Skip to main content
SpringerLink
Log in

Localization of the delta opioid receptor and corticotropin-releasing factor in the amygdalar complex: role in anxiety

  • Original Article
  • Published:
Brain Structure and Function Aims and scope Submit manuscript

Abstract

It is well established that central nervous system norepinephrine (NE) and corticotropin-releasing factor (CRF) systems are important mediators of behavioral responses to stressors. More recent studies have defined a role for delta opioid receptors (DOPR) in maintaining emotional valence including anxiety. The amygdala plays an important role in processing emotional stimuli, and has been implicated in the development of anxiety disorders. Activation of DOPR or inhibition of CRF in the amygdala reduces baseline and stress-induced anxiety-like responses. It is not known whether CRF- and DOPR-containing amygdalar neurons interact or whether they are regulated by NE afferents. Therefore, this study sought to better define interactions between the CRF, DOPR and NE systems in the basolateral (BLA) and central nucleus of the amygdala (CeA) of the male rat using anatomical and functional approaches. Irrespective of the amygdalar subregion, dual immunofluorescence microscopy showed that DOPR was present in CRF-containing neurons. Immunoelectron microscopy confirmed that DOPR was localized to both dendritic processes and axon terminals in the BLA and CeA. Semi-quantitative dual immunoelectron microscopy analysis of gold–silver labeling for DOPR and immunoperoxidase labeling for CRF revealed that 55 % of the CRF neurons analyzed contained DOPR in the BLA while 67 % of the CRF neurons analyzed contained DOPR in the CeA. Furthermore, approximately 41 % of DOPR-labeled axon terminals targeted BLA neurons that expressed CRF while 29 % of DOPR-labeled axon terminals targeted CeA neurons that expressed CRF. Triple label immunofluorescence microscopy revealed that DOPR and CRF were co-localized in common cellular profiles that were in close proximity to NE-containing fibers in both subregions. These anatomical results indicate significant interactions between DOPR and CRF in this critical limbic region and reveal that NE is poised to regulate these peptidergic systems in the amygdala. Functional studies were performed to determine if activation of DOPR could inhibit the anxiety produced by elevation of NE in the amygdala using the pharmacological stressor yohimbine. Administration of the DOPR agonist, SNC80, significantly attenuated elevated anxiogenic behaviors produced by yohimbine as measured in the rat on the elevated zero maze. Taken together, results from this study demonstrate the convergence of three important systems, NE, CRF, and DOPR, in the amygdala and provide insight into their functional role in modulating stress and anxiety responses.

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
Fig. 8

Similar content being viewed by others

References

  • Agnati LF, Fuxe K, Zoli M, Ozini I, Toffano G, Ferraguti F (1986) A correlation analysis of the regional distribution of central enkephalin and beta-endorphin immunoreactive terminals and of opiate receptors in adult and old male rats. Evidence for the existence of two main types of communication in the central nervous system: the volume transmission and the wiring transmission. Acta Physiol Scand 128:201–207

    Article  CAS  PubMed  Google Scholar 

  • Ambrose-Lanci LM, Peiris NB, Unterwald EM, Van Bockstaele EJ (2008) Cocaine withdrawal-induced trafficking of delta-opioid receptors in rat nucleus accumbens. Brain Res 1210:92–102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Andero R, Brothers SP, Jovanovic T, Chen YT, Salah-Uddin H, Cameron M, Bannister TD, Almli L, Stevens JS, Bradley B, Binder EB, Wahlestedt C, Ressler KJ (2013) Amygdala-dependent fear is regulated by Oprl1 in mice and humans with PTSD. Sci Transl Med 5:188ra173

    Article  CAS  Google Scholar 

  • Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB (1999) The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol 160:1–12

    Article  CAS  PubMed  Google Scholar 

  • Asan E (1998) The catecholaminergic innervation of the rat amygdala. Adv Anat Embryol Cell Biol 142:1–118

    Article  CAS  PubMed  Google Scholar 

  • Aston-Jones G, Foote SL, Bloom FE (1984) Anatomy and physiology of locus coeruleus neurons: functional implications. In: Ziegler M, Lake CR (eds) Norepinephrine, Frontiers of Clinical Neuroscience, vol 2. Williams and Wilkins, Baltimore, pp 92–116

    Google Scholar 

  • Bachtell RK, Weitemier AZ, Galvan-Rosas A, Tsivkovskaia NO, Risinger FO, Phillips TJ, Grahame NJ, Ryabinin AE (2003) The Edinger–Westphal-lateral septum urocortin pathway and its relationship to alcohol consumption. J Neurosci 23:2477–2487

    CAS  PubMed  Google Scholar 

  • Benmansour S, Altamirano AV, Jones DJ, Sanchez TA, Gould GG, Pardon MC, Morilak DA, Frazer A (2004) Regulation of the norepinephrine transporter by chronic administration of antidepressants. Biol Psychiatry 55:313–316

    Article  CAS  PubMed  Google Scholar 

  • Berger B, Rothmaier AK, Wedekind F, Zentner J, Feuerstein TJ, Jackisch R (2006) Presynaptic opioid receptors on noradrenergic and serotonergic neurons in the human as compared to the rat neocortex. Br J Pharmacol 148:795–806

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Berube P, Laforest S, Bhatnagar S, Drolet G (2013) Enkephalin and dynorphin mRNA expression are associated with resilience or vulnerability to chronic social defeat stress. Physiol Behav 122:237–245

    Article  CAS  PubMed  Google Scholar 

  • Braga MF, Aroniadou-Anderjaska V, Manion ST, Hough CJ, Li H (2004) Stress impairs alpha(1A) adrenoceptor-mediated noradrenergic facilitation of GABAergic transmission in the basolateral amygdala. Neuropsychopharmacology 29:45–58

