Abstract
The past decade has seen a rapid progression in our knowledge of the neurobiological basis of fear and anxiety. Specific neurochemical and neuropeptide systems have been demonstrated to play important roles in the behaviors associated with fear and anxiety-producing stimuli. Long-term dysregulation of these systems appears to contribute to the development of anxiety disorders, including panic disorder, posttraumatic stress disorder (PTSD), and social anxiety disorder. These neurochemical and neuropeptide systems have been shown to have effects on distinct cortical and subcortical brain areas that are relevant to the mediation of the symptoms associated with anxiety disorders. Moreover, advances in molecular genetics portend the identification of the genes that underlie the neurobiological disturbances that increase the vulnerability to anxiety disorders. This chapter reviews clinical research pertinent to the neurobiological basis of anxiety disorders. The implications of this synthesis for the discovery of anxiety disorder vulnerability genes and novel psychopharmacological approaches will also be discussed.
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References
Albus M, Zahn TP, Brier A (1992) Anxiogenic properties of yohimbine: behavioral, physiological and biochemical measures. Eur Arch Psychiatry Clin Neurosci 241:337–344
Aston-Jones G, Shipley MT, Chouvet G, Ennis M, VanBockstaele EJ, Pieribone V, Shiekhattar R (1991) Afferent regulation of locus coeruleus neurons: anatomy, physiology and pharmacology. Prog Brain Res 88:47–75
Baker DG, West SA, Orth DN, Hill KK, Nicholson WE, Ekhator NN, Bruce AB, Wortman MD, Keck PE, Geracioti JD (1997) Cerebrospinal fluid and plasma beta endorphin in combat veterans with post traumatic stress disorder. Psychoneuroendocrinology 22:517–529
Bauer EP, Schafe GE, LeDoux JE (2002) NMDA receptors and L-type voltage-gated calcium channels contribute to long-term potentiation and different components of fear memory formation in the lateral amygdala. J Neurosci 22:5239–5249
Blair HT, Schafe GE, Bauer EP, Rodrigues SM, LeDoux JE (2001) Synaptic plasticity in the lateral amygdala: a cellular hypothesis of fear conditioning. Learn Mem 8:229–242
Blanchard EB, Kolb LC, Prins A, Gates S, McCoy GC (1991) Changes in plasma norepinephrine to combat-related stimuli among Vietnam veterans with post traumatic stress disorder. J Nerv Ment Dis 179:371–373
Bremner JD, Randall P, Scott TM, Bronen RA, Seibyl JP, Southwick SM, Delaney RC, Mc-Carthy G, Charney DS, Innis RB (1995) MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. Am J Psychiatry 152:973–981
Bremner JD, Randall P, Vermetten E, Staib L, Bronen RA, Mazure C, Capelli S, McCarthy G, Innis RB, Charney DS (1997) Magnetic resonance imaging-based measurement of hippocampal volume in posttraumatic stress disorder related to childhood physical and sexual abuse—a preliminary report. Biol Psychiatry 41:23–32
Bremner JD, Krystal JH, Southwick SM, Charney DS (1996a) Noradrenergic mechanisms in stress and anxiety: I. Preclinical studies. Synapse 23:28–38
Bremner JD, Krystal JH, Southwick SM, Charney DS (1996b) Noradrenergic mechanisms in stress and anxiety: II. Clinical studies. Synapse 23:39–51
Bremner JD, Innis RB, Ng CK, Staib L, Duncan J, Bronen R, Zubal G, Rich D, Krystal JH, Dey H, Soufer R, Charney DS (1997b) PET measurement of central metabolic correlates of yohimbine administration in posttraumatic stress disorder. Arch Gen Psychiatry 54:246–256
Bremner JD, Staib LH, Kaloupek D, Southwick SM, Soufer R, Charney DS (1999) Neural correlates of exposure to traumatic pictures and sound in Vietnam combat veterans with and without posttraumatic stress disorder: a positron emission tomography study. Biol Psychiatry 45:806–816
