Cell and Tissue Research

, Volume 375, Issue 1, pp 103–122 | Cite as

Two ancient neuropeptides, PACAP and AVP, modulate motivated behavior at synapses in the extrahypothalamic brain: a study in contrast

  • Limei ZhangEmail author
  • Lee E. EidenEmail author


We examine evolutionary aspects of two primordial neuropeptides, arginine vasopressin (AVP) and pituitary adenylate cyclase-activating polypeptide (PACAP); the distribution of AVP and PACAP and their receptors in mammals; AVP and PACAP release patterns relevant to their roles in neuroendocrine control in brain and periphery; and finally the intricate interlocking of homeostatic and allostatic regulation created by extrahypothalamic AVP and PACAP projections to brain circuit nodes important in controlling appetitive, avoidance and aggressive motor responses. A cardinal feature of peptide neurotransmission important in regulatory control of organismic responses and emphasized in this review, is that neuropeptides are released from large dense-core vesicles docked not only within axonal varicosities and dendrites but also at presynaptic nerve terminal sites, along with small clear synaptic vesicles, at active zones. Peptide transmitter nerve terminals, from hypothalamic and other projections, are distributed widely to multiple brain areas important in integrative control of behavior. They converge with heterologous inputs that release other transmitters, including other peptides, in the same areas. The concept of a quasi-hormonal effect of peptide neurotransmission through coordinated release at multiple synapses throughout the brain echoes earlier conceptualizations of “action-at-a-distance” by diffusion following peptide release at non-synaptic sites. Yet, it recognizes that peptide delivery occurs with neuroanatomical precision, from discrete peptide-containing brain nuclei, via highly distributed projections to multiple extrahypothalamic nodes, registering multiple homeostatic, hedonistic, aversive and reproductive drives that modulate real-time motor decisions. There is paradigmatic value in the discussion of these two particular ancient neuropeptides, for peptide-centric translational neuroendocrinology and peptide GPCR-based neurotherapeutics.


Arginine vasopressin Pituitary adenylate cyclase-activating polypeptide Magnocellular neurons Neuropeptide GPCR Neuropeptide circuits in behavior 



We thank Vito Hernández for critical reading of the manuscript and Fernando Jáuregui for assistance in Fig. 3 preparation.

Funding information

This work was supported by DGAPA-UNAM-PAPIIT-IN216918, CONACYT-CB-238744 (to L.Z.) and NIMH-IRP-MH002386 (to L.E.E.). L.Z. was a Fulbright Visiting Scholar in the Section on Molecular Neuroscience during the initial stages of preparation of this review and was also supported by PASPA-DGAPA-UNAM fellowships for her sabbatical leave.


  1. Abad C, Gomariz RP, Waschek JA (2006) Neuropeptide mimetics and antagonists in the treatment of inflammatory disease: focus on VIP and PACAP. Curr Top Med Chem 6(2):151–163Google Scholar
  2. Agarwal A, Halvorson LM, Legradi G (2005) 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 138(1):45–57Google Scholar
  3. Alexander SP, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Spedding M, Peters JA, Harmar AJ, Collaborators C (2013) The concise guide to PHARMACOLOGY 2013/14: G protein-coupled receptors. Br J Pharmacol 170(8):1459–1581Google Scholar
  4. Arimura A (1998) Perspectives on pituitary adenylate cyclase activating polypeptide (PACAP) in the neuroendocrine, endocrine, and nervous systems. Jap J Physiol 48:301–331Google Scholar
  5. Arimura A, Somogyvari-Vigh A, Miyata A, Mizuno K, Coy DH, Kitada C (1991) Tissue distribution of PACAP as determined by RIA: highly abundant in the rat brain and testes. Endocrinology 129(5):2787–2789Google Scholar
  6. Armstrong WE (2004) Anatomical substrates of hypothalamic integration. In: Paxinos G (ed) The rat nervous system. Elsevier, Inc., Amsterdam, pp 369–388Google Scholar
  7. Armstrong WE, Hatton GI (1980) The localization of projection neurons in the rat hypothalamic paraventricular nucleus following vascular and neurohypophysial injections of HRP. Brain Res Bull 5(4):473–477Google Scholar
  8. Armstrong WE, Warach S, Hatton GI, McNeill TH (1980) Subnuclei in the rat hypothalamic paraventricular nucleus:a cytoarchitectural, horseradish peroxidase and immunocytochemical analysis. Neuroscience 5:1931–1958.
