Skip to main content
SpringerLink
Log in

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

  • Review
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Notes

  1. Referencing throughout this review emphasizes historical developments and translational implications of AVP and PACAP biology. Comprehensive reviews of the basic physiology of vasopressin, in particular, are plentiful and can easily be found within the citations of the literature referenced here.

References

  • 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):151–163

    Article  CAS  PubMed  Google Scholar 

  • 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):45–57

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):1459–1581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arimura A (1998) Perspectives on pituitary adenylate cyclase activating polypeptide (PACAP) in the neuroendocrine, endocrine, and nervous systems. Jap J Physiol 48:301–331

    Article  CAS  Google Scholar 

  • 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):2787–2789

    Article  CAS  PubMed  Google Scholar 

  • Armstrong WE (2004) Anatomical substrates of hypothalamic integration. In: Paxinos G (ed) The rat nervous system. Elsevier, Inc., Amsterdam, pp 369–388

    Chapter  Google Scholar 

  • 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):473–477

    Article  CAS  PubMed  Google Scholar 

  • 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. https://doi.org/10.1016/0306-4522(80)90040-8

  • 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):240–247

    Article  CAS  PubMed  Google Scholar 

  • 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):63–73

    Article  CAS  PubMed  Google Scholar 

  • 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 8:476–483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Banerjee P, Joy KP, Chaube R (2017) Structural and functional diversity of nonapeptide hormones from an evolutionary perspective: a review. Gen Comp Endocrinol 241:4–23

    Article  CAS  PubMed  Google Scholar 

  • Beaudet MM, Parsons RL, Braas KM, May V (2000) Mechanisms mediating pituitary adenylate cyclase-activating polypeptide depolarization of rat sympathetic neurons. J Neurosci 20:7353–7361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):126–134

    Article  CAS  Google Scholar 

  • Beets I, Temmerman L, Janssen T, Schoofs L (2013) Ancient neuromodulation by vasopressin/oxytocin-related peptides. Worm 2(2):e24246

    Article  PubMed  PubMed Central  Google Scholar 

  • 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):483–493

    Article  CAS  PubMed  Google Scholar 

  • 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):451–458

    Article  CAS  PubMed  Google Scholar 

  • Birnbaumer M (2002) Vasopressin receptors. Hormones, Brain and Behavior, Elsevier eScience 3:803–809

    Article  CAS  Google Scholar 

  • 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):27702–27710

    Article  CAS  PubMed  Google Scholar 

  • Brinton RD, Gonzalez TM, Cheung WS (1994) Vasopressin-induced calcium signaling in cultured hippocampal neurons. Brain Res 667(1):151–159

    Article  CAS  PubMed  Google Scholar 

  • 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):1236–1242

    Article  CAS  PubMed  Google Scholar 

  • 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):423–435

    Article  CAS  PubMed  Google Scholar 

  • 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):423–433

    Article  CAS  PubMed  Google Scholar 

  • Buijs RM, De Vries GJ, Van Leeuwen FW, Swaab DF (1983) Vasopressin and oxytocin: distribution and putative functions in the brain. Prog Brain Res 60:115–122

    Article  CAS  PubMed  Google Scholar 

  • 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):e5129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bunin MA, Wightman RM (1999) Paracrine neurotransmission in the CNS: involvement of 5-HT. Trends Neurosci 22(9):377–382

    Article  CAS  PubMed  Google Scholar 

  • 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 233:23–33

  • 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):237–252

    Article  CAS  PubMed  Google Scholar 

  • Caldwell HK (2012) Neurobiology of sociability. Adv Exp Med Biol 739:187–205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Castel M, Morris JF (1988) The neurophysin-containing innervation of the forebrain of the mouse. Neuroscience 24:937–966

  • Chretien M (2013) How the prohormone theory solved two important controversies in hormonal and neural peptide biosynthesis. Front Endocrinol (Lausanne) 4:148

    Article  Google Scholar 

  • 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–G421

    CAS  Google Scholar 

  • 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):1244–1252

  • Colwell CS, Waschek JA (2001) Role of PACAP in circadian function of the SCN. Regul Pept 102:49–68