    Article  CAS  PubMed  Google Scholar 

  • Braun AA, Skelton MR, Vorhees CV, Williams MT (2011) Comparison of the elevated plus and elevated zero mazes in treated and untreated male Sprague–Dawley rats: effects of anxiolytic and anxiogenic agents. Pharmacol Biochem Behav 97:406–415

    Article  CAS  PubMed  Google Scholar 

  • Brown ZJ, Nobrega JN, Erb S (2011) Central injections of noradrenaline induce reinstatement of cocaine seeking and increase c-fos mRNA expression in the extended amygdala. Behav Brain Res 217:472–476

    Article  CAS  PubMed  Google Scholar 

  • Bruchas MR, Land BB, Lemos JC, Chavkin C (2009) CRF1-R activation of the dynorphin/kappa opioid system in the mouse basolateral amygdala mediates anxiety-like behavior. PLoS One 4:e8528

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Buffalari DM, Grace AA (2007) Noradrenergic modulation of basolateral amygdala neuronal activity: opposing influences of alpha-2 and beta receptor activation. J Neurosci 27:12358–12366

    Article  CAS  PubMed  Google Scholar 

  • Cai L, Bakalli H, Rinaman L (2012) Yohimbine anxiogenesis in the elevated plus maze is disrupted by bilaterally disconnecting the bed nucleus of the stria terminalis from the central nucleus of the amygdala. Neuroscience 223:200–208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Camp RM, Johnson JD (2015) Repeated stressor exposure enhances contextual fear memory in a beta-adrenergic receptor-dependent process and increases impulsivity in a non-beta receptor-dependent fashion. Physiol Behav 150:64–68

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carlsen J, Heimer L (1988) The basolateral amygdaloid complex as a cortical-like structure. Brain Res 441:377–380

    Article  CAS  PubMed  Google Scholar 

  • Carvalho AF, Mackie K, Van Bockstaele EJ (2010) Cannabinoid modulation of limbic forebrain noradrenergic circuitry. Eur J Neurosci 31:286–301

    Article  PubMed  PubMed Central  Google Scholar 

  • Cassell MD, Gray TS (1989) Morphology of peptide-immunoreactive neurons in the rat central nucleus of the amygdala. J Comp Neurol 281:320–333

    Article  CAS  PubMed  Google Scholar 

  • Cassell MD, Gray TS, Kiss JZ (1986) Neuronal architecture in the rat central nucleus of the amygdala: a cytological, hodological, and immunocytochemical study. J Comp Neurol 246:478–499

    Article  CAS  PubMed  Google Scholar 

  • Chang GQ, Karatayev O, Barson JR, Liang SC, Leibowitz SF (2014) Common effects of fat, ethanol, and nicotine on enkephalin in discrete areas of the brain. Neuroscience 277:665–678

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chieng BC, Christie MJ, Osborne PB (2006) Characterization of neurons in the rat central nucleus of the amygdala: cellular physiology, morphology, and opioid sensitivity. J Comp Neurol 497:910–927

    Article  CAS  PubMed  Google Scholar 

  • Ciccocioppo R, de Guglielmo G, Hansson AC, Ubaldi M, Kallupi M, Cruz MT, Oleata CS, Heilig M, Roberto M (2014) Restraint stress alters nociceptin/orphanin FQ and CRF systems in the rat central amygdala: significance for anxiety-like behaviors. J Neurosci 34:363–372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ciocchi S, Herry C, Grenier F, Wolff SB, Letzkus JJ, Vlachos I, Ehrlich I, Sprengel R, Deisseroth K, Stadler MB, Muller C, Luthi A (2010) Encoding of conditioned fear in central amygdala inhibitory circuits. Nature 468:277–282

    Article  CAS  PubMed  Google Scholar 

  • Crespi F (2009) Anxiolytics antagonize yohimbine-induced central noradrenergic activity: a concomitant in vivo voltammetry-electrophysiology model of anxiety. J Neurosci Methods 180:97–105

    Article  CAS  PubMed  Google Scholar 

  • Criado JR, Morales M (2000) Acute ethanol induction of c-Fos immunoreactivity in pre-pro-enkephalin expressing neurons of the central nucleus of the amygdala. Brain Res 861:173–177

    Article  CAS  PubMed  Google Scholar 

  • Curtis AL, Lechner SM, Pavcovich LA, Valentino RJ (1997) Activation of the locus coeruleus noradrenergic system by intracoerulear microinfusion of corticotropin-releasing factor: effects on discharge rate, cortical norepinephrine levels and cortical electroencephalographic activity. J Pharmacol Exp Ther 281:163–172

    CAS  PubMed  Google Scholar 

  • Curtis AL, Bello NT, Valentino RJ (2001) Evidence for functional release of endogenous opioids in the locus ceruleus during stress termination. J Neurosci 21:RC152

    CAS  PubMed  Google Scholar 

  • Curtis AL, Bello NT, Connolly KR, Valentino RJ (2002) Corticotropin-releasing factor neurones of the central nucleus of the amygdala mediate locus coeruleus activation by cardiovascular stress. J Neuroendocrinol 14:667–682

    Article  CAS  PubMed  Google Scholar 

  • Day HE, Campeau S, Watson SJ Jr, Akil H (1997) Distribution of alpha 1a-, alpha 1b- and alpha 1d-adrenergic receptor mRNA in the rat brain and spinal cord. J Chem Neuroanat 13:115–139

    Article  CAS  PubMed  Google Scholar 

  • de Kloet ER, Joels M, Holsboer F (2005) Stress and the brain: from adaptation to disease. Nat Rev Neurosci 6:463–475

    Article  PubMed  CAS  Google Scholar 

  • degli Uberti EC, Ambrosio MR, Vergnani L, Portaluppi F, Bondanelli M, Trasforini G, Margutti A, Salvadori S (1993) Stress-induced activation of sympathetic nervous system is attenuated by the delta-opioid receptor agonist deltorphin in healthy man. The Journal of clinical endocrinology and metabolism 77:1490–1494

