Pituitary adenylate cyclase-activating polypeptide (PACAP) modulates dependence-induced alcohol drinking and anxiety-like behavior in male rats

Abstract

Alcohol use disorder (AUD) is a devastating illness defined by periods of heavy drinking and withdrawal, often leading to a chronic relapsing course. Initially, alcohol is consumed for its positive reinforcing effects, but later stages of AUD are characterized by drinking to alleviate withdrawal-induced negative emotional states. Brain stress response systems in the extended amygdala are recruited by excessive alcohol intake, sensitized by repeated withdrawal, and contribute to the development of addiction. In this study, we investigated one such brain stress response system, pituitary adenylate cyclase-activating polypeptide (PACAP), and its cognate receptor, PAC1R, in alcohol withdrawal-induced behaviors. During acute withdrawal, rats exposed to chronic intermittent ethanol vapor (ethanol-dependent) displayed a significant increase in PACAP levels in the bed nucleus of the stria terminalis (BNST), a brain area within the extended amygdala critically involved in both stress and withdrawal. No changes in PACAP levels were observed in the central nucleus of the amygdala. Site-specific microinfusion of the PAC1R antagonist PACAP(6–38) into the BNST dose-dependently blocked excessive alcohol intake in ethanol-dependent rats without affecting water intake overall or basal ethanol intake in control, nondependent rats. Intra-BNST PACAP(6–38) also reversed ethanol withdrawal-induced anxiety-like behavior in ethanol-dependent rats, but did not affect this measure in control rats. Our findings show that chronic intermittent exposure to ethanol recruits the PACAP/PAC1R system of the BNST and that these neuroadaptations mediate the heightened alcohol drinking and anxiety-like behavior observed during withdrawal, suggesting that this system represents a major brain stress element responsible for the negative reinforcement associated with the “dark side” of alcohol addiction.

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Fig. 1: Effect of chronic intermittent exposure to ethanol vapors on PACAP immunoreactivity in the BNST and in the CeA 8–10 h after vapor offset.
Fig. 2: Effect of chronic intermittent exposure to ethanol vapors on PAC1R-positive cell bodies in the BNST 8–10 h after vapor offset.
Fig. 3: Effect of chronic intermittent exposure to ethanol vapors on operant ethanol and water self-administration.
Fig. 4: Effects of intra-BNST PACAP(6–38) administration on operant ethanol and water self-administration in control and ethanol-dependent rats 8–10 h after ethanol vapor offset.
Fig. 5: Effects of intra-BNST PACAP(6–38) administration on anxiety-like behavior in the light/dark conflict test 8–10 h after ethanol vapor offset.

References

  1. 1.

    Heilig M, Koob GF. A key role for corticotropin-releasing factor in alcohol dependence. Trends Neurosci. 2007;30:399–406.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Dackis C, O’Brien C. Neurobiology of addiction: treatment and public policy ramifications. Nat Neurosci. 2005;8:1431–6.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Koob GF. The dark side of emotion: the addiction perspective. Eur J Pharm. 2015;753:73–87.

    CAS  Article  Google Scholar 

  4. 4.

    Koob GF, Schulkin J. Addiction and stress: an allostatic view. Neurosci Biobehav Rev. 2019;106:245–62.

    PubMed  Article  Google Scholar 

  5. 5.

    Breese GR, Sinha R, Heilig M. Chronic alcohol neuroadaptation and stress contribute to susceptibility for alcohol craving and relapse. Pharm Ther. 2011;129:149–71.

    CAS  Article  Google Scholar 

  6. 6.

    Pleil KE, Rinker JA, Lowery-Gionta EG, Mazzone CM, McCall NM, Kendra AM, et al. NPY signaling inhibits extended amygdala CRF neurons to suppress binge alcohol drinking. Nat Neurosci. 2015;18:545–52.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Koob GF, Volkow ND. Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry. 2016;3:760–73.

    PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Avery SN, Clauss JA, Blackford JU. The human BNST: functional role in anxiety and addiction. Neuropsychopharmacology. 2016;41:126–41.

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Kash TL, Baucum AJ,2nd, Conrad KL, Colbran RJ, Winder DG. Alcohol exposure alters NMDAR function in the bed nucleus of the stria terminalis. Neuropsychopharmacology. 2009;34:2420–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    McElligott ZA, Winder DG. Modulation of glutamatergic synaptic transmission in the bed nucleus of the stria terminalis. Prog Neuro-Psychopharmacol Biol psychiatry. 2009;33:1329–35.

