopharmacology. 2021;46:360–7. https://doi.org/10.1038/s41386-020-0754-4.

    CAS  Article  PubMed  Google Scholar 

  72. Stopponi S, Somaini L, Cippitelli A, Cannella N, Braconi S, Kallupi M, et al. Activation of nuclear PPARγ receptors by the antidiabetic agent pioglitazone suppresses alcohol drinking and relapse to alcohol seeking. Biol Psychiatry. 2011;69:642–9. https://doi.org/10.1016/j.biopsych.2010.12.010.

    CAS  Article  PubMed  Google Scholar 

  73. Stopponi S, Somaini L, Cippitelli A, de Guglielmo G, Kallupi M, Cannella N, et al. Pregabalin reduces alcohol drinking and relapse to alcohol seeking in the rat. Psychopharmacol (Berl). 2012;220:87–96. https://doi.org/10.1007/s00213-011-2457-3.

    CAS  Article  Google Scholar 

  74. Stopponi S, de Guglielmo G, Somaini L, Cippitelli A, Cannella N, Kallupi M, et al. Activation of PPARγ by pioglitazone potentiates the effects of naltrexone on alcohol drinking and relapse in msP rats. Alcohol Clin Exp Res. 2013;37:1351–60. https://doi.org/10.1111/acer.12091.

    CAS  Article  PubMed  Google Scholar 

  75. Stopponi S, Fotio Y, Cifani C, Li H, Haass-Koffler CL, Cannella N, et al. Andrographis paniculata and Its Main Bioactive Ingredient Andrographolide Decrease Alcohol Drinking and Seeking in Rats Through Activation of Nuclear PPARγ Pathway. Alcohol Alcohol. 2021;56:240–9. https://doi.org/10.1093/alcalc/agaa136.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. Rorick-Kehn LM, Ciccocioppo R, Wong CJ, Witkin JM, Martinez-Grau MA, Stopponi S, et al. A novel, orally bioavailable nociceptin receptor antagonist, LY2940094, reduces ethanol self-administration and ethanol seeking in animal models. Alcohol Clin Exp Res. 2016;40:945–54. https://doi.org/10.1111/acer.13052.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. Kastman HE, Blasiak A, Walker L, Siwiec M, Krstew EV, Gundlach AL, et al. Nucleus incertus Orexin2 receptors mediate alcohol seeking in rats. Neuropharmacology. 2016;110:82–91. https://doi.org/10.1016/j.neuropharm.2016.07.006.

    CAS  Article  PubMed  Google Scholar 

  78. Walker LC, Kastman HE, Koeleman JA, Smith CM, Perry CJ, Krstew EV, et al. Nucleus incertus corticotrophin-releasing factor 1 receptor signalling regulates alcohol seeking in rats. Addict Biol. 2017;22:1641–54. https://doi.org/10.1111/adb.12426.

    CAS  Article  PubMed  Google Scholar 

  79. Walker LC, Kastman HE, Krstew EV, Gundlach AL, Lawrence AJ. Central amygdala relaxin-3/relaxin family peptide receptor 3 signalling modulates alcohol seeking in rats. Br J Pharmacol. 2017;174:3359–69. https://doi.org/10.1111/bph.13955.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. Walker LC, Hand LJ, Letherby B, Huckstep KL, Campbell EJ, Lawrence AJ. Cocaine and amphetamine regulated transcript (CART) signalling in the central nucleus of the amygdala modulates stress-induced alcohol seeking. Neuropsychopharmacology. 2021;46:325–33. https://doi.org/10.1038/s41386-020-00807-4.

    CAS  Article  PubMed  Google Scholar 

  81. Walker LC, Kastman HE, Lawrence AJ. Pattern of neural activation following yohimbine-induced reinstatement of alcohol seeking in rats. Eur J Neurosci 2020;51:706–20. https://doi.org/10.1111/ejn.14431.

    Article  PubMed  Google Scholar 

  82. Opitz K. The effect of clonidine and related substances on voluntary ethanol consumption in rats. Drug Alcohol Depend. 1990;25:43–8. https://doi.org/10.1016/0376-8716(90)90139-6.