    CAS  PubMed  Google Scholar 

  • Domyancic AV, Morilak DA (1997) Distribution of alpha1A adrenergic receptor mRNA in the rat brain visualized by in situ hybridization. J Comp Neurol 386:358–378

    Article  CAS  PubMed  Google Scholar 

  • Drolet G, Dumont EC, Gosselin I, Kinkead R, Laforest S, Trottier JF (2001) Role of endogenous opioid system in the regulation of the stress response. Prog Neuropsychopharmacol Biol Psychiatry 25:729–741

    Article  CAS  PubMed  Google Scholar 

  • Farb CR, Ledoux JE (1999) Afferents from rat temporal cortex synapse on lateral amygdala neurons that express NMDA and AMPA receptors. Synapse 33:218–229

    Article  CAS  PubMed  Google Scholar 

  • Farley IJ, Hornykiewicz O (1977) Noradrenaline distribution insubcortical areas of the human brain. Brain Res 126:53–62

    Article  CAS  PubMed  Google Scholar 

  • Ferry B, McGaugh JL (2008) Involvement of basolateral amygdala alpha2-adrenoceptors in modulating consolidation of inhibitory avoidance memory. Learn Mem 15:238–243

    Article  PubMed  PubMed Central  Google Scholar 

  • Filliol D, Ghozland S, Chluba J, Martin M, Matthes HW, Simonin F, Befort K, Gaveriaux-Ruff C, Dierich A, LeMeur M, Valverde O, Maldonado R, Kieffer BL (2000) Mice deficient for delta- and mu-opioid receptors exhibit opposing alterations of emotional responses. Nat Genet 25:195–200

    Article  CAS  PubMed  Google Scholar 

  • Foote SL, Bloom FE, Aston-Jones G (1983) Nucleus locus ceruleus: new evidence of anatomical and physiological specificity. Physiol Rev 63:844–914

    CAS  PubMed  Google Scholar 

  • Francis DD, Caldji C, Champagne F, Plotsky PM, Meaney MJ (1999) The role of corticotropin-releasing factor–norepinephrine systems in mediating the effects of early experience on the development of behavioral and endocrine responses to stress. Biol Psychiatry 46:1153–1166

    Article  CAS  PubMed  Google Scholar 

  • Funk CK, O’Dell LE, Crawford EF, Koob GF (2006) Corticotropin-releasing factor within the central nucleus of the amygdala mediates enhanced ethanol self-administration in withdrawn, ethanol-dependent rats. J Neurosci 26:11324–11332

    Article  CAS  PubMed  Google Scholar 

  • Galvez R, Mesches MH, McGaugh JL (1996) Norepinephrine release in the amygdala in response to footshock stimulation. Neurobiol Learn Mem 66:253–257

    Article  CAS  PubMed  Google Scholar 

  • Glass MJ, Colago EE, Pickel VM (2002) Alpha-2A-adrenergic receptors are present on neurons in the central nucleus of the amygdala that project to the dorsal vagal complex in the rat. Synapse 46:258–268

    Article  CAS  PubMed  Google Scholar 

  • Grammatopoulos DK, Randeva HS, Levine MA, Kanellopoulou KA, Hillhouse EW (2001) Rat cerebral cortex corticotropin-releasing hormone receptors: evidence for receptor coupling to multiple G-proteins. J Neurochem 76:509–519

    Article  CAS  PubMed  Google Scholar 

  • Gray EG (1959) Axosomatic and axo-dendritic synapses of the cerebral cortex: an electron microscopic study. J Anat 93:420–433

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gray TS, Bingaman EW (1996) The amygdala: corticotropin-releasing factor, steroids, and stress. Crit Rev Neurobiol 10:155–168

    Article  CAS  PubMed  Google Scholar 

  • Haubensak W, Kunwar PS, Cai H, Ciocchi S, Wall NR, Ponnusamy R, Biag J, Dong HW, Deisseroth K, Callaway EM, Fanselow MS, Luthi A, Anderson DJ (2010) Genetic dissection of an amygdala microcircuit that gates conditioned fear. Nature 468:270–276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heinrichs SC, Pich EM, Miczek KA, Britton KT, Koob GF (1992) Corticotropin-releasing factor antagonist reduces emotionality in socially defeated rats via direct neurotropic action. Brain Res 581:190–197

    Article  CAS  PubMed  Google Scholar 

  • Heinrichs SC, Menzaghi F, Pich EM, Baldwin HA, Rassnick S, Britton KT, Koob GF (1994) Anti-stress action of a corticotropin-releasing factor antagonist on behavioral reactivity to stressors of varying type and intensity. Neuropsychopharmacology 11:179–186

    Article  CAS  PubMed  Google Scholar 

  • Herringa RJ, Nanda SA, Hsu DT, Roseboom PH, Kalin NH (2004) The effects of acute stress on the regulation of central and basolateral amygdala CRF-binding protein gene expression. Brain Res Mol Brain Res 131:17–25

    Article  CAS  PubMed  Google Scholar 

  • Hopkins AL (2007) Network pharmacology. Nat Biotechnol 25:1110–1111

    Article  CAS  PubMed  Google Scholar 

  • Hudzik TJ, Maciag C, Smith MA, Caccese R, Pietras MR, Bui KH, Coupal M, Adam L, Payza K, Griffin A, Smagin G, Song D, Swedberg MD, Brown W (2011) Preclinical pharmacology of AZD2327: a highly selective agonist of the delta-opioid receptor. J Pharmacol Exp Ther 338:195–204

    Article  CAS  PubMed  Google Scholar 

  • Iemolo A, Blasio A, St Cyr SA, Jiang F, Rice KC, Sabino V, Cottone P (2013) CRF-CRF1 receptor system in the central and basolateral nuclei of the amygdala differentially mediates excessive eating of palatable food. Neuropsychopharmacology 38:2456–2466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iwasaki-Sekino A, Mano-Otagiri A, Ohata H, Yamauchi N, Shibasaki T (2009) Gender differences in corticotropin and corticosterone secretion and corticotropin-releasing factor mRNA expression in the paraventricular nucleus of the hypothalamus and the central nucleus of the amygdala in response to footshock stress or psychological stress in rats. Psychoneuroendocrinology 34:226–237