  9. Armstrong BD, Hu Z, Abad C, Yamamoto M, Rodriguez WI, Cheng J, Tam J, Gomariz RP, Patterson PH, Waschek JA (2003) Lymphocyte regulation of neuropeptide gene expression after neuronal injury. J Neurosci Res 74(2):240–247Google Scholar
  10. Armstrong BD, Abad C, Chhith S, Cheung-Lau G, Hajji OE, Nobuta H, Waschek JA (2008) Impaired nerve regeneration and enhanced neuroinflammatory response in mice lacking pituitary adenylyl cyclase activating peptide. Neuroscience 151(1):63–73Google Scholar
  11. Aton SJ, Colwell CS, Harmar AJ, Waschek J, Herzog ED (2005) Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons. Nat Neurosci 8:476–483Google Scholar
  12. Banerjee P, Joy KP, Chaube R (2017) Structural and functional diversity of nonapeptide hormones from an evolutionary perspective: a review. Gen Comp Endocrinol 241:4–23Google Scholar
  13. Beaudet MM, Parsons RL, Braas KM, May V (2000) Mechanisms mediating pituitary adenylate cyclase-activating polypeptide depolarization of rat sympathetic neurons. J Neurosci 20:7353–7361Google Scholar
  14. Beaule C, Mitchell JW, Lindberg PT, Damadzic R, Eiden LE, Gillette MU (2009) Temporally restricted role of retinal PACAP: integration of the phase-advancing light signal to the SCN. J Biol Rhythm 24(2):126–134Google Scholar
  15. Beets I, Temmerman L, Janssen T, Schoofs L (2013) Ancient neuromodulation by vasopressin/oxytocin-related peptides. Worm 2(2):e24246Google Scholar
  16. Bielsky IF, Hu SB, Szegda KL, Westphal H, Young LJ (2004) Profound impairment in social recognition and reduction in anxiety-like behavior in vasopressin V1a receptor knockout mice. Neuropsychopharmacology 29(3):483–493Google Scholar
  17. Bilezikjian LM, Blount AL, Vale WW (1987) The cellular actions of vasopressin on corticotrophs of the anterior pituitary: resistance to glucocorticoid action. Mol Endocrinol 1(7):451–458Google Scholar
  18. Birnbaumer M (2002) Vasopressin receptors. Hormones, Brain and Behavior, Elsevier eScience 3:803–809Google Scholar
  19. Braas KM, May V (1999) Pituitary adenylate cyclase-activating polypeptides directly stimulate sympathetic neuron neuropeptide Y release through PAC(1) receptor isoform activation of specific intracellular signaling pathways. J Biol Chem 274(39):27702–27710Google Scholar
  20. Brinton RD, Gonzalez TM, Cheung WS (1994) Vasopressin-induced calcium signaling in cultured hippocampal neurons. Brain Res 667(1):151–159Google Scholar
  21. Brown CH, Scott V, Ludwig M, Leng G, Bourque CW (2007) Somatodendritic dynorphin release: orchestrating activity patterns of vasopressin neurons. Biochem Soc Trans 35(Pt 5):1236–1242Google Scholar
  22. Buijs RM (1978) Intra- and extrahypothalamic vasopressin and oxytocin pathways in the rat. Pathways to the limbic system, medulla oblongata and spinal cord. Cell Tissue Res 192(3):423–435Google Scholar
  23. Buijs RM, Swaab DF, Dogterom J, van Leeuwen FW (1978) Intra- and extrahypothalamic vasopressin and oxytocin pathways in the rat. Cell Tissue Res 186(3):423–433Google Scholar
  24. Buijs RM, De Vries GJ, Van Leeuwen FW, Swaab DF (1983) Vasopressin and oxytocin: distribution and putative functions in the brain. Prog Brain Res 60:115–122Google Scholar
  25. Bunck M, Czibere L, Horvath C, Graf C, Frank E, Kessler MS, Murgatroyd C, Muller-Myhsok B, Gonik M, Weber P, Putz B, Muigg P, Panhuysen M, Singewald N, Bettecken T, Deussing JM, Holsboer F, Spengler D, Landgraf R (2009) A hypomorphic vasopressin allele prevents anxiety-related behavior. PLoS One 4(4):e5129Google Scholar
  26. Bunin MA, Wightman RM (1999) Paracrine neurotransmission in the CNS: involvement of 5-HT. Trends Neurosci 22(9):377–382Google Scholar
  27. Caffe AR, van Leeuwen FW (1983) Vasopressin-immunoreactive cells in the dorsomedial hypothalamic region, medial amygdaloid nucleus and locus coeruleus of the rat. Cell Tissue Res 233:23–33Google Scholar
  28. Caffe AR, van Leeuwen FW, Luiten PG (1987) Vasopressin cells in the medial amygdala of the rat project to the lateral septum and ventral hippocampus. J Comp Neurol 261(2):237–252Google Scholar
  29. Caldwell HK (2012) Neurobiology of sociability. Adv Exp Med Biol 739:187–205Google Scholar
  30. Castel M, Morris JF (1988) The neurophysin-containing innervation of the forebrain of the mouse. Neuroscience 24:937–966Google Scholar
  31. Chretien M (2013) How the prohormone theory solved two important controversies in hormonal and neural peptide biosynthesis. Front Endocrinol (Lausanne) 4:148Google Scholar