    CAS  Article  PubMed  Google Scholar 

  83. Lê AD, Funk D, Juzytsch W, Coen K, Navarre BM, Cifani C, et al. Effect of prazosin and guanfacine on stress-induced reinstatement of alcohol and food seeking in rats. Psychopharmacol (Berl). 2011;218:89–99. https://doi.org/10.1007/s00213-011-2178-7.

    CAS  Article  Google Scholar 

  84. Schank JR, King CE, Sun H, Cheng K, Rice KC, Heilig M, et al. The role of the neurokinin-1 receptor in stress-induced reinstatement of alcohol and cocaine seeking. Neuropsychopharmacology. 2014;39:1093–101. https://doi.org/10.1038/npp.2013.309.

    CAS  Article  PubMed  Google Scholar 

  85. Nelson BS, Fulenwider HD, Nennig SE, Smith BM, Sequeira MK, Chimberoff SH, et al. Escalated alcohol self-administration and sensitivity to yohimbine-induced reinstatement in alcohol preferring rats: potential role of neurokinin-1 receptors in the amygdala. Neuroscience. 2019;413:77–85. https://doi.org/10.1016/j.neuroscience.2019.06.023.

    CAS  Article  PubMed  Google Scholar 

  86. Ayanwuyi LO, Carvajal F, Lerma-Cabrera JM, Domi E, Björk K, Ubaldi M, et al. Role of a genetic polymorphism in the corticotropin-releasing factor receptor 1 gene in alcohol drinking and seeking behaviors of marchigian sardinian alcohol-preferring rats. Front Psychiatry. 2013;4:23 https://doi.org/10.3389/fpsyt.2013.00023.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  87. Zgombick JM, Erwin VG. Central mechanisms of ethanol-induced adrenocortical response in selectively bred lines of mice. Neuroendocrinology. 1987;46:324–32. https://doi.org/10.1159/000124840.

    CAS  Article  PubMed  Google Scholar 

  88. Reid LD, Delconte JD, Amendola CA, Nichols ML, Krupsky GW, Dharia NS, et al. alpha(2)-Adrenoceptor antagonists and propensity to take alcoholic beverages. Behav Pharmacol. 1994;5:485–93. https://doi.org/10.1097/00008877-199408000-00009.

    CAS  Article  PubMed  Google Scholar 

  89. Funk D, Li Z, Lê AD. Effects of environmental and pharmacological stressors on c-fos and corticotropin-releasing factor mRNA in rat brain: Relationship to the reinstatement of alcohol seeking. Neuroscience. 2006;138:235–43. https://doi.org/10.1016/j.neuroscience.2005.10.062.

    CAS  Article  PubMed  Google Scholar 

  90. Krystal JH, Webb E, Cooney N, Kranzler HR, Charney DS. Specificity of ethanollike effects elicited by serotonergic and noradrenergic mechanisms. Arch Gen Psychiatry. 1994;51:898–911. https://doi.org/10.1001/archpsyc.1994.03950110058008.

    CAS  Article  PubMed  Google Scholar 

  91. Krystal JH, Webb E, Cooney NL, Kranzler HR, Southwick SW, Heninger GR, et al. Serotonergic and noradrenergic dysregulation in alcoholism: m-chlorophenylpiperazine and yohimbine effects in recently detoxified alcoholics and healthy comparison subjects. Am J Psychiatry. 1996;153:83–92. https://doi.org/10.1176/ajp.153.1.83.

    CAS  Article  PubMed  Google Scholar 

  92. Krystal JH, Webb E, Grillon C, Cooney N, Casal L, Morgan CA 3rd, et al. Evidence of acoustic startle hyperreflexia in recently detoxified early onset male alcoholics: modulation by yohimbine and m-chlorophenylpiperazine (mCPP). Psychopharmacol (Berl). 1997;131:207–15. https://doi.org/10.1007/s002130050285.