    CAS  Article  Google Scholar 

  11. 11.

    Harris NA, Winder DG. Synaptic plasticity in the bed nucleus of the stria terminalis: underlying mechanisms and potential ramifications for reinstatement of drug- and alcohol-seeking behaviors. ACS Chem Neurosci. 2018;9:2173–87.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Pati D, Marcinkiewcz CA, DiBerto JF, Cogan ES, McElligott ZA, Kash TL. Chronic intermittent ethanol exposure dysregulates a GABAergic microcircuit in the bed nucleus of the stria terminalis. Neuropharmacology. 2020;168:107759.

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Huang MM, Overstreet DH, Knapp DJ, Angel R, Wills TA, Navarro M, et al. Corticotropin-releasing factor (CRF) sensitization of ethanol withdrawal-induced anxiety-like behavior is brain site specific and mediated by CRF-1 receptors: relation to stress-induced sensitization. J Pharm Exp Ther. 2010;332:298–307.

    CAS  Article  Google Scholar 

  14. 14.

    Kwako LE, Koob GF. Neuroclinical framework for the role of stress in addiction. Chronic Stress. 2017;1:1–14.

  15. 15.

    Aston-Jones G, Kalivas PW. Brain norepinephrine rediscovered in addiction research. Biol Psychiatry. 2008;63:1005–6.

    PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Logrip ML, Koob GF, Zorrilla EP. Role of corticotropin-releasing factor in drug addiction: potential for pharmacological intervention. CNS Drugs. 2011;25:271–87.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Kash TL, Pleil KE, Marcinkiewcz CA, Lowery-Gionta EG, Crowley N, Mazzone C, et al. Neuropeptide regulation of signaling and behavior in the BNST. Mol Cells. 2015;38:1–13.

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Marcinkiewcz CA, Dorrier CE, Lopez AJ, Kash TL. Ethanol induced adaptations in 5-HT2c receptor signaling in the bed nucleus of the stria terminalis: implications for anxiety during ethanol withdrawal. Neuropharmacology. 2015;89:157–67.

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Marcinkiewcz CA, Mazzone CM, D’Agostino G, Halladay LR, Hardaway JA, DiBerto JF, et al. Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala. Nature. 2016;537:97–101.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Iemolo A, Seiglie M, Blasio A, Cottone P, Sabino V. Pituitary adenylate cyclase-activating polypeptide (PACAP) in the central nucleus of the amygdala induces anxiety via melanocortin receptors. Psychopharmacology (Berl). 2016;233:3269–77. https://doi.org/10.1007/s00213-016-4366-y.

  21. 21.

    Dore R, Iemolo A, Smith KL, Wang X, Cottone P, Sabino V. CRF mediates the anxiogenic and anti-rewarding, but not the anorectic effects of PACAP. Neuropsychopharmacology. 2013;38:2160–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Hammack SE, May V. Pituitary adenylate cyclase activating polypeptide in stress-related disorders: data convergence from animal and human studies. Biol Psychiatry. 2015;78:167–77.

  23. 23.

    Varodayan FP, Minnig MA, Steinman MQ, Oleata CS, Riley MW, Sabino V, et al. PACAP regulation of central amygdala GABAergic synapses is altered by restraint stress. Neuropharmacology. 2020;168:107752.

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Lebow MA, Chen A. Overshadowed by the amygdala: the bed nucleus of the stria terminalis emerges as key to psychiatric disorders. Mol Psychiatry. 2016;21:450–63.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Palkovits M, Somogyvari-Vigh A, Arimura A. Concentrations of pituitary adenylate cyclase activating polypeptide (PACAP) in human brain nuclei. Brain Res. 1995;699:116–20.

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Piggins HD, Stamp JA, Burns J, Rusak B, Semba K. Distribution of pituitary adenylate cyclase activating polypeptide (PACAP) immunoreactivity in the hypothalamus and extended amygdala of the rat. J Comp Neurol. 1996;376:278–94.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Hannibal J. Pituitary adenylate cyclase-activating peptide in the rat central nervous system: an immunohistochemical and in situ hybridization study. J Comp Neurol. 2002;453:389–417.