  32. Christofi FL, Wood JD (1993) Effects of PACAP on morphologically identified myenteric neurons in Guinea pig small bowel. Am J Phys 264(3 Pt 1):G414–G421Google Scholar
  33. Chrousos GP, Gold PW (1992) The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. J Amer Med Assoc 267(9):1244–1252Google Scholar
  34. Colwell CS, Waschek JA (2001) Role of PACAP in circadian function of the SCN. Regul Pept 102:49–68Google Scholar
  35. Colwell CS, Michel S, Itri J, Rodriguez W, Tam J, Lelievre V, Hu Z, Liu X, Waschek JA (2003) Disrupted circadian rhythms in VIP and PHI deficient mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 285:R939–R949Google Scholar
  36. Colwell CS, Michel S, Itri J, Rodriguez W, Tam J, Lelievre V, Hu Z, Waschek JA (2004) Selective deficits in the circadian light response in mice lacking PACAP. Am J Physiol Regul Integr Comp Physiol 287(5):R1194–R1201Google Scholar
  37. Costa L, Santangelo F, Li Volsi G, Ciranna L (2008) Modulation of AMPA receptor-mediated ion current by pituitary adenylate cyclase-activating polypeptide (PACAP) in CA1 pyramidal neurons from rat hippocampus. HippocampusGoogle Scholar
  38. Crestani CC, Alves FH, Gomes FV, Resstel LB, Correa FM, Herman JP (2013) Mechanisms in the bed nucleus of the stria terminalis involved in control of autonomic and neuroendocrine functions: a review. Curr Neuropharmacol 11(2):141–159Google Scholar
  39. Csikota P, Fodor A, Balazsfi D, Pinter O, Mizukami H, Weger S, Heilbronn R, Engelmann M, Zelena D (2016) Vasopressinergic control of stress-related behavior: studies in Brattleboro rats. Stress 19(4):349–361Google Scholar
  40. Cui Z, Gerfen CR, Young WS 3rd (2013) Hypothalamic and other connections with dorsal CA2 area of the mouse hippocampus. J Comp Neurol 521(8):1844–1866Google Scholar
  41. Darlinson MG, Richter D (1999) Multiple genes for neuropeptides and their receptors: co-evolution and physiology. Trends Neurosci 22:81–88Google Scholar
  42. Dickinson T, Fleetwood-Walker SM (1999) VIP and PACAP: very important in pain? TIPS 20:324–329Google Scholar
  43. Eiden LE, Emery AC, Zhang L, Smith CB (2018) PACAP signaling in stress: insights from the chromaffin cell. Pflugers Arch 470(1):79–88Google Scholar
  44. Elde R, Haber S, Ho R, Holets V, de Lanerolle N, Maley B, Micevych P, Seybold V (1980) Interspecies conservation and variation in peptidergic neurons. Peptides 1:21–26Google Scholar
  45. Emery AC, Eiden LE (2012) Signaling through the neuropeptide GPCR PAC1 induces neuritogenesis via a single linear cAMP- and ERK-dependent pathway using a novel cAMP sensor. FASEB J 26:3199–3211Google Scholar
  46. Emery A, Eiden MV, Mustafa T, Eiden LE (2013) GPCR-Gs signaling to ERK is controlled by the cAMP-sensing guanine nucleotide exchange factor NCS/Rapgef2 in neuronal and endocrine cells. Sci Sign 6:ra51Google Scholar
  47. Emery AC, Eiden MV, Eiden LE (2014) Separate cyclic AMP sensors for neuritogenesis, growth arrest, and survival of neuroendocrine cells. J Biol Chem 289(14):10126–10139Google Scholar
  48. Emery AC, Alvarez RA, Abboud P, Xu W, Westover CD, Eiden MV, Eiden LE (2016) C-terminal amidation of PACAP-38 and P peptides ACAP-27 is dispensable for biological activity at the PAC1 receptor. 79:39–48Google Scholar
  49. Emery AC, Alvarez RA, Eiden MV, Xu W, Simeon FG, Eiden LE (2017a) Differential pharmacophore definition of the cAMP binding sites of neuritogenic cAMP sensor-Rapgef2, protein kinase a, and exchange protein activated by cAMP in neuroendocrine cells using an adenine-based scaffold. ACS Chem Neurosci 8:1500–1509Google Scholar
  50. Emery AC, Xu W, Eiden MV, Eiden LE (2017b) Guanine nucleotide exchange factor Epac2-dependent activation of the GTP-binding protein Rap2A mediates cAMP-dependent growth arrest in neuroendocrine cells. J Biol Chem 292(29):12220–12231Google Scholar
  51. Fredriksson R, Lagerstrom MC, Lundin LG, Schioth HB (2003) The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol 63(6):1256–1272Google Scholar
  52. Furness JB (2016) Integrated neural and endocrine control of gastrointestinal function. Adv Exp Med Biol S. Brierley and M. Costa 891:159–174Google Scholar
  53. Gimpl G, Fahrenholz F (2001) The oxytocin receptor system: structure, function, and regulation. Physiol Rev 81(2):629–683Google Scholar
  54. Girard BM, Keller ET, Schutz KC, May V, Braas KM (2004) Pituitary adenylate cyclase activating polypeptide and PAC1 receptor signaling increase Homer 1a expression in central and peripheral neurons. Regul Pept 123(1–3):107–116Google Scholar