    CAS  Article  Google Scholar 

  93. Edenberg HJ, Foroud T. Genetics and alcoholism. Nat Rev Gastroenterol Hepatol. 2013;10:487–94. https://doi.org/10.1038/nrgastro.2013.86.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. Crabbe JC. Rodent models of genetic contributions to motivation to abuse alcohol. Nebr Symp Motiv. 2014;61:5–29. https://doi.org/10.1007/978-1-4939-0653-6_2.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Rosenblum LA, Coplan JD, Friedman S, Bassoff T. Dose-response effects of oral yohimbine in unrestrained primates. Biol Psychiatry. 1991;29:647–57. https://doi.org/10.1016/0006-3223(91)90134-8.

    CAS  Article  PubMed  Google Scholar 

  96. Moore CF, Lynch WJ. Alcohol preferring (P) rats as a model for examining sex differences in alcohol use disorder and its treatment. Pharm Biochem Behav. 2015;132:1–9. https://doi.org/10.1016/j.pbb.2015.02.014.

    CAS  Article  Google Scholar 

  97. Barker JM, Taylor JR. Sex differences in incentive motivation and the relationship to the development and maintenance of alcohol use disorders. Physiol Behav. 2019;203:91–9. https://doi.org/10.1016/j.physbeh.2017.09.027.

    CAS  Article  PubMed  Google Scholar 

  98. Seo D, Jia Z, Lacadie CM, Tsou KA, Bergquist K, Sinha R. Sex differences in neural responses to stress and alcohol context cues. Hum Brain Mapp 2011;32:1998–2013. https://doi.org/10.1002/hbm.21165.

    Article  PubMed  Google Scholar 

  99. Li S, Zou S, Coen K, Funk D, Shram MJ, Lê AD. Sex differences in yohimbine-induced increases in the reinforcing efficacy of nicotine in adolescent rats. Addict Biol. 2014;19:156–64. https://doi.org/10.1111/j.1369-1600.2012.00473.x.

    CAS  Article  PubMed  Google Scholar 

  100. Feltenstein MW, Henderson AR, See RE. Enhancement of cue-induced reinstatement of cocaine-seeking in rats by yohimbine: sex differences and the role of the estrous cycle. Psychopharmacol (Berl). 2011;216:53–62. https://doi.org/10.1007/s00213-011-2187-6.

    CAS  Article  Google Scholar 

  101. Anker JJ, Carroll ME. Sex differences in the effects of allopregnanolone on yohimbine-induced reinstatement of cocaine seeking in rats. Drug Alcohol Depend 2010;107:264–7. https://doi.org/10.1016/j.drugalcdep.2009.11.002.

    CAS  Article  PubMed  Google Scholar 

  102. Moran-Santa Maria MM, Sherman BJ, Brady KT, Baker NL, Hyer JM, Ferland C, et al. Impact of endogenous progesterone on reactivity to yohimbine and cocaine cues in cocaine-dependent women. Pharm Biochem Behav. 2018;165:63–9. https://doi.org/10.1016/j.pbb.2017.11.001.

    CAS  Article  Google Scholar 

  103. Sinha R, Fox H, Hong KI, Sofuoglu M, Morgan PT, Bergquist KT. Sex steroid hormones, stress response, and drug craving in cocaine-dependent women: implications for relapse susceptibility. Exp Clin Psychopharmacol. 2007;15:445–52. https://doi.org/10.1037/1064-1297.15.5.445.

    CAS  Article  PubMed  Google Scholar 

  104. Domi E, Domi A, Adermark L, Heilig M, Augier E. Neurobiology of alcohol seeking behavior. J Neurochem 2021;157:1585–614. https://doi.org/10.1111/jnc.15343.

    CAS  Article  PubMed  Google Scholar 

  105. Keyes KM, Hatzenbuehler ML, Grant BF, Hasin DS. Stress and alcohol: epidemiologic evidence. Alcohol Res 2012;34:391–400.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Powers RJ, Kutash IL. Stress and alcohol. Int J Addict. 1985;20:461–82. https://doi.org/10.3109/10826088509044926.