    Article  Google Scholar 

  • 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–R949

    Article  CAS  PubMed  Google Scholar 

  • 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–R1201

    Article  CAS  PubMed  Google Scholar 

  • 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. Hippocampus

  • 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):141–159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):349–361

    Article  CAS  PubMed  Google Scholar 

  • 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):1844–1866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Darlinson MG, Richter D (1999) Multiple genes for neuropeptides and their receptors: co-evolution and physiology. Trends Neurosci 22:81–88

    Article  Google Scholar 

  • Dickinson T, Fleetwood-Walker SM (1999) VIP and PACAP: very important in pain? TIPS 20:324–329

    CAS  PubMed  Google Scholar 

  • Eiden LE, Emery AC, Zhang L, Smith CB (2018) PACAP signaling in stress: insights from the chromaffin cell. Pflugers Arch 470(1):79–88

    Article  CAS  PubMed  Google Scholar 

  • 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 1:21–26

    Article  CAS  Google Scholar 

  • 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 26:3199–3211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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:ra51

    Google Scholar 

  • 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):10126–10139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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. 79:39–48

  • 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 8:1500–1509

    Article  CAS  PubMed  Google Scholar 

  • 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):12220–12231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):1256–1272

    Article  CAS  PubMed  Google Scholar 

  • Furness JB (2016) Integrated neural and endocrine control of gastrointestinal function. Adv Exp Med Biol S. Brierley and M. Costa 891:159–174

    Article  CAS  PubMed  Google Scholar 

  • Gimpl G, Fahrenholz F (2001) The oxytocin receptor system: structure, function, and regulation. Physiol Rev 81(2):629–683

    Article  CAS  PubMed  Google Scholar 

  • 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):107–116

    Article  CAS  PubMed  Google Scholar 

  • 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 86:3915–3918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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–R568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):190–196

    Article  CAS  PubMed  Google Scholar 

  • Guillemin R (1977) Peptides in the brain. The new endocrinology of the neuron. Nobel Lecture 8 December, 1977

  • 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):585–587

    Article  CAS  PubMed  Google Scholar 

  • 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 99:461–466

    Article  CAS  PubMed  Google Scholar 

  • 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 227–250

    Chapter  Google Scholar 

  • Hammack SE, May V (2015) Pituitary adenylate cyclase activating polypeptide in stress-related disorders: data convergence from animal and human studies. Biol Psychiatry 78:167–177

    Article  CAS  PubMed  Google Scholar 

  • 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):389–417

    Article  CAS  PubMed  Google Scholar 

  • Hannibal J (2006) Roles of PACAP-containing retinal ganglion cells in circadian timing. Int Rev Cytol 251:1–39

    Article  CAS  PubMed  Google Scholar 

  • 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:RC191

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 109:497–508

    Article  CAS  PubMed  Google Scholar 

  • 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):4–17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harris GW (1955) Neural control of the pituitary gland. Edward Arnold, London

    Google Scholar 

  • 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):321–330

    Article  CAS  PubMed  Google Scholar 

  • 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 9:130

    PubMed  PubMed Central  Google Scholar 

  • 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 10:92

    Google Scholar 

  • 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):42459–42469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hökfelt T, Broberger C, Xu Z-QD, Sergeyev V, Ubink R, Diez M (2000) Neuropeptides--an overview. Neuropharmacology 39:1337–1356

    Article  PubMed  Google Scholar 

  • Hokfelt T, Bartfai T, Bloom F (2003) Neuropeptides:opportunities for drug discovery. Lancet Neurol 2:463–472

    Article  PubMed  Google Scholar 

  • Hoyle CH (1999) Neuropeptide families and their receptors: evolutionary perspectives. Brain Res 848(1–2):1–25

    Article  CAS  PubMed  Google Scholar 

  • 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):753–761

    Article  CAS  PubMed  Google Scholar 

  • 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):1383–1392

  • 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):374–382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 11