  55. Goto K, Kasya Y, Takuwa YM, Kurihara H, Ischikawa I, Kimura S, Yanagisawa M, Masaki T (1989) Endothelin activates the dihydropyridine-sensitive, voltage-dependent Ca2+ channel in vascular smooth muscle. Proc Natl Acad Sci U S A 86:3915–3918Google Scholar
  56. Greenwood MP, Mecawi AS, Hoe SZ, Mustafa MR, Johnson KR, Al-Mahmoud GA, Elias LL, Paton JF, Antunes-Rodrigues J, Gainer H, Murphy D, Hindmarch CC (2015) A comparison of physiological and transcriptome responses to water deprivation and salt loading in the rat supraoptic nucleus. Am J Physiol Regul Integr Comp Physiol 308(7):R559–R568Google Scholar
  57. Grinevich V, Fournier A, Pelletier G (1997) Effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on corticotropin-releasing hormone (CRH) gene expression in the rat hypothalamic paraventricular nucleus. Brain Res 773(1–2):190–196Google Scholar
  58. Guillemin R (1977) Peptides in the brain. The new endocrinology of the neuron. Nobel Lecture 8 December, 1977Google Scholar
  59. Guillemin R, Brazeau P, Bohlen P, Esch F, Ling N, Wehrenberg WB (1982) Growth hormone-releasing factor from a human pancreatic tumor that caused acromegaly. Science 218(4572):585–587Google Scholar
  60. Hamelink C, Tjurmina O, Damadzic R, Young WS, Weihe E, Lee H-W, Eiden LE (2002) Pituitary adenylate cyclase activating polypeptide is a sympathoadrenal neurotransmitter involved in catecholamine regulation and glucohomeostasis. Proc Natl Acad Sci U S A 99:461–466Google Scholar
  61. Hamelink C, Weihe E, Eiden LE (2003) In: Vaudry H, Arimura A (eds) PACAP: an ‘emergency response’ co-transmitter in the adrenal medulla. Pituitary adenylate cyclase-activating polypeptide. Kluwer- Academic Press, Norwell, pp 227–250Google Scholar
  62. Hammack SE, May V (2015) Pituitary adenylate cyclase activating polypeptide in stress-related disorders: data convergence from animal and human studies. Biol Psychiatry 78:167–177Google Scholar
  63. Hannibal J (2002) Pituitary adenylate cyclase-activating peptide in the rat central nervous system: an immunohistochemical and in situ hybridization study. J Comp Neurol 453(4):389–417Google Scholar
  64. Hannibal J (2006) Roles of PACAP-containing retinal ganglion cells in circadian timing. Int Rev Cytol 251:1–39Google Scholar
  65. Hannibal J, Hindersson P, Knudsen SM, Georg B, Fahrenkrug SM GBJ, Fahrenkrug J, B. H. Department of Clinical Biochemistry, University of Copenhagen, DK-2400 Copenhagen, Denmark (2002) The photopigment melanopsin is exclusively present in pituitary adenylate cyclase-activating polypeptide-containing retinal ganglion cells of the retinohypothalamic tract. J Neurosci 22:RC191Google Scholar
  66. Harmar AJ, Marston HM, Shen S, Spratt C, West KM, Sheward WJ, Morrison CF, Dorin JR, Piggins HD, Reubi J-C, Kelly JS, Maywood ES, Hastings MH (2002) The VPAC2 receptor is essential for circadian function in the mouse suprachiasmatic nuclei. Cell 109:497–508Google Scholar
  67. Harmar AJ, Fahrenkrug J, Gozes I, Laburthe M, May V, Pisegna JR, Vaudry D, Vaudry H, Waschek JA, Said SI (2012) Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR review 1. Br J Pharmacol 166(1):4–17Google Scholar
  68. Harris GW (1955) Neural control of the pituitary gland. Edward Arnold, LondonGoogle Scholar
  69. Hauser F, Williamson M, Cazzamali G, Grimmelikhuijzen CJ (2006) Identifying neuropeptide and protein hormone receptors in Drosophila melanogaster by exploiting genomic data. Brief Funct Genomic Proteomic 4(4):321–330Google Scholar
  70. Hernandez VS, Vazquez-Juarez E, Marquez MM, Jauregui-Huerta F, Barrio RA, Zhang L (2015) Extra-neurohypophyseal axonal projections from individual vasopressin-containing magnocellular neurons in rat hypothalamus. Front Neuroanat 9:130Google Scholar
  71. Hernandez VS, Hernandez OR, Perez de al Mora M, Gomora JJ, Fuxe K, Eiden LE, Zhang L (2016) Hypothalamic Vasopressinergic projections innervate central amygdala GABAergic neurons: implications for anxiety and stress coping. Front Neural Circ 10:92Google Scholar
  72. Hill J, Chan SA, Kuri B, Smith C (2011) Pituitary adenylate cyclase-activating peptide (PACAP) recruits low voltage-activated T-type calcium influx under acute sympathetic stimulation in mouse adrenal chromaffin cells. J Biol Chem 286(49):42459–42469Google Scholar
  73. Hökfelt T, Broberger C, Xu Z-QD, Sergeyev V, Ubink R, Diez M (2000) Neuropeptides--an overview. Neuropharmacology 39:1337–1356Google Scholar
  74. Hokfelt T, Bartfai T, Bloom F (2003) Neuropeptides:opportunities for drug discovery. Lancet Neurol 2:463–472Google Scholar