    Article  CAS  PubMed  Google Scholar 

  • Jaremko KM, Thompson NL Jr, Reyes BA, Jin J, Ebersole B, Jenney CB, Grigson PS, Levenson R, Berrettini WH, Van Bockstaele EJ (2014) Morphine-induced trafficking of a mu-opioid receptor interacting protein in rat locus coeruleus neurons. Prog Neuropsychopharmacol Biol Psychiatry 50:53–65

    Article  CAS  PubMed  Google Scholar 

  • Jasovic-Gasic M (2015) Is treatment-resistance in psychiatric disorders a trap for polypharmacy? Psychiatria Danubina 27:308–313

    PubMed  Google Scholar 

  • Jensen BC, Swigart PM, Simpson PC (2009) Ten commercial antibodies for alpha-1-adrenergic receptor subtypes are nonspecific. Naunyn-Schmiedeberg’s Arch Pharmacol 379:40–412

    Article  CAS  Google Scholar 

  • Johnson LR, Hou M, Prager EM, Ledoux JE (2011) Regulation of the fear network by mediators of stress: norepinephrine alters the balance between cortical and subcortical afferent excitation of the lateral amygdala. Front Behav Neurosci 5:23

    Article  PubMed  PubMed Central  Google Scholar 

  • Kang J, Shi Y, Xiang B, Qu B, Su W, Zhu M, Zhang M, Bao G, Wang F, Zhang X, Yang R, Fan F, Chen X, Pei G, Ma L (2005) A nuclear function of beta-arrestin1 in GPCR signaling: regulation of histone acetylation and gene transcription. Cell 123:833–847

    Article  CAS  PubMed  Google Scholar 

  • Kaplan JS, Arnkoff DB, Glass CR, Tinsley R, Geraci M, Hernandez E, Luckenbaugh D, Drevets WC, Carlson PJ (2012) Avoidant coping in panic disorder: a yohimbine biological challenge study. Anxiety Stress Coping 25:425–442

    Article  PubMed  Google Scholar 

  • Karkhanis AN, Alexander NJ, McCool BA, Weiner JL, Jones SR (2015) Chronic social isolation during adolescence augments catecholamine response to acute ethanol in the basolateral amygdala. Synapse 69:385–395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khoshbouei H, Cecchi M, Dove S, Javors M, Morilak DA (2002) Behavioral reactivity to stress: amplification of stress-induced noradrenergic activation elicits a galanin-mediated anxiolytic effect in central amygdala. Pharmacol Biochem Behav 71:407–417

    Article  CAS  PubMed  Google Scholar 

  • Knoll AT, Muschamp JW, Sillivan SE, Ferguson D, Dietz DM, Meloni EG, Carroll FI, Nestler EJ, Konradi C, Carlezon WA Jr (2011) Kappa opioid receptor signaling in the basolateral amygdala regulates conditioned fear and anxiety in rats. Biol Psychiatry 70:425–433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Konig M, Zimmer AM, Steiner H, Holmes PV, Crawley JN, Brownstein MJ, Zimmer A (1996) Pain responses, anxiety and aggression in mice deficient in pre-proenkephalin. Nature 383:535–538

    Article  CAS  PubMed  Google Scholar 

  • Koob GF (1999) Stress, corticotropin-releasing factor, and drug addiction. Ann N Y Acad Sci 897:27–45

    Article  CAS  PubMed  Google Scholar 

  • Kravets JL, Reyes BAS, Unterwald EM, Van Bockstaele EJ (2015) Direct targeting of peptidergic amygdalar neurons by noradrenergic afferents: linking stress-integrative circuitry. Brain Struct Funct 220:541–558

    Article  CAS  PubMed  Google Scholar 

  • Lam MP, Gianoulakis C (2011) Effects of acute ethanol on corticotropin-releasing hormone and beta-endorphin systems at the level of the rat central amygdala. Psychopharmacology 218:229–239

    Article  CAS  PubMed  Google Scholar 

  • LeDoux J (2000) Emotion circuits in the brain. Annu Rev Neurosci 23:155–184

    Article  CAS  PubMed  Google Scholar 

  • LeDoux JE, Farb CR, Romanski LM (1991) Overlapping projections to the amygdala and striatum from auditory processing areas of the thalamus and cortex. Neurosci Lett 134:139–144

    Article  CAS  PubMed  Google Scholar 

  • Leranth C, Pickel VM (1989) Electron microscopic preembedding double-labeling methods. In: Heimer L, Zaborszky L (eds) Neuroanatomical tracing methods 2, 1st edn. Plenum Press, New York, pp 129–172

    Chapter  Google Scholar 

  • Levitt ES, Purington LC, Traynor JR (2011) Gi/o-coupled receptors compete for signaling to adenylyl cyclase in SH-SY5Y cells and reduce opioid-mediated cAMP overshoot. Mol Pharmacol 79:461–471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liang KC, Melia KR, Campeau S, Falls WA, Miserendino MJ, Davis M (1992) Lesions of the central nucleus of the amygdala, but not the paraventricular nucleus of the hypothalamus, block the excitatory effects of corticotropin-releasing factor on the acoustic startle reflex. J Neurosci 12:2313–2320

    CAS  PubMed  Google Scholar 

  • Lim MM, Liu Y, Ryabinin AE, Bai Y, Wang Z, Young LJ (2007) CRF receptors in the nucleus accumbens modulate partner preference in prairie voles. Horm Behav 51:508–515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mamalaki E, Kvetnansky R, Brady LS, Gold PW, Herkenham M (1992) Repeated immobilization stress alters tyrosine hydroxylase, corticotropin-releasing hormone and corticosteroid receptor messenger ribonucleic acid levels in rat brain. J Neuroendocrinol 4:689–699

