Panic Disorder-A Malfunction of Multiple Transmitter Control Systems within the Midbrain Periaqueductal Gray Matter?

Abstract

The clinical and psychopharmacological profile of panic disorder in human patients shows a remarkable similarity to the defensive behavioral response evoked in experimental animals by activation of neurons in the dorsal part of the midbrain periaqueductal gray matter (PAG). Studies of the neural circuitry within the PAG indicate that a subpopulation of GABAergic neurons in the dorsolateral sector may act as an amplifying stage that potentiates inhibitory serotonergic input to the "defense area" within the PAG. These neurons may function as a gain-control system that sets the level of excitability of efferent output neurons, which mediate the autonomic and somatomotor components of panic behavior. Dysfunctional activity within the dorsolateral PAG leading to a destabilization of this control system may be a factor underlying panic behavior and predisposes to the development of panic disorder in susceptible persons. NEUROSCIENTIST 6:48-59, 2000

Keywords

Periaqueductal gray matter,Panic behavior,Panic disorder,Serotonin,Nitric oxide,GABA

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References

American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 3rd ed. Rev. Washington (DC): American Psychological Press; 1987.

Bennett JA , Moioffer M , Stanton SP , Dwight M , Keck PE Jr. A risk-benefit assessment of pharmacological treatments for panic disorder. Drug Saf 1998;18:419-30.

Von Korf M , Eaton W. Epidemiological findings on panic. In: Baker R , editor. Panic disorder: research and therapy. Chichester (UK): Wiley and Sons; 1989. p. 35-50.

Sansone RA , Sansone LA , Righter EL. Panic disorder. the ultimate anxiety. J Womens Health 1998;7:983-9.

Ballenger JC. Co-morbidity of panic and depression: implications for clinical management. Int Clin Psychopharmacol 1998; 13(Suppl 4):S13-7.

Chignon JM. Cardiovascular-disease and panic disorder. Can J Psychiatr 1993;38:127-33.

Ballenger JC. New treatments for panic. Eur Psychiatr 1998; 13(Suppl 2):S75-81.

DenBoer JA , Slaap BR. Review of current treatment in panic disorder . Int Clin Psychopharmacol 1998;13(Suppl. 4):S25-30.

Abelson JL , Nesse RM.

Pentagastrin infusions in patients with panic disorder. I Symptoms and cardiovascular-responses

Biol Psychiatry 1994;36:73-83.

10.

Bradwejn J , Koszycki D , Annable L , Couetoux du Tertre A , Reines S , Karkamas C. A dose-ranging study of the behavioural and cardiovascular effects of CCK-tetrapeptide in panic disorder. Biol Psychiatry 1992;32:903-12.

11.

Bradwejn J , Koszycki D , Couetoux du Tertre A , van Megen H , den Boer J , Westenberg H. The panicogenic effects of cholecystokinin-tetrapeptide are antagomzed by L-365,260, a central cholecystokmm receptor antagonist, in patients with panic disorder . Arch Gen Psychiat 1994;51:486-93.

12.

Goetz RR , Klem DF , Gully R , Kahn J , Liebowitz MR , Fyer AJ , et al. Panic attacks during placebo procedures in the laboratory. Physiology and symptomatology. Arch Gen Psychiatry 1993:50. 280-5.

13.

van Megen HJ , Westenberg HG , den Boer JA , Haigh JR , Traub M. Pentagastnn induced panic attacks. enhanced sensitivity in panic disorder patients. Psychopharmacology (Berl) 1994;114: 449-55.

14.

Bates JHT , Bradwejn J. Ventilatory response to cholecystokinin tetrapeptide in anaesthetised dogs. Neuroreport 1995,6:2513-7.

15.

Rupmak NMJ , Schaffer L , Siegl P , Iversen SD. Failure of mtravenous pentagastrm challenge to induce panic-like effects in rhesus-monkeys. Neuropeptides 1992;25:115-9.

16.

Facchinetti R , Romano G , Fava M , Genazzani AR. Lactate mfusion induces panic attacks in patients with premenstrual-syndrome. Psychosom Med 1992;54:288-96.

17.

Le Melledo JM , Meram S , Koszycki D , Bellavance F , Palmour R , Gutkowska J , et al. Sensitivity to CCK-4 in women with and without premenstrual dysphonc disorder (PMDD) during their follicular and luteal phases. Neuropsychopharmacology 1999;20: 81-91.

18.

Sandberg D , Endicott J , Hamson W , Nee J , Gorman J. Sodium lactate mfusion in late luteal phase dysphonc disorder. J Psychiatry Res 1993;46:79-88

19.

Paul SM , Purdy RH. Neuroactive steroids FASEB J 1992 ;6: 2311-22

20.

Nguyen Q , Sapp DW , Van Ness PC , Olsen RW Modulation of GABAA receptor-binding in human brain by neuroactive steroids : species and brain regional differences . Synapse 1995;19: 77-87.

21.

Schmid G , Sala R , Bonanno G , Raiteri M. Neurosteroids may differentially affect the function of two native GABA(A) receptor subtypes m the rat brain . Naunyn Schmiedebergs Arch Pharmacol 1998 ;357:401-7

22.

Bitran D , Purdy RH , Kellogg CK. Anxiolytic effect of progesterone is associated with increases in cortical allopregnanolone and GABAA receptor function. Pharmacol Biochem Behav 1993; 45:423-8.