    CAS  Article  PubMed  Google Scholar 

  107. Getachew B, Hauser SR, Csoka AB, Taylor RE, Tizabi Y. Role of cortical alpha-2 adrenoceptors in alcohol withdrawal-induced depression and tricyclic antidepressants. Drug Alcohol Depend. 2017;175:133–9. https://doi.org/10.1016/j.drugalcdep.2017.03.004.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  108. Sáiz J, Pazos A, Del Olmo E, Sáiz V, Sánchez A. Yohimbine-induced alterations in alpha(2)-adrenoceptors in kidney regions of the spontaneously hypertensive rats: an autoradiographic analysis. Pharm Rep. 2008;60:391–8.

    Google Scholar 

  109. Jahanshahi M, Nikmahzar E, Elyasi L, Babakordi F, Hooshmand E. α(2)-Adrenoceptor-ir neurons’ density changes after single dose of clonidine and yohimbine administration in the hippocampus of male rat. Int J Neurosci. 2018;128:404–11. https://doi.org/10.1080/00207454.2017.1389926.

    CAS  Article  PubMed  Google Scholar 

  110. Smith SM, Vale WW. The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues Clin Neurosci. 2006;8:383–95. https://doi.org/10.31887/DCNS.2006.8.4/ssmith.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Stephens MA, Wand G. Stress and the HPA axis: role of glucocorticoids in alcohol dependence. Alcohol Res. 2012;34:468–83.

    PubMed  PubMed Central  Google Scholar 

  112. Dai X, Thavundayil J, Santella S, Gianoulakis C. Response of the HPA-axis to alcohol and stress as a function of alcohol dependence and family history of alcoholism. Psychoneuroendocrinology. 2007;32:293–305. https://doi.org/10.1016/j.psyneuen.2007.01.004.

    CAS  Article  PubMed  Google Scholar 

  113. Chen YW, Fiscella KA, Bacharach SZ, Tanda G, Shaham Y, Calu DJ. Effect of yohimbine on reinstatement of operant responding in rats is dependent on cue contingency but not food reward history. Addict Biol. 2015;20:690–700. https://doi.org/10.1111/adb.12164.

    CAS  Article  PubMed  Google Scholar 

  114. Koob GF. A role for brain stress systems in addiction. Neuron. 2008;59:11–34. https://doi.org/10.1016/j.neuron.2008.06.012.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  115. Vazey EM, den Hartog CR, Moorman DE. Central noradrenergic interactions with alcohol and regulation of alcohol-related behaviors. Handb Exp Pharm. 2018;248:239–60. https://doi.org/10.1007/164_2018_108.