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Missig G, Roman CW, Vizzard MA, Braas KM, Hammack SE, May V. Parabrachial nucleus (PBn) pituitary adenylate cyclase activating polypeptide (PACAP) signaling in the amygdala: implication for the sensory and behavioral effects of pain. Neuropharmacology. 2014;86:38–48.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Missig G, Mei L, Vizzard MA, Braas KM, Waschek JA, Ressler KJ, et al. Parabrachial pituitary adenylate cyclase-activating polypeptide activation of amygdala endosomal extracellular signal-regulated kinase signaling regulates the emotional component of pain. Biol Psychiatry. 2017;81:671–82.

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Agarwal A, Halvorson LM, Legradi G. Pituitary adenylate cyclase-activating polypeptide (PACAP) mimics neuroendocrine and behavioral manifestations of stress: Evidence for PKA-mediated expression of the corticotropin-releasing hormone (CRH) gene. Brain Res Mol Brain Res. 2005;138:45–57.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Seiglie MP, Huang L, Cottone P, Sabino V. Role of the PACAP system of the extended amygdala in the acoustic startle response in rats. Neuropharmacology. 2019;160:107761.

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Lezak KR, Roman CW, Braas KM, Schutz KC, Falls WA, Schulkin J, et al. Regulation of bed nucleus of the stria terminalis PACAP expression by stress and corticosterone. J Mol Neurosci. 2014;54:477–84.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Roman CW, Lezak KR, Hartsock MJ, Falls WA, Braas KM, Howard AB, et al. PAC1 receptor antagonism in the bed nucleus of the stria terminalis (BNST) attenuates the endocrine and behavioral consequences of chronic stress. Psychoneuroendocrinology. 2014;47:151–65.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Kovanen L, Saarikoski ST, Haukka J, Pirkola S, Aromaa A, Lonnqvist J, et al. Circadian clock gene polymorphisms in alcohol use disorders and alcohol consumption. Alcohol Alcohol. 2010;45:303–11.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Dragan WL, Czerski PM, Dragan M. PAC1 receptor (ADCYAP1R1) genotype and problematic alcohol use in a sample of young women. Neuropsychiatr Dis Treat. 2017;13:1483–89.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Marquez P, Bebawy D, Lelievre V, Coute AC, Evans CJ, Waschek JA, et al. The role of endogenous PACAP in motor stimulation and conditioned place preference induced by morphine in mice. Psychopharmacology. 2009;204:457–63.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Gargiulo AT, Curtis GR, Barson JR. Pleiotropic pituitary adenylate cyclase-activating polypeptide (PACAP): Novel insights into the role of PACAP in eating and drug intake. Brain Res. 2020;1729:146626.

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Stojakovic A, Ahmad SM, Malhotra S, Afzal Z, Ahmed M, Lutfy K. The role of pituitary adenylyl cyclase-activating polypeptide in the motivational effects of addictive drugs. Neuropharmacology. 2020;171:108109.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  39. 39.

    Feany MB, Quinn WG. A neuropeptide gene defined by the Drosophila memory mutant amnesiac. Science. 1995;268:869–73.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  40. 40.

    Tanaka K, Hashimoto H, Shintani N, Yamamoto A, Baba A. Reduced hypothermic and hypnotic responses to ethanol in PACAP-deficient mice. Regul Pept. 2004;123:95–8.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Tanaka K, Kunishige-Yamamoto A, Hashimoto H, Shintani N, Hayata A, Baba A. Increased ethanol preference and serotonin 1A receptor-dependent attenuation of ethanol-induced hypothermia in PACAP-deficient mice. Biochem Biophys Res Commun. 2010;391:773–7.

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    He DY, Vagts AJ, Yaka R, Ron D. Ethanol induces gene expression via nuclear compartmentalization of receptor for activated C kinase 1. Mol Pharm. 2002;62:272–80.

    CAS  Article  Google Scholar 

  43. 43.

    Gupta A, Gargiulo AT, Curtis GR, Badve PS, Pandey S, Barson JR. Pituitary adenylate cyclase-activating polypeptide-27 (PACAP-27) in the thalamic paraventricular nucleus is stimulated by ethanol drinking. Alcohol Clin Exp Res. 2018;42:1650–60.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Miles OW, Thrailkill EA, Linden AK, May V, Bouton ME, Hammack SE. Pituitary adenylate cyclase-activating peptide in the bed nucleus of the stria terminalis mediates stress-induced reinstatement of cocaine seeking in rats. Neuropsychopharmacology. 2018;43:978–86.