    Google Scholar 

  • 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–F940

    Article  CAS  PubMed  Google Scholar 

  • Kandel ER, Squire LR (2000) Neuroscience: breaking down scientific barriers to the study of brain and mind. Science 290(5494):1113–1120

    Article  CAS  PubMed  Google Scholar 

  • 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):380–386

    CAS  PubMed  Google Scholar 

  • 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):81–89

    Article  CAS  PubMed  Google Scholar 

  • King SB, Toufexis DJ, Hammack SE (2017) Pituitary adenylate cyclase activating polypeptide (PACAP), stress, and sex hormones. Stress 20(5):465–475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):553–566

    Article  CAS  PubMed  Google Scholar 

  • 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):443–450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):1214–1225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Land H, Schutz G, Schmale H, Richter D (1982) Nucleotide sequence of cloned cDNA encoding bovine arginine vasopressin-neurophysin II precursor. Nature 295(5847):299–303

    Article  CAS  PubMed  Google Scholar 

  • 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):150–176

    Article  CAS  PubMed  Google Scholar 

  • 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):145–148

    Article  CAS  PubMed  Google Scholar 

  • 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 38:702–715

    Article  CAS  PubMed  Google Scholar 

  • Leng G, Ludwig M (2008) Neurotransmitters and peptides: whispered secrets and public announcements. J Physiol 586(Pt 23):5625–5632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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. 2004

  • Loewi O (1921) Uber humorale ubertragbarkeit der hirzenwickung. Pflugers Arch 189:239–242

    Article  Google Scholar 

  • 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):741–744

    Article  PubMed  Google Scholar 

  • 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):11374–11384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):1171–1175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):609–628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):511–526

    Article  CAS  PubMed  Google Scholar 

  • 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):9749–9761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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–C1079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 Neurosci

  • 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):4614–4622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):524–538

    Article  CAS  PubMed  Google Scholar 

  • Michel S, Itri J, Han JH, Gniotczynski K, Colwell CS (2006) Regulation of glutamatergic signalling by PACAP in the mammalian suprachiasmatic nucleus. BMC Neurosci 7:15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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. Neuropsychopharmacology

  • 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):720–731

    Article  CAS  PubMed  Google Scholar 

  • 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 86:38–48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 164:567–574

    Article  CAS  PubMed  Google Scholar 

  • 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 57:725–732

    Article  CAS  PubMed  Google Scholar 

  • Morris JF, Pow DV (1988) Capturing and quantifying the exocytotic event. J Exp Biol 139:81–103

    CAS  PubMed  Google Scholar 

  • 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 1–36

    Google Scholar 

  • 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):341–352

    Article  CAS  Google Scholar 

  • Neumann ID, Landgraf R (2012) Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors. Trends Neurosci 35(11):649–659

    Article  CAS  PubMed  Google Scholar 

  • 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):1055–1081

    Article  CAS  PubMed  Google Scholar 

  • 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 Psychiatry

  • 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)

  • Pearse AG, Takor TT (1976) Neuroendocrine embryology and the APUD concept. Clin Endocrinol (Oxf) 5 Suppl:229S–244S

    Article  CAS  Google Scholar 

  • 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):6345–6349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):17267–17274

    Article  CAS  PubMed  Google Scholar 

  • Porges SW (1997) Emotion: an evolutionary by-product of the neural regulation of the autonomic nervous system. Ann N Y Acad Sci 807:62–77

    Article  CAS  PubMed  Google Scholar 

  • 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):385–392

    Article  CAS  PubMed  Google Scholar 

  • Rashid AJ, O'Dowd BF, George SR (2004) Minireview: diversity and complexity of signaling through peptidergic G protein-coupled receptors. Endocrinology 145(6):2645–2652

    Article  CAS  PubMed  Google Scholar 

  • 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):492–497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Richter D (1999) Regulatory peptides and their cognate receptors. Springer-Verlag

  • Rood BD, de Vries GJ (2011) Vasopressin innervation of the mouse (Mus musculus) brain and spinal cord. J Comp Neurol 518:2434–2474