    Article  CAS  PubMed  Google Scholar 

  • Mansour A, Fox CA, Akil H, Watson SJ Jr (1995) Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications. Trends Neurosci 18:22–29

    Article  CAS  PubMed  Google Scholar 

  • McCall JG, Al-Hasani R, Siuda ER, Hong DY, Norris AJ, Ford CP, Bruchas MR (2015) CRH engagement of the locus coeruleus noradrenergic system mediates stress-induced anxiety. Neuron 87:605–620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McDonald AJ (1982) Cytoarchitecture of the central amygdaloid nucleus of the rat. J comp Neurol 208:401–418

    Article  CAS  PubMed  Google Scholar 

  • McDonald AJ (1998) Cortical pathways to the mammalian amygdala. Prog Neurobiol 55:257–332

    Article  CAS  PubMed  Google Scholar 

  • McDonald AJ, Mascagni F, Mania I, Rainnie DG (2005) Evidence for a perisomatic innervation of parvalbumin-containing interneurons by individual pyramidal cells in the basolateral amygdala. Brain Res 1035:32–40

    Article  CAS  PubMed  Google Scholar 

  • McEwen BS (2006) Stress, adaptation, and disease: allostasis and allostatic load, vol 840. Wiley, New York, pp 33–44

    Google Scholar 

  • McGaugh JL, Roozendaal B (2009) Drug enhancement of memory consolidation: historical perspective and neurobiological implications. Psychopharmacology 202:3–14

    Article  CAS  PubMed  Google Scholar 

  • McGaugh JL, McIntyre CK, Power AE (2002) Amygdala modulation of memory consolidation: interaction with other brain systems. Neurobiol Learn Mem 78:539–552

    Article  CAS  PubMed  Google Scholar 

  • McIntyre CK, Pal SN, Marriott LK, Gold PE (2002) Competition between memory systems: acetylcholine release in the hippocampus correlates negatively with good performance on an amygdala-dependent task. J Neurosci 22:1171–1176

    CAS  PubMed  Google Scholar 

  • McKenzie FR, Milligan G (1990) Delta-opioid-receptor-mediated inhibition of adenylate cyclase is transduced specifically by the guanine-nucleotide-binding protein Gi2. Biochem J 267:391–398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Merali Z, McIntosh J, Kent P, Michaud D, Anisman H (1998) Aversive and appetitive events evoke the release of corticotropin-releasing hormone and bombesin-like peptides at the central nucleus of the amygdala. J Neurosci 18:4758–4766

    CAS  PubMed  Google Scholar 

  • Merlo Pich E, Lorang M, Yeganeh M, Rodriguez de Fonseca F, Raber J, Koob GF, Weiss F (1995) Increase of extracellular corticotropin-releasing factor-like immunoreactivity levels in the amygdala of awake rats during restraint stress and ethanol withdrawal as measured by microdialysis. J Neurosci 15:5439–5447

    CAS  PubMed  Google Scholar 

  • Moga MM, Saper CB, Gray TS (1990) Neuropeptide organization of the hypothalamic projection to the parabrachial nucleus in the rat. J Comp Neurol 295:662–682

    Article  CAS  PubMed  Google Scholar 

  • Nieto MM, Guen SL, Kieffer BL, Roques BP, Noble F (2005) Physiological control of emotion-related behaviors by endogenous enkephalins involves essentially the delta opioid receptors. Neuroscience 135:305–313

    Article  CAS  PubMed  Google Scholar 

  • Onur OA, Walter H, Schlaepfer TE, Rehme AK, Schmidt C, Keysers C, Maier W, Hurlemann R (2009) Noradrenergic enhancement of amygdala responses to fear. Soc Cogn Affect Neurosci 4:119–126

    Article  PubMed  PubMed Central  Google Scholar 

  • Pacak K, Palkovits M, Kvetnansky R, Fukuhara K, Armando I, Kopin IJ, Goldstein DS (1993) Effects of single or repeated immobilization on release of norepinephrine and its metabolites in the central nucleus of the amygdala in conscious rats. Neuroendocrinology 57:626–633

    Article  CAS  PubMed  Google Scholar 

  • Page ME, Abercrombie ED (1999) Discrete local application of corticotropin-releasing factor increases locus coeruleus discharge and extracellular norepinephrine in rat hippocampus. Synapse 33:304–313

    Article  CAS  PubMed  Google Scholar 

  • Park PE, Vendruscolo LF, Schlosburg JE, Edwards S, Schulteis G, Koob GF (2013) Corticotropin-releasing factor (CRF) and alpha 2 adrenergic receptors mediate heroin withdrawal-potentiated startle in rats. Int J Neuropsychopharmacol 16:1867–1875

    Article  CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic Press, New York

    Google Scholar 

  • Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates, Academic Press, Orlando, FL

    Google Scholar 

  • Perez de la Mora M, Jacobsen KX, Crespo-Ramirez M, Flores-Gracia C, Fuxe K (2008) Wiring and volume transmission in rat amygdala. Implications for fear and anxiety. Neurochem Res 33:1618–1633

    Article  CAS  PubMed  Google Scholar 

  • Perrine SA, Hoshaw BA, Unterwald EM (2006) Delta opioid receptor ligands modulate anxiety-like behaviors in the rat. Br J Pharmacol 147:864–872

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perrine SA, Sheikh IS, Nwaneshiudu CA, Schroeder JA, Unterwald EM (2008) Withdrawal from chronic administration of cocaine decreases delta opioid receptor signaling and increases anxiety- and depression-like behaviors in the rat. Neuropharmacology 54:355–364

    Article  CAS  PubMed  Google Scholar 

  • Peters A, Palay SL (1996) The morphology of synapses. J Neurocytol 25:687–700

    Article  CAS  PubMed  Google Scholar 

  • Peters A, Palay SL, Webster Hd (1991) The fine structure of the nervous system. Oxford University Press, New York