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Seiglie MP, Smith KL, Blasio A, Cottone P, Sabino V. Pituitary adenylate cyclase-activating polypeptide induces a depressive-like phenotype in rats. Psychopharmacology. 2015;232:3821–31.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Burgos JR, Iresjo BM, Smedh U. Pituitary adenylate cyclase-activating polypeptide 6-38 blocks cocaine- and amphetamine-regulated transcript Peptide-induced hypophagia in rats. PLoS ONE. 2013;8:e72347.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Telegdy G, Adamik A. Neurotransmitter-mediated anxiogenic action of PACAP-38 in rats. Behav Brain Res. 2015;281:333–8.

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Sabino V, Cottone P, Blasio A, Iyer MR, Steardo L, Rice KC, et al. Activation of sigma-receptors induces binge-like drinking in Sardinian alcohol-preferring rats. Neuropsychopharmacology. 2011;36:1207–18.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Sabino V, Cottone P, Zhao Y, Iyer MR, Steardo L Jr., Steardo L, et al. The sigma-receptor antagonist BD-1063 decreases ethanol intake and reinforcement in animal models of excessive drinking. Neuropsychopharmacology. 2009;34:1482–93.

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    O’Dell LE, Roberts AJ, Smith RT, Koob GF. Enhanced alcohol self-administration after intermittent versus continuous alcohol vapor exposure. Alcohol Clin Exp Res. 2004;28:1676–82.

    PubMed  Article  Google Scholar 

  51. 51.

    Funk CK, Zorrilla EP, Lee MJ, Rice KC, Koob GF. Corticotropin-releasing factor 1 antagonists selectively reduce ethanol self-administration in ethanol-dependent rats. Biol Psychiatry. 2007;61:78–86.

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Iemolo A, Ferragud A, Cottone P, Sabino V. Pituitary Adenylate Cyclase-Activating Peptide in the Central Amygdala Causes Anorexia and Body Weight Loss via the Melanocortin and the TrkB Systems. Neuropsychopharmacology. 2015;40:1846–55. https://doi.org/10.1038/npp.2015.34.

  53. 53.

    Iemolo A, Blasio A,St, Cyr SA, Jiang F, Rice KC, Sabino V, et al. CRF-CRF1 receptor system in the central and basolateral nuclei of the amygdala differentially mediates excessive eating of palatable food. Neuropsychopharmacology. 2013;38:2456–66.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Norrholm SD, Das M, Legradi G. Behavioral effects of local microinfusion of pituitary adenylate cyclase activating polypeptide (PACAP) into the paraventricular nucleus of the hypothalamus (PVN). Regul Pept. 2005;128:33–41.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Das M, Vihlen CS, Legradi G. Hypothalamic and brainstem sources of pituitary adenylate cyclase-activating polypeptide nerve fibers innervating the hypothalamic paraventricular nucleus in the rat. J Comp Neurol. 2007;500:761–76.

    PubMed  PubMed Central  Article  Google Scholar 

  56. 56.

    Liu Q, Wong-Riley MTT. Pituitary adenylate cyclase-activating polypeptide: postnatal development in multiple brain stem respiratory-related nuclei in the rat. Respir Physiol Neurobiol. 2019;259:149–55.

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Nakamura K, Nakamachi T, Endo K, Ito K, Machida T, Oka T, et al. Distribution of pituitary adenylate cyclase-activating polypeptide (PACAP) in the human testis and in testicular germ cell tumors. Andrologia. 2014;46:465–71.

    CAS  PubMed  Article  Google Scholar 

  58. 58.

    Matsumoto M, Nakamachi T, Watanabe J, Sugiyama K, Ohtaki H, Murai N, et al. Pituitary adenylate cyclase-activating polypeptide (PACAP) is involved in adult mouse hippocampal neurogenesis after stroke. J Mol Neurosci. 2016;59:270–9.

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    Meloni EG, Kaye KT, Venkataraman A, Carlezon WA Jr. PACAP increases Arc/Arg 3.1 expression within the extended amygdala after fear conditioning in rats. Neurobiol Learn Mem. 2019;157:24–34.

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    Csati A, Tajti J, Kuris A, Tuka B, Edvinsson L, Warfvinge K. Distribution of vasoactive intestinal peptide, pituitary adenylate cyclase-activating peptide, nitric oxide synthase, and their receptors in human and rat sphenopalatine ganglion. Neuroscience. 2012;202:158–68.