  75. Hoyle CH (1999) Neuropeptide families and their receptors: evolutionary perspectives. Brain Res 848(1–2):1–25Google Scholar
  76. Hrabovszky E, Csapo AK, Kallo I, Wilheim T, Turi GF, Liposits Z (2006) Localization and osmotic regulation of vesicular glutamate transporter-2 in magnocellular neurons of the rat hypothalamus. Neurochem Int 48(8):753–761Google Scholar
  77. Hrabovszky E, Deli L, Turi GF, Kallo I, Liposits Z (2007) Glutamatergic innervation of the hypothalamic median eminence and posterior pituitary of the rat. Neuroscience 144(4):1383–1392Google Scholar
  78. Jiang SZ, Eiden LE (2016a) Activation of the HPA axis and depression of feeding behavior induced by restraint stress are separately regulated by PACAPergic neurotransmission in the mouse. Stress 19(4):374–382Google Scholar
  79. Jiang SZ, Eiden LE (2016b) PACAPergic synaptic signaling and circuitry mediating mammalian responses to psychogenic and systemic stressors. In: Tamas DRAA (ed) Pituitary adenylate cyclase-activating polypeptide-PACAP. Springer International, Switzerland, p 11Google Scholar
  80. Juul KV, Bichet DG, Nielsen S, Norgaard JP (2014) The physiological and pathophysiological functions of renal and extrarenal vasopressin V2 receptors. Am J Physiol Renal Physiol 306(9):F931–F940Google Scholar
  81. Kandel ER, Squire LR (2000) Neuroscience: breaking down scientific barriers to the study of brain and mind. Science 290(5494):1113–1120Google Scholar
  82. Kim JK, Schrier RW (1998) Vasopressin processing defects in the Brattleboro rat: implications for hereditary central diabetes insipidus in humans? Proc Assoc Am Physicians 110(5):380–386Google Scholar
  83. Kimura C, Ohkubo S, Ogi K, Hosoya M, Itoh Y, Onda H, Miyata A, Jiang L, Dahl RR, Stibbs HH et al (1990) A novel peptide which stimulates adenylate cyclase: molecular cloning and characterization of the ovine and human cDNAs. Biochem Biophys Res Commun 166(1):81–89Google Scholar
  84. King SB, Toufexis DJ, Hammack SE (2017) Pituitary adenylate cyclase activating polypeptide (PACAP), stress, and sex hormones. Stress 20(5):465–475Google Scholar
  85. Knobloch HS, Charlet A, Hoffmann LC, Eliava M, Khrulev S, Cetin AH, Osten P, Schwarz MK, Seeburg PH, Stoop R, Grinevich V (2012) Evoked axonal oxytocin release in the central amygdala attenuates fear response. Neuron 73(3):553–566Google Scholar
  86. Koide M, Syed AU, Braas KM, May V, Wellman GC (2014) Pituitary adenylate cyclase activating polypeptide (PACAP) dilates cerebellar arteries through activation of large-conductance Ca(2+)-activated (BK) and ATP-sensitive (K ATP) K (+) channels. J Mol Neurosci 54(3):443–450Google Scholar
  87. Kuri BA, Chan SA, Smith CB (2009) PACAP regulates immediate catecholamine release from adrenal chromaffin cells in an activity-dependent manner through a protein kinase C-dependent pathway. J Neurochem 110(4):1214–1225Google Scholar
  88. Land H, Schutz G, Schmale H, Richter D (1982) Nucleotide sequence of cloned cDNA encoding bovine arginine vasopressin-neurophysin II precursor. Nature 295(5847):299–303Google Scholar
  89. Landgraf R, Neumann ID (2004) Vasopressin and oxytocin release within the brain: a dynamic concept of multiple and variable modes of neuropeptide communication. Front Neuroendocrinol 25(3–4):150–176Google Scholar
  90. Legradi G, Hannibal J, Lechan RM (1998) Pituitary adenylate cyclase-activating polypeptide-nerve terminals densely innervate corticotropin-releasing hormone-neurons in the hypothalamic paraventricular nucleus of the rat. Neurosci Lett 246(3):145–148Google Scholar
  91. Lehmann ML, Mustafa T, Eiden AM, Herkenham M, Eiden LE (2013) PACAP-deficient mice show attenuated corticosterone secretion and fail to develop depressive behavior during chronic social defeat stress. Psychoneuroendocrinology 38:702–715Google Scholar
  92. Leng G, Ludwig M (2008) Neurotransmitters and peptides: whispered secrets and public announcements. J Physiol 586(Pt 23):5625–5632Google Scholar
  93. Lindberg PT, Hamelink C, Damadzic R, Eiden LE, Gillette MU (2004) Pituitary adenylate cyclase-activating peptide plays a time-dependent role in light-induced phase shifts of circadian rhythms. Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience. Online. Program No 195.14. 2004Google Scholar
  94. Loewi O (1921) Uber humorale ubertragbarkeit der hirzenwickung. Pflugers Arch 189:239–242Google Scholar
  95. Lu B, Su Y, Das S, Wang H, Wang Y, Liu J, Ren D (2009) Peptide neurotransmitters activate a cation channel complex of NALCN and UNC-80. Nature 457(7230):741–744Google Scholar