    Google Scholar 

  • Petrovich GD, Canteras NS, Swanson LW (2001) Combinatorial amygdalar inputs to hippocampal domains and hypothalamic behavior systems. Brain Res Brain Res Rev 38:247–289

    Article  CAS  PubMed  Google Scholar 

  • Pinard CR, Mascagni F, Muller JF, McDonald AJ (2010) Limited convergence of rhinal cortical and dopaminergic inputs in the rat basolateral amygdala: an ultrastructural analysis. Brain Res 1332:48–56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pitkänen A (2000) Connectivity of the rat amygdaloid complex. In: Aggleton J (ed) The amygdala: a functional analysis. Oxford University Press, New York, pp 31–115

    Google Scholar 

  • Pitkanen A, Savander M, Nurminen N, Ylinen A (2003) Intrinsic synaptic circuitry of the amygdala. Ann N Y Acad Sci 985:34–49

    Article  PubMed  Google Scholar 

  • Pitts MW, Todorovic C, Blank T, Takahashi LK (2009) The central nucleus of the amygdala and corticotropin-releasing factor: insights into contextual fear memory. J Neurosci 29:7379–7388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pomrenze MB, Millan EZ, Hopf FW, Keiflin R, Maiya R, Blasio A, Dadgar J, Kharazia V, De Guglielmo G, Crawford E, Janak PH, George O, Rice KC, Messing RO (2015) A transgenic rat for investigating the anatomy and function of corticotrophin releasing factor circuits. Front Neurosci 9:487

    Article  PubMed  PubMed Central  Google Scholar 

  • Porterfield VM, Gabella KM, Simmons MA, Johnson JD (2012) Repeated stressor exposure regionally enhances beta-adrenergic receptor-mediated brain IL-1beta production. Brain Behav Immun 26:1249–1255

    Article  CAS  PubMed  Google Scholar 

  • Poulin JF, Chevalier B, Laforest S, Drolet G (2006) Enkephalinergic afferents of the centromedial amygdala in the rat. J Comp Neurol 496:859–876

    Article  PubMed  Google Scholar 

  • Price JL, Russchen FT, Amaral DG (1987a) The limbic region. II: the amygdaloid complex. Elsevier Science, New York

    Google Scholar 

  • Price JL, Russchen FT, Amaral DG (1987b) The limbic region. II: The amygdaloid complex. In: Bjorklund A et al (eds) Handbook of chemical neuroanatomy. Elsevier Science, Amsterdam, pp 279–386

    Google Scholar 

  • Primeaux SD, Wilson SP, McDonald AJ, Mascagni F, Wilson MA (2006) The role of delta opioid receptors in the anxiolytic actions of benzodiazepines. Pharmacol Biochem Behav 85:545–554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Quirarte GL, Galvez R, Roozendaal B, McGaugh JL (1998) Norepinephrine release in the amygdala in response to footshock and opioid peptidergic drugs. Brain Res 808:134–140

    Article  CAS  PubMed  Google Scholar 

  • Raber J, Koob GF, Bloom FE (1995) Interleukin-2 (IL-2) induces corticotropin-releasing factor (CRF) release from the amygdala and involves a nitric oxide-mediated signaling; comparison with the hypothalamic response. J Pharmacol Exp Ther 272:815–824

    CAS  PubMed  Google Scholar 

  • Radley J, Morilak D, Viau V, Campeau S (2015) Chronic stress and brain plasticity: mechanisms underlying adaptive and maladaptive changes and implications for stress-related CNS disorders. Neurosci Biobehav Rev 58:79–91

    Article  PubMed  PubMed Central  Google Scholar 

  • Rajbhandari AK, Baldo BA, Bakshi VP (2015) Predator stress-induced CRF release causes enduring sensitization of basolateral amygdala norepinephrine systems that promote PTSD-like startle abnormalities. J Neurosci 35:14270–14285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Randall-Thompson JF, Pescatore KA, Unterwald EM (2010) A role for delta opioid receptors in the central nucleus of the amygdala in anxiety-like behaviors. Psychopharmacology 212:585–595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Retson TA, Hoek JB, Sterling RC, Van Bockstaele EJ (2015) Amygdalar neuronal plasticity and the interactions of alcohol, sex, and stress. Brain Struct Funct 220:3211–3232

    Article  CAS  PubMed  Google Scholar 

  • Reyes BAS, Glaser JD, Magtoto R, Van Bockstaele EJ (2006) Pro-opiomelanocortin colocalizes with corticotropin- releasing factor in axon terminals of the noradrenergic nucleus locus coeruleus. Eur J Neurosci 23:2067–2077

    Article  PubMed  Google Scholar 

  • Reyes BAS, Johnson AD, Glaser JD, Commons KG, Van Bockstaele EJ (2007) Dynorphin-containing axons directly innervate noradrenergic neurons in the rat nucleus locus coeruleus. Neuroscience 145:1077–1086

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reyes BAS, Drolet G, Van Bockstaele EJ (2008) Dynorphin and stress-related peptides in rat locus coeruleus: contribution of amygdalar efferents. J Comp Neurol 508:663–675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reyes BAS, Carvalho AF, Vakharia K, Van Bockstaele EJ (2011) Amygdalar peptidergic circuits regulating noradrenergic locus coeruleus neurons: linking limbic and arousal centers. Exp Neurol 230:96–105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reyes BAS, Vakharia K, Ferraro TN, Levenson R, Berrettini WH, Van Bockstaele EJ (2012) Opiate agonist-induced re-distribution of Wntless, a mu-opioid receptor interacting protein, in rat striatal neurons. Exp Neurol 233:205–213

    Article  CAS  PubMed  Google Scholar 

  • Rodriguez de Fonseca F, Carrera MR, Navarro M, Koob GF, Weiss F (1997) Activation of corticotropin-releasing factor in the limbic system during cannabinoid withdrawal. Science 276:2050–2054