Bremner JD, Vythilingam M, Vermetten E, Southwick SM, McGlashan T, Staib LH, Soufer R, Charney DS (2003) Neural correlates of declarative memory for emotionally valenced words in women with posttraumatic stress disorder related to early childhood sexual abuse. Biol Psychiatry 53:879–889
Cain C, Blouin A, Barad MG (2002) L-type voltage-gated calcium channels are required for extinction but not for acquisition or expression, of conditional fear in mice. J Neurosci 22:9113–9121
Cassens G, Kuruc A, Roffman M, Orsulak P, Schildkraut JJ (1981) Alterations in brain norepinephrine metabolism and behavior induced by environmental stimuli previously paired with inescapable shock. Behav Brain Res 2:387–407
Charney DS, Deutch A (1996) A functional neuroanatomy of anxiety and fear: implications for the pathophysiology and treatment of anxiety disorders. Crit Rev Neurobiol 10:419–446
Charney DS, Heninger GR, Breier A (1984) Noradrenergic function in panic anxiety: effects of yohimbine in healthy subjects and patientswith agoraphobia and panic disorder. Arch Gen Psychiatry 41:751–763
Charney DS, Woods SW, Goodman WK, Heninger GR (1987a) Neurobiological mechanisms of panic anxiety: biochemical and behavioral correlates of yohimbine-induced panic attacks. Am J Psychiatry 144:1030–1036
Charney DS, Deutch AY, Krystal JH, Southwick SM, Davis M (1993) Psychobiologic mechanisms of posttraumatic stress disorder. Arch Gen Psychiatry 50:294–299
Comings DE, Muhleman D, Gysin R (1996) Dopamine D2 receptor (DRD2) gene and susceptibility to posttraumatic stress disorder: a study and replication. Biol Psychiatry 40:368–372
Coplan JD, Pine D, Papp L, Martinez J, Cooper T, Rosenblum LA, Gorman JM (1995a) Uncoupling of the noradrenergic-hypothalamic-pituitary adrenal axis in panic disorder patients. Neuropsychopharmacology 13:65–73
Coplan JD, Papp LA, Martinez MA, Pine P, Rosenblum LA, Cooper T, Liebowitz MR, Gorman JM (1995b) Persistence of blunted human growth hormone response to clonidine in fluoxetine-treated patients with panic disorder. Am J Psychiatry 152:619–622
Cose BJ, Robbins TW (1987) Dissociable effects of lesions to dorsal and ventral noradrenergic bundle on the acquisition, performance, and extinction of aversive conditioning. Behav Neurosci 101:476–488
Davidson J, Lipper S, Kilts CD, Mahorney S, Hammett E (1985) Platelet MAO activity in posttraumatic stress disorder. Am J Psychiatry 142:1341–1343
Davis M (2002) The role of NMDA receptors and MAP kinase in the amygdala in extinction of fear: clinical implications for exposure therapy. Eur J Neurosci 16:395–398
DeBellis MD, Lefter L, Trickett PK, Putnam FW (1994) Urinary catecholamine excretion in sexually abused girls. J Am Acad Child Adoles Psychiatry 33:320–327
Debiec J, LeDoux JE, Nader K (2002) Cellular and systems reconsolidation in the hippocampus. Neuron 36:527–538
DeRijk RH, Schaaf M, de Kloet ER (2002) Glucocorticoid receptor variants: clinical implications. J Steroid Biochem Mol Biol 81:103–122
Finlay JM, Abercrombie ED (1991) Stress induced sensitization of norepinephrine release in the medial prefrontal cortex. Soc Neurosci 17:151 (abstract)
Franowicz JS, Kessler LE, Borja CM, Kobilka BK, Limbird LE, Arnsten AF (2002) Mutation of the alpha2A-adrenoceptor impairs working memory performance annuls cognitive enhancement by guanfacine. J Neurosci 22:8771–8777
Garcia-Sevilla JA, Escriba PV, Ozaita A, LaHarpe R, Walzer C, Eytan A, Guimon J (1999) Upregulation of immunolabeled alpha2A-adrenoceptors Gi coupling proteins regulatory receptor kinases in the prefrontal cortex of depressed suicides. J Neurochem 72:282–291
Garpenstrand H, Annas P, Ekblom J, Oreland L, Fredrikson M (2001) Human fear conditioning is related to dopaminergic and serotonergic biologicalmarkers. Behav Neurosci 115:358–364
Gelernter J, Southwick S, Goodson S, Morgan A, Nagy L, Charney DS (1999) No association between D2 dopamine receptor (DRD2) “A” system alleles or DRD2 haplotypes, and posttraumatic stress disorder. Biol Psychiatry 45:620–625