  96. Macdonald DS, Weerapura M, Beazely MA, Martin L, Czerwinski W, Roder JC, Orser BA, MacDonald JF (2005) Modulation of NMDA receptors by pituitary adenylate cyclase activating peptide in CA1 neurons requires G alpha q, protein kinase C, and activation of Src. J Neurosci 25(49):11374–11384Google Scholar
  97. Macosko EZ, Pokala N, Feinberg EH, Chalasani SH, Butcher RA, Clardy J, Bargmann CI (2009) A hub-and-spoke circuit drives pheromone attraction and social behaviour in C. elegans. Nature 458(7242):1171–1175Google Scholar
  98. Manning M, Misicka A, Olma A, Bankowski K, Stoev S, Chini B, Durroux T, Mouillac B, Corbani M, Guillon G (2012) Oxytocin and vasopressin agonists and antagonists as research tools and potential therapeutics. J Neuroendocrinol 24(4):609–628Google Scholar
  99. Manzano-Garcia A, Gonzalez-Hernandez A, Tello-Garcia IA, Martinez-Lorenzana G, Condes-Lara M (2018) The role of peripheral vasopressin 1A and oxytocin receptors on the subcutaneous vasopressin antinociceptive effects. Eur J Pain 22(3):511–526Google Scholar
  100. May V, Lutz E, MacKenzie C, Schutz KC, Dozark K, Braas KM (2010) Pituitary adenylate cyclase-activating polypeptide (PACAP)/PAC1HOP1 receptor activation coordinates multiple neurotrophic signaling pathways: Akt activation through phosphatidylinositol 3-kinase gamma and vesicle endocytosis for neuronal survival. J Biol Chem 285(13):9749–9761Google Scholar
  101. May V, Buttolph TR, Girard BM, Clason TA, Parsons RL (2014a) PACAP-induced ERK activation in HEK cells expressing PAC1 receptors involves both receptor internalization and PKC signaling. Am J Physiol Cell Physiol 306(11):C1068–C1079Google Scholar
  102. May V, Clason TA, Buttolph TR, Girard BM, Parsons RL (2014b) Calcium influx, but not intracellular calcium release, supports PACAP-mediated ERK activation in HEK PAC1 receptor cells. J Mol NeurosciGoogle Scholar
  103. Merriam LA, Baran CN, Girard BM, Hardwick JC, May V, Parsons RL (2013) Pituitary adenylate cyclase 1 receptor internalization and endosomal signaling mediate the pituitary adenylate cyclase activating polypeptide-induced increase in Guinea pig cardiac neuron excitability. J Neurosci 33(10):4614–4622Google Scholar
  104. Meyer-Lindenberg A, Domes G, Kirsch P, Heinrichs M (2011) Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine. Nat Rev Neurosci 12(9):524–538Google Scholar
  105. Michel S, Itri J, Han JH, Gniotczynski K, Colwell CS (2006) Regulation of glutamatergic signalling by PACAP in the mammalian suprachiasmatic nucleus. BMC Neurosci 7:15Google Scholar
  106. Miles OW, Thrailkill EA, Linden AK, May V, Bouton ME, Hammack SE (2017) Pituitary adenylate cyclase-activating peptide in the bed nucleus of the stria terminalis mediates stress-induced reinstatement of cocaine seeking in rats. NeuropsychopharmacologyGoogle Scholar
  107. Millar RP, Aehnelt C, Rossier G (1977) Higher molecular weight immunoreactive species of luteinizing hormone releasing hormone: possible precursors of the hormone. Biochem Biophys Res Commun 74(2):720–731Google Scholar
  108. Missig G, Roman CW, Vizzard MA, Braas KM, Hammack SE, May V (2014) Parabrachial nucleus (PBn) pituitary adenylate cyclase activating polypeptide (PACAP) signaling in the amygdala: implication for the sensory and behavioral effects of pain. Neuropharmacology 86:38–48Google Scholar
  109. Miyata A, Arimura A, Dahl RR, Minamino N, Uehara A, Jiang L, Culler MD, Coy DH (1989) Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells. Biochem Biophys Res Commun 164:567–574Google Scholar
  110. Moller K, Zhang Y-Z, Hakanson R, Luts A, Sjölund B, Uddman R, Sundler F (1993) Pituitary adenylate cyclase activating peptide is a sensory neuropeptide: immunocytochemical and immunochemical evidence. Neuroscience 57:725–732Google Scholar
  111. Morris JF, Pow DV (1988) Capturing and quantifying the exocytotic event. J Exp Biol 139:81–103Google Scholar
  112. Mustafa T, Eiden LE (2006) The secretin superfamily: PACAP, VIP and related peptides. Handbook of neurochemistry and molecular neurobiology: XIII. In: Lim R (ed) Neuroactive peptides and proteins, vol XIII. Springer, Heidelberg, pp 1–36Google Scholar
  113. Nagahama M, Tsuzuki M, Mochizuki T, Iguchi K, Kuwahara A (1998) Light and electron microscopic studies of pituitary adenylate cyclase-activating peptide (PACAP)--immunoreactive neurons in the enteric nervous system of rat small and large intestine. Anat Embryol (Berl) 198(5):341–352Google Scholar