  • 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):2321–2358

    Article  CAS  PubMed  Google Scholar 

  • 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, 1977

  • Seeburg PH, Adelman JP (1984) Characterization of cDNA for precursor of human luteinizing hormone releasing hormone. Nature 311(5987):666–668

    Article  CAS  PubMed  Google Scholar 

  • Sherwood NM, Krueckl SL, McRory JE (2000) The origin and function of the pituitary adenylate cyclase-activating polypeptide (PACAP)/glucagon superfamily. Endocr Rev 21:619–670

    CAS  PubMed  Google Scholar 

  • 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 347–360

    Chapter  Google Scholar 

  • Smith CB, Eiden LE (2012) Is PACAP the major neurotransmitter for stress transduction at the adrenomedullary synapse? J Mol Neurosci 48:403–412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sofroniew MV (1983) Morphology of vasopressin and oxytocin neurones and their central and vascular projections. Prog Brain Res 60:101–114

  • 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 365:170–175

    Article  CAS  PubMed  Google Scholar 

  • 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):e1003472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Streefkerk JO, van Zwieten PA (2006) Vasopressin receptor antagonists: pharmacological tools and potential therapeutic agents. Auton Autacoid Pharmacol 26(2):141–148

    Article  CAS  PubMed  Google Scholar 

  • 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 165:1025–1030

    Article  CAS  PubMed  Google Scholar 

  • 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):330–339

    Article  CAS  PubMed  Google Scholar 

  • Tam JK, Lee LT, Chow BK (2007) PACAP-related peptide (PRP)--molecular evolution and potential functions. Peptides 28:1920–1929

  • 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):2012–2017

    Article  PubMed  PubMed Central  Google Scholar 

  • 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):2339–2345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):4109–4122

    Article  CAS  PubMed  Google Scholar 

  • 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):292–298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 14:368–375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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):1394–1397

    Article  CAS  PubMed  Google Scholar 

  • 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. 170

  • Waschek JA (2013) VIP and PACAP: neuropeptide modulators of CNS inflammation, injury, and repair. Br J Pharmacol 169(3):512–523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wisden W (2016) A tribute to Peter H Seeburg (1944-2016): a founding father of molecular neurobiology. Front Mol Neurosci 9:133

    Article  PubMed  PubMed Central  Google Scholar 

  • Young WSI (1992) Expression of the oxytocin and vasopressin genes. J Neuroendocrinol 4:527–540

    Article  CAS  PubMed  Google Scholar 

  • Yuste R (2015) The discovery of dendritic spines by Cajal. Front Neuroanat 9:18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang L, Hernandez VS (2013) Synaptic innervation to rat hippocampus by vasopressin-immuno-positive fibres from the hypothalamic supraoptic and paraventricular nuclei. Neuroscience 228:139–162

    Article  CAS  PubMed  Google Scholar 

  • 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 215:135–148

    Article  CAS  PubMed  Google Scholar 

  • 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 10:13

    Google Scholar 

  • 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):50

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zimmerman EA, Robinson AG (1976) Hypothalamic neurons secreting vasopressin and neurophysin. Kidney Int 10(1):12–24

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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

Funding

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.

Author information

Authors and Affiliations

  1. Section on Molecular Neuroscience, Laboratory of Cellular and Molecular Regulation, NIMH-IRP, Building 49, Room 5A-32, 9000 Rockville Pike, Bethesda, MD, USA

    Limei Zhang & Lee E. Eiden

  2. Department of Physiology, Faculty of Medicine, National Autonomous University of Mexico (UNAM), Av. Universidad 3000, 04510, CDMX, Mexico

    Limei Zhang

Authors
  1. Limei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lee E. Eiden
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Limei Zhang or Lee E. Eiden.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, L., Eiden, L.E. Two ancient neuropeptides, PACAP and AVP, modulate motivated behavior at synapses in the extrahypothalamic brain: a study in contrast. Cell Tissue Res 375, 103–122 (2019). https://doi.org/10.1007/s00441-018-2958-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-018-2958-z

Keywords

Search

Navigation