Gilbertson MW, Shenton ME, Ciszewski A, Kasai K, Lasko NB, Orr SP, Pitman RK (2002) Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma. Nat Neurosci 5:1242–1247
Goddard AW, Mason GF, Almai A, Rothman DL, Behar KL, Petroff OA, Charney DS, Krystal JH (2001) Reductions in occipital cortex GABA levels in panic disorder detected with 1h-magnetic resonance spectroscopy. Arch Gen Psychiatry 58:556–561
Grant MM, Weiss JM (2001) Effects of chronic antidepressant drug administration electroconvulsive shock on locus coeruleus electrophysiologic activity. Biol Psychiatry 49:117–129
Grillon C (2002) Associative learning deficits increase symptoms of anxiety in humans. Biol Psychiatry 51:851–858
Grossman F, Potter W Z, Brown EA, Maislin GA (1999) Double-blind study comparing idazoxan and bupropion in bipolar depressed patients. J Affect Disord 56 237–43
Gurguis GNM, Uhde TW (1990) Plasma 3-methoxy-4 hydroxyphenylethylene glycol (MHPG) and growth hormone responses in panic disorder patients and normal controls. Psychoneuroendocrinology 15:217–224
Gurvits TV, Shenton ME, Hokama H, Ohta H, Lasko NB, Gilbertson MW, Orr SP, Kikinis R, Jolesz FA, McCarley W, Pitman RK (1996) Magnetic resonance imaging study of hippocampal volume in chronic, combat-related posttraumatic stress disorder. Biol Psychiatry 40:1091–1099
Hariri AR, Mattay VS, Tessitore A, Kolachana B, Fera F, Goldman D, Egan MF, Weinberger DR (2002) Serotonin transporter genetic variation and the response of the human amygdala. Science 297:400–403
Herry C, Garcia R (2002) Prefrontal cortex long-term potentiation but not long-term depression is associated with maintenance of extinction of learned fear inmice. J Neurosci 22:577–583
Holmes A, Yang RJ, Crawley JN (2002) Evaluation of an anxiety-related phenotype in galanin overexpresing transgenic mice. J Mol Neurosci 18:151–165
Ishikawa-Brush Y, Powell JF, Bolton P, Miller AP, Francis F, Willard HF, Lehrach H, Monaco AP (1997) Autism and multiple exostoses associated with an X-8 translocation occurring within the GRPR gene and 3' to the SDC2 gene. Hum Mol Genet 6:1241–1250
Kallio J, Personen U, Kaipio K, Karvonen MK, Heinonen OJ, Uusitupa MI, Koulu M (2001) Altered intracellular processing and release of neuropeptide Y due to leucine 7 to proline 7 polymorphism in the signal peptide of preproneuropeptide Yin man. FASEB J 15:1242–1244
Kida S, Josselyn SA, de Ortiz SP, Kogan JH, Chevere I, Masushige S, Silva AJ (2002) CREB required for the stability of new and reactivated fear memories. Nat Neurosci 4:348–355
LeDoux JE (2000) Emotion circuits in the brain. Annu Rev Neurosci 23:155–184
Lemieux AM, Coe CL (1995) Abuse-related PTSD: evidence for chronic neuroendocrine activation in women. Psychosom Med 57:105–115
Lerer B, Ebstein RP, Shestatsky M, Shemesh Z, Greenberg D (1987) Cyclic AMP signal transduction in posttraumatic stress disorder. Am J Psychiatry 144:1324–1327
Marshall RD, Blanco C, Printz D, Liebowitz MR, Klein DF, Coplan J (2002) A pilot study of noradrenergic and HPA axis functioning in PTS vs. panic disorder. Psychiatry Res 110:219–230
McFall ME, Veith RC, Murburg MM (1992) Basal sympathoadrenal function in posttraumatic stress disorder. Biol Psychiatry 31:1050–1056
McGaugh JL (2002) Memory consolidation and the amygdala: a systems perspective. Trends Neurosci 25:456–461
McGaugh JL, Roozendaal B (2002) Role of adrenal stress hormones in forming lasting memory in the brain. Curr Opin Neurobiol 12:205–210
McGaugh JL, Castellano C, Brioni J (1990) Picrotoxin enhances latent extinction of conditioned fear. Behav Neurosci 104:264–267
McIntyre CK, Hatfield T, McGaugh JL (2002) Amygdala norepinephrine levels after training predict inhibitory avoidance retention performance in rats. Eur J Neurosci 16:1223–1226
Milad MR, Quirk GJ (2002) Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420:70–74
Milekic MH, Alberini CM (2002) Temporally graded requirement for protein synthesis following memory reactivation. Neuron 36:521–525