  114. Neumann ID, Landgraf R (2012) Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors. Trends Neurosci 35(11):649–659Google Scholar
  115. Otero-Garcia M, Martin-Sanchez A, Fortes-Marco L, Martinez-Ricos J, Agustin-Pavon C, Lanuza E, Martinez-Garcia F (2014) Extending the socio-sexual brain: arginine-vasopressin immunoreactive circuits in the telencephalon of mice. Brain Struct Funct 219(3):1055–1081Google Scholar
  116. Pagani JH, Zhao M, Cui Z, Williams Avram SK, Caruana DA, Dudek SM, Young WS (2014) Role of the vasopressin 1b receptor in rodent aggressive behavior and synaptic plasticity in hippocampal area CA2. Mol PsychiatryGoogle Scholar
  117. Paul MJ, Peters NV, Holder MK, Kim AM, Whylings J, Terranova JI, de Vries GJ (2016) Atypical social development in vasopressin-deficient Brattleboro rats. eNeuro 3(2)Google Scholar
  118. Pearse AG, Takor TT (1976) Neuroendocrine embryology and the APUD concept. Clin Endocrinol (Oxf) 5 Suppl:229S–244SGoogle Scholar
  119. Pisegna JR, Wank SA (1993) Molecular cloning and functional expression of the pituitary adenylate cyclase-activating polypeptide type I receptor. Proc Natl Acad Sci U S A 90(13):6345–6349Google Scholar
  120. Pisegna JR, Wank SA (1996) Cloning and characterization of the signal transduction of four splice variants of the human pituitary adenylate cyclase activating polypeptide receptor. Evidence for dual coupling to adenylate cyclase and phospholipase C. J Biol Chem 271(29):17267–17274Google Scholar
  121. Porges SW (1997) Emotion: an evolutionary by-product of the neural regulation of the autonomic nervous system. Ann N Y Acad Sci 807:62–77Google Scholar
  122. Portbury AL, McConalogue K, Furness JB, Young HM (1995) Distribution of pituitary adenylyl cyclase activating peptide (PACAP) immunoreactivity in neurons of the guinea-pig digestive tract and their projections in the ileum and colon. Cell Tissue Res 279(2):385–392Google Scholar
  123. Rashid AJ, O'Dowd BF, George SR (2004) Minireview: diversity and complexity of signaling through peptidergic G protein-coupled receptors. Endocrinology 145(6):2645–2652Google Scholar
  124. Ressler KJ, Mercer KB, Bradley B, Jovanovic T, Mahan A, Kerley K, Norrholm SD, Kilaru V, Smith AK, Myers AJ, Ramirez M, Engel A, Hammack SE, Toufexis D, Braas KM, Binder EB, May V (2011) Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor. Nature 470(7335):492–497Google Scholar
  125. Richter D (1999) Regulatory peptides and their cognate receptors. Springer-VerlagGoogle Scholar
  126. Rood BD, de Vries GJ (2011) Vasopressin innervation of the mouse (Mus musculus) brain and spinal cord. J Comp Neurol 518:2434–2474Google Scholar
  127. Rood BD, Stott RT, You S, Smith CJ, Woodbury ME, De Vries GJ (2013) Site of origin of and sex differences in the vasopressin innervation of the mouse (Mus musculus) brain. J Comp Neurol 521(10):2321–2358Google Scholar
  128. Schally AV (1977) Aspects of hypothalamic regulation of the pituitary gland with major emphasis on its implications for the control of reproductive processes. Nobel lecture, 8 December, 1977Google Scholar
  129. Seeburg PH, Adelman JP (1984) Characterization of cDNA for precursor of human luteinizing hormone releasing hormone. Nature 311(5987):666–668Google Scholar
  130. Sherwood NM, Krueckl SL, McRory JE (2000) The origin and function of the pituitary adenylate cyclase-activating polypeptide (PACAP)/glucagon superfamily. Endocr Rev 21:619–670Google Scholar
  131. Sherwood NM, Gray SL, Cummings KJ (2003) Consequences of PACAP gene knockout. In: Vaudry H, Arimura Norwell A (eds) Pituitary adenylate cyclase-activating polypeptide. Kluwer Academic Publishers, Massachusetts, pp 347–360Google Scholar
  132. Smith CB, Eiden LE (2012) Is PACAP the major neurotransmitter for stress transduction at the adrenomedullary synapse? J Mol Neurosci 48:403–412Google Scholar
  133. Sofroniew MV (1983) Morphology of vasopressin and oxytocin neurones and their central and vascular projections. Prog Brain Res 60:101–114Google Scholar
  134. Spengler D, Bweber C, Pantaloni C, Hlsboer F, Bockaert J, Seeburg PH, Journot L (1993) Differential signal transduction by five splice variants of the PACAP receptor. Nature 365:170–175Google Scholar
  135. Stawicki TM, Takayanagi-Kiya S, Zhou K, Jin Y (2013) Neuropeptides function in a homeostatic manner to modulate excitation-inhibition imbalance in C. elegans. PLoS Genet 9(5):e1003472Google Scholar