    Article  CAS  PubMed  Google Scholar 

  • Rudoy CA, Van Bockstaele EJ (2005) Cocaine effects on norepinephrine in the amygdala: Cocaine withdrawal-related anxiety and stress-related relapse. Cell Sci Rev 2

  • Rudoy CA, Reyes AR, Van Bockstaele EJ (2009) Evidence for beta1-adrenergic receptor involvement in amygdalar corticotropin-releasing factor gene expression: implications for cocaine withdrawal. Neuropsychopharmacology 34:1135–1148

  • Sah P, Lopez De Armentia M (2003) Excitatory synaptic transmission in the lateral and central amygdala. Ann N Y Acad Sci 985:67–77

    Article  CAS  PubMed  Google Scholar 

  • Sah P, Faber ES, Lopez De Armentia M, Power J (2003) The amygdaloid complex: anatomy and physiology. Physiol Rev 83:803–834

    Article  CAS  PubMed  Google Scholar 

  • Saitoh A, Kimura Y, Suzuki T, Kawai K, Nagase H, Kamei J (2004) Potential anxiolytic and antidepressant-like activities of SNC80, a selective delta-opioid agonist, in behavioral models in rodents. J Pharmacol Sci 95:374–380

    Article  CAS  PubMed  Google Scholar 

  • Saitoh A, Yoshikawa Y, Onodera K, Kamei J (2005) Role of delta-opioid receptor subtypes in anxiety-related behaviors in the elevated plus-maze in rats. Psychopharmacology 182:327–334

    Article  CAS  PubMed  Google Scholar 

  • Sajdyk TJ, Fitz SD, Shekhar A (2006) The role of neuropeptide Y in the amygdala on corticotropin-releasing factor receptor-mediated behavioral stress responses in the rat. Stress 9:21–28

    Article  CAS  PubMed  Google Scholar 

  • Sakanaka M, Shibasaki T, Lederis K (1986) Distribution and efferent projections of corticotropin-releasing factor-like immunoreactivity in the rat amygdaloid complex. Brain Res 382:213–238

    Article  CAS  PubMed  Google Scholar 

  • Salman S, Buttigieg J, Zhang M, Nurse CA (2013) Chronic exposure of neonatal rat adrenomedullary chromaffin cells to opioids in vitro blunts both hypoxia and hypercapnia chemosensitivity. J Physiol 591:515–529

    Article  CAS  PubMed  Google Scholar 

  • Salman S, Holloway AC, Nurse CA (2014) Chronic opioids regulate KATP channel subunit Kir6.2 and carbonic anhydrase I and II expression in rat adrenal chromaffin cells via HIF-2alpha and protein kinase A. Am J Physiol Cell Physiol 307:C266–C277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sawada K, Fukui Y, Hawkes R (2008) Spatial distribution of corticotropin-releasing factor immunopositive climbing fibers in the mouse cerebellum: analysis by whole mount immunohistochemistry. Brain Res 1222:106–117

    Article  CAS  PubMed  Google Scholar 

  • Schulte K, Kumar M, Zajac JM, Schlicker E (2011) Noradrenaline release in rodent tissues is inhibited by interleukin-1beta but is not affected by urotensin II, MCH, NPW and NPFF. Pharmacol Rep 63:102–111

    Article  CAS  PubMed  Google Scholar 

  • Seguela P, Watkins KC, Geffard M, Descarries L (1990) Noradrenaline axon terminals in adult rat neocortex: an immunocytochemical analysis in serial thin sections. Neuroscience 35:249–264

    Article  CAS  PubMed  Google Scholar 

  • Sharif NA, Hughes J (1989) Discrete mapping of brain Mu and delta opioid receptors using selective peptides: quantitative autoradiography, species differences and comparison with kappa receptors. Peptides 10:499–522

    Article  CAS  PubMed  Google Scholar 

  • Silberman Y, Winder DG (2015) Ethanol and corticotropin releasing factor receptor modulation of central amygdala neurocircuitry: an update and future directions. Alcohol 49:179–184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith HR, Beveridge TJ, Porrino LJ (2006) Distribution of norepinephrine transporters in the non-human primate brain. Neuroscience 138:703–714

    Article  CAS  PubMed  Google Scholar 

  • Spanagel R, Noori HR, Heilig M (2014) Stress and alcohol interactions: animal studies and clinical significance. Trends Neurosci 37:219–227

    Article  CAS  PubMed  Google Scholar 

  • Sterling P, Eyer J (1988) Allostasis: a new paradigm to explain arousal pathology. In: Fisher S, Reason J (eds) Handbook of life stress, cognition and health. Wiley, New York, pp 629–649

    Google Scholar 

  • Swanson LW, Petrovich GD (1998) What is the amygdala? Trends Neurosci 21:323–331

    Article  CAS  PubMed  Google Scholar 

  • Swanson LW, Sawchenko PE, Rivier J, Vale WW (1983) Organization of ovine corticotropin-releasing factor immunoreactive cells and fibers in the rat brain: an immunohistochemical study. Neuroendocrinology 36:165–186

    Article  CAS  PubMed  Google Scholar 

  • Swiergiel AH, Takahashi LK, Kalin NH (1993) Attenuation of stress-induced behavior by antagonism of corticotropin-releasing factor receptors in the central amygdala in the rat. Brain Res 623:229–234

    Article  CAS  PubMed  Google Scholar 

  • Tanaka M, Tsuda A, Yokoo H, Yoshida M, Mizoguchi K, Shimizu T (1991a) Psychological stress-induced increases in noradrenaline release in rat brain regions are attenuated by diazepam, but not by morphine. Pharmacol Biochem Behav 39:191–195

    Article  CAS  PubMed  Google Scholar 

  • Tanaka T, Yokoo H, Mizoguchi K, Yoshida M, Tsuda A, Tanaka M (1991b) Noradrenaline release in the rat amygdala is increased by stress: studies with intracerebral microdialysis. Brain Res 544:174–176