Morgan MA, Romanski LM, LeDoux JE (1993) Extinction of emotional learning: contribution of medial prefrontal cortex. Neurosci Lett 163:109–113
Myers KM, Davis M (2002) Systems-level reconsolidation: re-engagement of the hippocampus with memory reactivation. Neuron 36:340–343
Myers KM, Davis M (2004) AX+, BX-discrimination learning in the fear-potentiated startle paradigm: possible relevance to inhibitory fear learning in extinction. Learn Mem 11:464–475
Nalepa I, Kreiner G, Kowalska M, Sanak M, Zelek-Molik A, Vetulani J (2002) Repeated imipramine electroconvulsive shock increase alpha(1A)-adrenoceptor mRNA level in rat prefrontal cortex. Eur J Clin Pharmacol 444:151–159
Nesse RM, Curtis GC, Thyer BA, McCann DS, Huber-Smith MJ, Knopf RF (1985) Endocrine and cardiovascular responses during phobic anxiety. Psychosom Med 47:320–332
Nisenbaum LK, Zigmund MJ, Sved AF, Abercrombie ED (1991) Prior exposure to chronic stress results in enhanced synthesis and release of hippocampal norepinephrine in response to a novel stressor. J Neurosci 11:1473–1484
Nutt DJ (1989) Altered alpha2-adrenoceptor sensitivity in panic disorder. Arch Gen Psychiatry 46:165–169
Orr SP, Metzger LJ, Pitman RK (2002) Psychophysiology of post-traumatic stress disorder. Psychiatr Clin North Am 25:271–293
Perry BD, Giller EL, Southwick SM (1987) Altered platelet alpha2 adrenergic binding sites in posttraumatic stress disorder. Am J Psychiatry 144:1511–1512
Przbyslawski J, Sara SJ (1997) Reconsolidation of memory after its reactivation. Behav Brain Res 84:241–246
Przbyslawski J, Roullet P, Sara SJ (1999) Attenuation of emotional and nonemotional memories after their reactivation: role of β adrenergic receptors. J Neurosci 19:6623–6628
Quirk GJ, Russo GK, Barron JL, Lebron K (2000) The role of ventral medial prefrontal cortex in the recovery of extinguished fear. J Neurosci 20:6225–6231
Rasmussen K, Marilak DA, Jacobs BL (1986) Single unit activity of the locus coeruleus in the freely moving cat. I. During naturalistic behaviors and in response to simple and complex stimuli. Brain Res 371:324–334
Rodrigues SM, Schafe GE, LeDoux JE (2001) Intra-amygdala blockade of theNR2B subunit of the NMDA receptor disrupts the acquisition but not the expression of fear conditioning. J Neurosci 21:6889–6896
Rogoz Z, Skuza G, Dlaboga D, Maj J, Dziedzicka-Wasylewska M (2001) Effect of repeated treatment with tianeptine fluoxetine on the central alpha(1)-adrenergic system. Neuropharmacology 41:360–368
Roozendaal B, Brunson KL, Holloway BL, McGaugh JL, Baram TZ (2002) Involvement of stress-released corticotrophin-releasing hormone in the basolateral amygdala in regulating memory consolidation. Proc Natl Acad Sci U S A 99:13908–13913
Royer S, Martina M, Pare D (2000) Bistable behaviour of inhibitory neurons controlling impulse traffic through the amygdala: role of a slowly deinactivating Kb current. J Neurosci 20:9034–9039
Sallee FR, Sethuraman G, Sine L, Liu H (2000) Yohimbine challenge in children with anxiety disorders. Am J Psychiatry 157:1236–1242
Sallinen J, Haapalinna A, MacDonald E, Viitamaa T, Lahdesmaki J, Rybnikova E, Pelto-Huikko M, Kobilka BK, Scheinin M (1999) Genetic alteration of the alpha2-adrenoceptor subtype c in mice affects the development of behavioral despair and stress-induced increases in plasma corticosterone levels. Mol Psychiatry 4:443–452
Sanacora G, Berman RM, Cappiello A, Oren DA, Kugaya A, Liu N, Gueorguieva R, Fasula D, Charney DS (2004) Addition of the alpha2-antagonist yohimbine to fluoxetine: effects on rate of antidepressant response. Neuropsychopharmacology 29:1166–1171
Sara SJ (2000) Retrieval and reconsolidation: toward a neurobiology of remembering. Learn Mem 7:73–84
Schafe GE, Nader K, Blair HT, LeDoux JE (2001) Memory consolidation of Pavlovian fear conditioning: a cellular and molecular perspective. Trends Neurosci 24:540–546