    CAS  Article  Google Scholar 

  116. Atzori M, Cuevas-Olguin R, Esquivel-Rendon E, Garcia-Oscos F, Salgado-Delgado RC, Saderi N, et al. Locus ceruleus norepinephrine release: a central regulator of CNS spatio-temporal activation? Front Synaptic Neurosci. 2016;8:25 https://doi.org/10.3389/fnsyn.2016.00025.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  117. Walker BM, Rasmussen DD, Raskind MA, Koob GF. alpha1-noradrenergic receptor antagonism blocks dependence-induced increases in responding for ethanol. Alcohol. 2008;42:91–7. https://doi.org/10.1016/j.alcohol.2007.12.002.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  118. Haass-Koffler CL, Goodyear K, Zywiak WH, Magill M, Eltinge SE, Wallace PM, et al. Higher pretreatment blood pressure is associated with greater alcohol drinking reduction in alcohol-dependent individuals treated with doxazosin. Drug Alcohol Depend. 2017;177:23–8. https://doi.org/10.1016/j.drugalcdep.2017.03.016.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  119. Wilcox CE, Tonigan JS, Bogenschutz MP, Clifford J, Bigelow R, Simpson T. A randomized, placebo-controlled, clinical trial of prazosin for the treatment of alcohol use disorder. J Addict Med. 2018;12:339–45. https://doi.org/10.1097/adm.0000000000000413.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  120. Simpson TL, Saxon AJ, Stappenbeck C, Malte CA, Lyons R, Tell D, et al. Double-blind randomized clinical trial of prazosin for alcohol use disorder. Am J Psychiatry. 2018;175:1216–24. https://doi.org/10.1176/appi.ajp.2018.17080913.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Milivojevic V, Angarita GA, Hermes G, Sinha R, Fox HC. Effects of prazosin on provoked alcohol craving and autonomic and neuroendocrine response to stress in alcohol use disorder. Alcohol Clin Exp Res. 2020;44:1488–96. https://doi.org/10.1111/acer.14378.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  122. Haass-Koffler CL, Leggio L, Kenna GA. Pharmacological approaches to reducing craving in patients with alcohol use disorders. CNS Drugs. 2014;28:343–60. https://doi.org/10.1007/s40263-014-0149-3.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  123. Laurila JM, Xhaard H, Ruuskanen JO, Rantanen MJ, Karlsson HK, Johnson MS, et al. The second extracellular loop of alpha2A-adrenoceptors contributes to the binding of yohimbine analogues. Br J Pharmacol. 2007;151:1293–304. https://doi.org/10.1038/sj.bjp.0707330.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  124. Etzel JP, Rana BK, Wen G, Parmer RJ, Schork NJ, O’Connor DT, et al. Genetic variation at the human alpha2B-adrenergic receptor locus: role in blood pressure variation and yohimbine response. Hypertension. 2005;45:1207–13. https://doi.org/10.1161/01.HYP.0000166721.42734.49.

    CAS  Article  PubMed  Google Scholar 

  125. Gozzi A, Lepore S, Vicentini E, Merlo-Pich E, Bifone A. Differential effect of orexin-1 and CRF-1 antagonism on stress circuits: a fMRI study in the rat with the pharmacological stressor Yohimbine. Neuropsychopharmacology. 2013;38:2120–30. https://doi.org/10.1038/npp.2013.109.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  126. Rosen MI, Kosten TR, Kreek MJ. The effects of naltrexone maintenance on the response to yohimbine in healthy volunteers. Biol Psychiatry. 1999;45:1636–45. https://doi.org/10.1016/s0006-3223(98)00259-5.

    CAS  Article  PubMed  Google Scholar 

  127. Greenwald MK, Lundahl LH, Steinmiller CL. Yohimbine increases opioid-seeking behavior in heroin-dependent, buprenorphine-maintained individuals. Psychopharmacol (Berl). 2013;225:811–24. https://doi.org/10.1007/s00213-012-2868-9.

    CAS  Article  Google Scholar 

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Acknowledgements

The authors also would like to thank the Brown University librarians, Laura Pavlech and Kelsey Sawyer, for constructing the systematic database searches. They would also like to thank Paul S. Soliman for his contributions during manuscript revision.

Funding

DEC is supported by the National Institute on Alcohol Abuse and Alcoholism (R01 AA027760 and Research Supplements to Promote Diversity in Health-Related Research). CLH-K is supported by the National Institute on Alcohol Abuse and Alcoholism (K01 AA023867; R01 AA026589; R01 AA027760; R21 AA027614) and by the National Institute of General Medical Sciences (NIGMS), Center of Biomedical Research Excellence (COBRE, P20 GM130414). RC is supported by the PRIN 2017SXEXT5, and NC is supported by the Hetzler Foundation (Grant 202213).

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DEC and TRV-K served as two independent reviewers, RC and NC served as consensus reviewers for the animal studies, CLH-K as consensus reviewer for the human studies. DEC and CLH-K wrote the manuscript; CLH-K supervised the project; TRV-K, NC and RC contributed to the writing of the manuscript. All authors approved the final version of the manuscript and agree to be accountable for the content of the work.

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Correspondence to Carolina L. Haass-Koffler.

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Curley, D.E., Vasaturo-Kolodner, T.R., Cannella, N. et al. Yohimbine as a pharmacological probe for alcohol research: a systematic review of rodent and human studies. Neuropsychopharmacol. (2022). https://doi.org/10.1038/s41386-022-01363-9

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