    Article  CAS  PubMed  Google Scholar 

  • Tejani-Butt SM (1992) [3H]nisoxetine: a radioligand for quantitation of norepinephrine uptake sites by autoradiography or by homogenate binding. J Pharmacol Exp Ther 260:427–436

    CAS  PubMed  Google Scholar 

  • Tejani-Butt SM, Pare WP, Yang J (1994) Effect of repeated novel stressors on depressive behavior and brain norepinephrine receptor system in Sprague-Dawley and Wistar Kyoto (WKY) rats. Brain Res 649:27–35

    Article  CAS  PubMed  Google Scholar 

  • Tovote P, Fadok JP, Luthi A (2015) Neuronal circuits for fear and anxiety. Nat Rev Neurosci 16:317–331

    Article  CAS  PubMed  Google Scholar 

  • Tye KM, Prakash R, Kim SY, Fenno LE, Grosenick L, Zarabi H, Thompson KR, Gradinaru V, Ramakrishnan C, Deisseroth K (2011) Amygdala circuitry mediating reversible and bidirectional control of anxiety. Nature 471:358–362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Van Bockstaele EJ, Chan J, Pickel VM (1996a) Input from central nucleus of the amygdala efferents to pericoerulear dendrites, some of which contain tyrosine hydroxylase immunoreactivity. J Neurosci Res 45:289–302

    Article  PubMed  Google Scholar 

  • Van Bockstaele EJ, Colago EE, Valentino RJ (1996b) Corticotropin-releasing factor-containing axon terminals synapse onto catecholamine dendrites and may presynaptically modulate other afferents in the rostral pole of the nucleus locus coeruleus in the rat brain. J Comp Neurol 364:523–534

    Article  PubMed  Google Scholar 

  • Van Bockstaele EJ, Colago EE, Valentino RJ (1998) Amygdaloid corticotropin-releasing factor targets locus coeruleus dendrites: substrate for the co-ordination of emotional and cognitive limbs of the stress response. J Neuroendocrinol 10:743–757

    Article  PubMed  Google Scholar 

  • Van Bockstaele EJ, Reyes BA, Valentino RJ (2010) The locus coeruleus: A key nucleus where stress and opioids intersect to mediate vulnerability to opiate abuse. Brain Res 1314:162–174

    Article  PubMed  CAS  Google Scholar 

  • Veening JG, Swanson LW, Sawchenko PE (1984) The organization of projections from the central nucleus of the amygdala to brainstem sites involved in central autonomic regulation: a combined retrograde transport-immunohistochemical study. Brain Res 303:337–357

    Article  CAS  PubMed  Google Scholar 

  • Wenzel JM, Cotten SW, Dominguez HM, Lane JE, Shelton K, Su ZI, Ettenberg A (2014) Noradrenergic beta-receptor antagonism within the central nucleus of the amygdala or bed nucleus of the stria terminalis attenuates the negative/anxiogenic effects of cocaine. J Neurosci 34:3467–3474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Williams TJ, Milner TA (2011) Delta opioid receptors colocalize with corticotropin releasing factor in hippocampal interneurons. Neuroscience 179:9–22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Williams CL, Men D, Clayton EC, Gold PE (1998) Norepinephrine release in the amygdala after systemic injection of epinephrine or escapable footshock: contribution of the nucleus of the solitary tract. Behav Neurosci 112:1414–1422

    Article  CAS  PubMed  Google Scholar 

  • Williams TJ, Akama KT, Knudsen MG, McEwen BS, Milner TA (2011) Ovarian hormones influence corticotropin releasing factor receptor colocalization with delta opioid receptors in CA1 pyramidal cell dendrites. Exp Neurol 230:186–196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu GP, Van Bockstaele E, Reyes B, Bethea T, Valentino RJ (2004) Chronic morphine sensitizes the brain norepinephrine system to corticotropin-releasing factor and stress. J Neurosci 24:8193–8197

    Article  CAS  PubMed  Google Scholar 

  • Yeung M, Lu L, Hughes AM, Treit D, Dickson CT (2013) FG7142, yohimbine, and betaCCE produce anxiogenic-like effects in the elevated plus-maze but do not affect brainstem activated hippocampal theta. Neuropharmacology 75:47–52

    Article  CAS  PubMed  Google Scholar 

  • Yilmaz B, Gilmore DP (1999) Effects of mu, kappa, and delta opioid receptor agonists and antagonists on rat hypothalamic noradrenergic neurotransmission. Brain Res Bull 48:491–495

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, McDonald AJ (2016) Light and electron microscopic analysis of enkephalin-like immunoreactivity in the basolateral amygdala, including evidence for convergence of enkephalin-containing axon terminals and norepinephrine transporter-containing axon terminals onto common targets. Brain Res 1636:62–73

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Muller JF, McDonald AJ (2013) Noradrenergic innervation of pyramidal cells in the rat basolateral amygdala. Neuroscience 228:395–408

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This project was supported by the National Institutes of Health Grants DA009082 to E.J.V.B. and R01 DA018326 and T32 DA07237 to E.M.U.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Physiology, College of Medicine, Drexel University, 245 S. 15th Street, Philadelphia, PA, 19102, USA

    Beverly A. S. Reyes, J. L. Kravets & E. J. Van Bockstaele

  2. Center for Substance Abuse Research, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, 19140, USA

    K. L. Connelly & E. M. Unterwald

Authors
  1. Beverly A. S. Reyes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. L. Kravets
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K. L. Connelly
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E. M. Unterwald
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E. J. Van Bockstaele
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Beverly A. S. Reyes.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Reyes, B.A.S., Kravets, J.L., Connelly, K.L. et al. Localization of the delta opioid receptor and corticotropin-releasing factor in the amygdalar complex: role in anxiety. Brain Struct Funct 222, 1007–1026 (2017). https://doi.org/10.1007/s00429-016-1261-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00429-016-1261-6

Keywords

Search

Navigation