Schmidt P, Holsboer F, Spengler D (2001) Beta(2)-adrenergic receptors potentiate glucocorticoid receptor transactivation via G protein beta gamma-subunits and the phosphoinositide 3-kinase pathway. Mol Endocrinol 15:553–564
Schramm NL, McDonald MP, Limbird LE (2001) The alpha(2a)-adrenergic receptor plays a protective role in mouse behavioral models of depression and anxiety. J Neurosci 21:4875–4882
Shumyatsky G, Tsvetkov E, Malleret G, Vronskaya S, Horton M, Hampton L, Battey JF, Dulac C, Kandel ER, Bolshakov VY (2002) Identification of a signaling network in lateral nucleus of amygdala important for inhibiting memory specifically related to learned fear. Cell 111:905–918
Small KM, Wagoner LE, Levin AM, Kardia SL, Liggett SB (2002) Synergistic polymorphisms of β1and α2c adrenergic receptors the risk of congestive heart failure. N Engl J Med 347:1135–1142
Southwick SM, Krystal JH, Morgan CA, Johnson D, Nagy LM, Nicolaou A, Heninger GR, Charney DS (1993) Abnormal noradrenergic function in posttraumatic stress disorder. Arch Gen Psychiatry 50:266–274
Southwick SM, Krystal JH, Bremner JD, Morgan CA, Nicolaou A, Nagy LM, Johnson DR, Heninger GR, Charney DS (1997) Noradrenergic and serotonergic function in posttraumatic stress disorder. Arch Gen Psychiatry 54:749–758
Stein MB, Tancer ME, Uhde TW (1992) Heart rate and plasma norepinephrine responsivity to orthostatic challenge in anxiety disorders. Comparison of patientswith panic disorder and social phobia and normal control subjects. Arch Gen Psychiatry 49:311–317
Stein MB, Huzel LL, Delaney SM (1993) Lymphocyte b-adrenoceptors in social phobia. Biol Psychiatry 34:45–50
Tancer ME, Stein MB, Uhde TW (1990) Effects of thyrotropin-releasing hormone on blood pressure and heart rate in phobic and panic patients: a pilot study. Biol Psychiatry 27:781–783
True WR, Rice J, Eisen SA, Heath AC, Goldberg J, Lyons MJ, Nowak J, (1993) A twin study of genetic and environmental contributions to liability for posttraumatic stress symptoms. Arch Gen Psychiatry 50:257–264
Uhde T, Joffe RT, Jimerson DC, Post RM (1988) Normal urinary free cortisol and plasma MHPG in panic disorder: clinical and theoretical implications. Biol Psychiatry 23:575–585
Ventura R, Cabib S, Puglisi-Allegra S (2002) Genetic susceptibility of mesocortical dopamine to stress determines liability to inhibition of mesoaccumbens dopamine and to behavioral despair in a mouse model of depression. Neuroscience 115:99–1007
Walker DL, Davis M (2000) Involvement of NMDA receptors within the amygdala in shortversus long-termmemory for fear conditioning as assessed with fear-potentiated startle. Behav Neurosci 114:1019–1033
Weiss JM, Bonsall RW, Demetrikopoulos MK, Emery MS, West CH Galanin (1998) A significant role in depression? Ann N Y Acad Sci 863:364–382
Willick ML, Kokkinidis L (1995) Cocaine enhances the expression of fear-potentiated startle: evaluation of state-dependent extinction and the shock-sensitization of acoustic startle. Behav Neurosci 109:929–938
Yau JL, Noble J, Hibberd C, Rowe WB, Meaney MJ, Morris RG, Seckl JR (2002) Chronic treatment with the antidepressant amitriptyline prevents impairments in water maze learning in aging rats. J Neurosci 22:1436–1442
Yehuda R, Boisoneau D, Lowy MT, Giller EL Jr (1995b) Dose response changes in plasma cortisol and lymphocyte glucocoriticooid receptors following dexamethasone administration in combat veterans with and without posttraumatic stress disorder. Arch Gen Psychiatry 52:583–593
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Neumeister, A., Daher, R., Charney, D. (2005). Anxiety Disorders: Noradrenergic Neurotransmission. In: Holsboer, F., Ströhle, A. (eds) Anxiety and Anxiolytic Drugs. Handbook of Experimental Pharmacology, vol 169. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-28082-0_8
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