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Steinberg A, Frederiksen SD, Blixt FW, Warfvinge K, Edvinsson L. Expression of messenger molecules and receptors in rat and human sphenopalatine ganglion indicating therapeutic targets. J Headache Pain. 2016;17:78.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  62. 62.

    Castorina A, Scuderi S, D’Amico AG, Drago F, D’Agata V. PACAP and VIP increase the expression of myelin-related proteins in rat schwannoma cells: involvement of PAC1/VPAC2 receptor-mediated activation of PI3K/Akt signaling pathways. Exp Cell Res. 2014;322:108–21.

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Giunta S, Castorina A, Bucolo C, Magro G, Drago F, D’Agata V. Early changes in pituitary adenylate cyclase-activating peptide, vasoactive intestinal peptide and related receptors expression in retina of streptozotocin-induced diabetic rats. Peptides. 2012;37:32–9.

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Han X, Ran Y, Su M, Liu Y, Tang W, Dong Z, et al. Chronic changes in pituitary adenylate cyclase-activating polypeptide and related receptors in response to repeated chemical dural stimulation in rats. Mol Pain. 2017;13:1744806917720361.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Ferragud A, Velazquez-Sanchez C, Abdullatif AA, Sabino V, Cottone P. Withdrawal from extended, intermittent access to a highly palatable diet impairs hippocampal memory function and neurogenesis: effects of memantine. Nutrients. 2020;12.

  66. 66.

    Paxinos G, Watson C. The Rat brain in stereotaxic coordinates. 6th edn. Elsevier Academic Press; 2007.

  67. 67.

    Hammack SE, Cheung J, Rhodes KM, Schutz KC, Falls WA, Braas KM, et al. Chronic stress increases pituitary adenylate cyclase-activating peptide (PACAP) and brain-derived neurotrophic factor (BDNF) mRNA expression in the bed nucleus of the stria terminalis (BNST): roles for PACAP in anxiety-like behavior. Psychoneuroendocrinology. 2009;34:833–43.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Gilpin NW, Richardson HN, Koob GF. Effects of CRF1-receptor and opioid-receptor antagonists on dependence-induced increases in alcohol drinking by alcohol-preferring (P) rats. Alcohol Clin Exp Res. 2008;32:1535–42.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Zorrilla EP, Logrip ML, Koob GF. Corticotropin releasing factor: a key role in the neurobiology of addiction. Front Neuroendocrinol. 2014;35:234–44.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Crawley J, Goodwin FK. Preliminary report of a simple animal behavior model for the anxiolytic effects of benzodiazepines. Pharmacol Biochem Behav. 1980;13:167–70.

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    Lutfy K, Shankar G. Emerging evidence for the role of pituitary adenylate cyclase-activating peptide in neuropsychiatric disorders. Prog Mol Biol Transl Sci. 2019;167:143–57.

    PubMed  Article  Google Scholar 

  72. 72.

    Koob GF. Addiction is a reward deficit and stress surfeit disorder. Front Psychiatry. 2013;4:72.

    PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    Roberts AJ, Cole M, Koob GF. Intra-amygdala muscimol decreases operant ethanol self-administration in dependent rats. Alcohol Clin Exp Res. 1996;20:1289–98.

    CAS  PubMed  Article  Google Scholar 

  74. 74.

    Vendruscolo LF, Roberts AJ. Operant alcohol self-administration in dependent rats: focus on the vapor model. Alcohol. 2014;48:277–86.

    CAS  PubMed  Article  Google Scholar 

  75. 75.

    Sabino V, Cottone P, Koob GF, Steardo L, Lee MJ, Rice KC, et al. Dissociation between opioid and CRF1 antagonist sensitive drinking in Sardinian alcohol-preferring rats. Psychopharmacology. 2006;189:175–86.

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    Holmes A, Heilig M, Rupniak NM, Steckler T, Griebel G. Neuropeptide systems as novel therapeutic targets for depression and anxiety disorders. Trends Pharm Sci. 2003;24:580–8.

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Silberman Y, Matthews RT, Winder DG. A corticotropin releasing factor pathway for ethanol regulation of the ventral tegmental area in the bed nucleus of the stria terminalis. J Neurosci. 2013;33:950–60.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Olive MF, Koenig HN, Nannini MA, Hodge CW. Elevated extracellular CRF levels in the bed nucleus of the stria terminalis during ethanol withdrawal and reduction by subsequent ethanol intake. Pharmacol Biochem Behav. 2002;72:213–20.