  136. Streefkerk JO, van Zwieten PA (2006) Vasopressin receptor antagonists: pharmacological tools and potential therapeutic agents. Auton Autacoid Pharmacol 26(2):141–148Google Scholar
  137. Stroth N, Eiden LE (2010) Stress hormone synthesis in mouse hypothalamus and adrenal gland triggered by restraint is dependent on pituitary adenylate cyclase-activating polypeptide signaling. Neuroscience 165:1025–1030Google Scholar
  138. Stroth N, Kuri BA, Mustafa T, Chan SA, Smith CB, Eiden LE (2013) PACAP controls adrenomedullary catecholamine secretion and expression of catecholamine biosynthetic enzymes at high splanchnic nerve firing rates characteristic of stress transduction in male mice. Endocrinology 154(1):330–339Google Scholar
  139. Tam JK, Lee LT, Chow BK (2007) PACAP-related peptide (PRP)--molecular evolution and potential functions. Peptides 28:1920–1929Google Scholar
  140. Tan YV, Abad C, Lopez R, Dong H, Liu S, Lee A, Gomariz RP, Leceta J, Waschek JA (2009) Pituitary adenylyl cyclase-activating polypeptide is an intrinsic regulator of Treg abundance and protects against experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 106(6):2012–2017Google Scholar
  141. Terada Y, Tomita K, Nonoguchi H, Yang T, Marumo F (1993) Different localization and regulation of two types of vasopressin receptor messenger RNA in microdissected rat nephron segments using reverse transcription polymerase chain reaction. J Clin Invest 92(5):2339–2345Google Scholar
  142. Thibonnier M, Preston JA, Dulin N, Wilkins PL, Berti-Mattera LN, Mattera R (1997) The human V3 pituitary vasopressin receptor: ligand binding profile and density-dependent signaling pathways. Endocrinology 138(10):4109–4122Google Scholar
  143. Tompkins JD, Parsons RL (2008) Identification of intracellular signaling cascades mediating the PACAP-induced increase in guinea pig cardiac neuron excitability. J Mol Neurosci 36(1–3):292–298Google Scholar
  144. Tsukiyama N, Saida Y, Kakuda M, Shintani N, Hayata A, Morita Y, Tanida M, Tajiri M, Hazama K, Ogata K, Hashimoto H, Baba A (2011) PACAP centrally mediates emotional stress-induced corticosterone responses in mice. Stress 14:368–375Google Scholar
  145. Vale W, Spiess J, Rivier C, Rivier J (1981) Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 213(4514):1394–1397Google Scholar
  146. Veenema AH, Neumann ID (2008) Central vasopressin and oxytocin release: regulation of complex social behaviors. Prog Brain Res I. D. N. a. R. Landgraf, Elsevier. p. 170Google Scholar
  147. Waschek JA (2013) VIP and PACAP: neuropeptide modulators of CNS inflammation, injury, and repair. Br J Pharmacol 169(3):512–523Google Scholar
  148. Wisden W (2016) A tribute to Peter H Seeburg (1944-2016): a founding father of molecular neurobiology. Front Mol Neurosci 9:133Google Scholar
  149. Young WSI (1992) Expression of the oxytocin and vasopressin genes. J Neuroendocrinol 4:527–540Google Scholar
  150. Yuste R (2015) The discovery of dendritic spines by Cajal. Front Neuroanat 9:18Google Scholar
  151. Zhang L, Hernandez VS (2013) Synaptic innervation to rat hippocampus by vasopressin-immuno-positive fibres from the hypothalamic supraoptic and paraventricular nuclei. Neuroscience 228:139–162Google Scholar
  152. Zhang L, Hernandez VS, Liu B, Medina MP, Nava-Kopp AT, Irles C, Morales M (2012) Hypothalamic vasopressin system regulation by maternal separation: its impact on anxiety in rats. Neuroscience 215:135–148Google Scholar
  153. Zhang L, Hernandez VS, Vazquez-Juarez E, Chay FK, Barrio RA (2016) Thirst is associated with suppression of habenula output and active stress coping: is there a role for a non-canonical vasopressin-glutamate pathway? Front Neural Circ 10:13Google Scholar
  154. Zhang L, Hernandez VS, Swinny JD, Verma AK, Giesecke T, Emery AC, Mutig K, Garcia-Segura LM, Eiden LE (2018) A GABAergic cell type in the lateral habenula links hypothalamic homeostatic and midbrain motivation circuits with sex steroid signaling. Transl Psychiatry 8(1):50Google Scholar
  155. Zimmerman EA, Robinson AG (1976) Hypothalamic neurons secreting vasopressin and neurophysin. Kidney Int 10(1):12–24Google Scholar

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© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2018

Authors and Affiliations

  1. 1.Section on Molecular Neuroscience, Laboratory of Cellular and Molecular RegulationNIMH-IRPBethesdaUSA
  2. 2.Department of Physiology, Faculty of MedicineNational Autonomous University of Mexico (UNAM)CDMXMexico

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