    CAS  PubMed  Article  Google Scholar 

  79. 79.

    de Guglielmo G, Kallupi M, Pomrenze MB, Crawford E, Simpson S, Schweitzer P, et al. Inactivation of a CRF-dependent amygdalofugal pathway reverses addiction-like behaviors in alcohol-dependent rats. Nat Commun. 2019;10:1238.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  80. 80.

    Miles OW, May V, Hammack SE. Pituitary adenylate cyclase-activating peptide (PACAP) signaling and the dark side of addiction. J Mol Neurosci. 2019;68:453–64.

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    Tsukiyama N, Saida Y, Kakuda M, Shintani N, Hayata A, Morita Y, et al. PACAP centrally mediates emotional stress-induced corticosterone responses in mice. Stress. 2011;14:368–75.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Kozicz T, Vigh S, Arimura A. Axon terminals containing PACAP- and VIP-immunoreactivity form synapses with CRF-immunoreactive neurons in the dorsolateral division of the bed nucleus of the stria terminalis in the rat. Brain Res. 1997;767:109–19.

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Legradi G, Shioda S, Arimura A. Pituitary adenylate cyclase-activating polypeptide-like immunoreactivity in autonomic regulatory areas of the rat medulla oblongata. Neurosci Lett. 1994;176:193–6.

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    Kirry AJ, Herbst MR, Poirier SE, Maskeri MM, Rothwell AC, Twining RC, et al. Pituitary adenylate cyclase-activating polypeptide (PACAP) signaling in the prefrontal cortex modulates cued fear learning, but not spatial working memory, in female rats. Neuropharmacology. 2018;133:145–54.

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Weller KL, Smith DA. Afferent connections to the bed nucleus of the stria terminalis. Brain Res. 1982;232:255–70.

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    Harmar AJ, Fahrenkrug J, Gozes I, Laburthe M, May V, Pisegna JR, et al. Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR review 1. Br J Pharm. 2012;166:4–17.

    CAS  Article  Google Scholar 

  87. 87.

    Jaworski DM, Proctor MD. Developmental regulation of pituitary adenylate cyclase-activating polypeptide and PAC(1) receptor mRNA expression in the rat central nervous system. Brain Res Dev Brain Res. 2000;120:27–39.

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    Hashimoto H, Nogi H, Mori K, Ohishi H, Shigemoto R, Yamamoto K, et al. Distribution of the mRNA for a pituitary adenylate cyclase-activating polypeptide receptor in the rat brain: an in situ hybridization study. J Comp Neurol. 1996;371:567–77.

    CAS  PubMed  Article  Google Scholar 

  89. 89.

    Ishihara T, Shigemoto R, Mori K, Takahashi K, Nagata S. Functional expression and tissue distribution of a novel receptor for vasoactive intestinal polypeptide. Neuron. 1992;8:811–9.

    CAS  PubMed  Article  Google Scholar 

  90. 90.

    Sheward WJ, Lutz EM, Harmar AJ. The distribution of vasoactive intestinal peptide2 receptor messenger RNA in the rat brain and pituitary gland as assessed by in situ hybridization. Neuroscience. 1995;67:409–18.

    CAS  PubMed  Article  Google Scholar 

  91. 91.

    King SB, Toufexis DJ, Hammack SE. Pituitary adenylate cyclase activating polypeptide (PACAP), stress, and sex hormones. Stress. 2017;20:465–75.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. 92.

    Nega S, Marquez P, Hamid A, Ahmad SM, Lutfy K. The role of pituitary adenylyl cyclase activating polypeptide in affective signs of nicotine withdrawal. J Neurosci Res. 2020;98:1549–60.

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Acknowledgements

We thank Lillian Huang, Tina Ta, and Rachel May Leavitt for their technical help.

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AF, PC, and VS designed the experiments; AF and CVS performed the experiments; AF and MAM analyzed the data; AF and MAM wrote a first draft of the manuscript, all authors edited the manuscript and approved the final version.

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Correspondence to Valentina Sabino or Pietro Cottone.

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Ferragud, A., Velazquez-Sanchez, C., Minnig, M.A. et al. Pituitary adenylate cyclase-activating polypeptide (PACAP) modulates dependence-induced alcohol drinking and anxiety-like behavior in male rats. Neuropsychopharmacol. (2020). https://doi.org/10.1038/s41386-020-00904-4

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