23.

Rapkin AJ , Morgan M , Goldman L , Brann DW , Simone D , Mahesh VB. Progesterone metabolite allopregnanolone in women with premenstrual syndrome. Obstet Gynecol 1997;90: 709-14.

24.

Bicikova M , Dibbelt L , Hill M , Hampl R , Starka L. Allopregnanolone in women with premenstrual syndrome. Horm Metab Res 1998;3:227-9.

25.

Schmidt PJ , Purdy RH , Moore PH Jr , Paul SM , Rubmow DR. Circulating levels of anxiolytic steroids in the luteal phase in women with premenstrual syndrome and in control subjects. J Clin Endocnnol Metab 1994;79:1256-60.

26.

Sundstrom I , Andersson A , Nyberg S , Ashbrook D , Purdy RH , Backstrom T. Patients with premenstrual syndrome have a different sensitivity to a neuroactive steroid during the menstrual cycle compared to control subjects. Neuroendocnnology 1998; 67:126-38.

27.

Randall PK , Bremner JD , Krystal JH , Nagy LM , Heninger GR , Nicolaou AL , et al. Effects of the benzodiazepine antagonist flumazenil in PTSD. Biol Psychiatry 1995;38:319-24.

28.

Nutt DJ , Glue P , Lawson C , Wilson S. Flumazenil provocation of panic attacks Evidence for altered benzodiazepine receptor sensitivity in panic disorder. Arch Gen Psychiatry 1990,47:917-25

29.

Strohle A , Kellner M , Yassoundis A , Holsboer F , Wiedemann K. Effect of flumazenil m lactate-sensitive patients with panic disorder. Am J Psychiatry 1998;155:610-2.

30.

HarrisonRead PE , Tyrer P , Lawson C , Lack S , Fernandes C , File S. Flumazenil-precipitated panic and dysphona in patients dependent on benzodiazepines: a possible aid to abstinence . J Psychopharmacol 1996;10:89-97.

31.

Brandt CA , Meller J , Keweloh L , Hoschel K , Staedt J , Munz D , et al. Increased benzodiazepine receptor density in the prefrontal cortex in patients with panic disorder. J Neural Transm 1998, 105:1325-33.

32.

Kuikka JT , Pitkanen A , Lepola U , Partanen K , Vainio P , Bergstrom KA , et al. Abnormal regional benzodiazepine receptor uptake in the prefrontal cortex in patients with panic disorder. Nuclear Med Commun 1995;16:273-80.

33.

Malizia AL , Cunningham VJ , Bell CJ , Liddle PF , Jones T , Nutt DJ , et al. Decreased brain GABA(A)-benzodiazepme receptor binding in panic disorder preliminary results from a quantitative PET study. Arch Gen Psychiatry 1998;55:715-20.

34.

Deakm JW The role of serotonin in depression and anxiety. Eur Psychiatry 1998;13(Suppl. 2):S57-S63.

35.

Blanchard RJ , Gnebel G , Henrie JA , Blanchard DC. Differentiation of anxiolytic and panicolytic drugs by effects on rat and mouse defense test batteries . Neurosci Biobehav Rev 1997;21 783-9.

36.

Beckett SRG , Aspley S , Graham M , Marsden CA. Pharmacological manipulation of ultrasound induced defence behaviour in the rat Psychopharmacology (Berl) 1996;127:384-90.

37.

Molewijk HE , van der Poel AM , Mos J , van der Heyden JA , Olivier B. Conditioned ultrasonic distress vocalizations in adult male rats as a behavioural paradigm for screening anti-panic drugs. Psychopharmacology (Berl) 1995;117:32-40.

38.

Graeff FG , Netto CF , Zangrossi H Jr. The elevated T-maze as an experimental model of anxiety. Neurosci Biobehav Rev 1998; 23237-46.

39.

Bandler R , Shipley MT. Columnar organisation in the midbrain periaqueductal gray: modules for emotional expression. Trends Neurosci 1994;17.379-89.

40.

Graeff FG. Neuroanatomy and neurotransmitter regulation of defensive behaviors and related emotions in mammals. Braz J Med Biol Res 1994,27:811-29.

41.

Beckett SRG , Duxon MS , Aspley S , Marsden CA. Central C-fos expression following 20KHz ultrasound induced defense behaviour in the rat. Brain Res Bull 1997,424:421-6.

42.

Canteras NS , Goto M. FOS-like immunoreactivity in the penaqueductal gray of rats exposed to a natural predator. Neuroreport 1999;10:43-8.

43.

Jenck F , Martin JR , Moreau JL. Behavioural effects of CCKB receptor ligands in a validated simulation of panic anxiety in rats. Eur Neuropsychopharmacol 1996;6:291-8.

44.

Gnebel G , Perrault G , Sanger DJ CCK receptor antagonists in animal models of anxiety: comparison between exploration tests, conflict procedures and a model based on defensive behaviours . Behav Pharmacol 1997;8:549-60.

45.

Siegel A , Roeling TAP , Gregg TR , Kruk MR. Neuropharmacology of brain-stimulation-evoked aggression. Neurosci Biobehav Rev 1999;23.359-89.

46.

Luo B , Cheu JW , Siegel A. Cholecystokmm B receptors in the periaqueductal gray potentiate defensive rage behavior elicited from the medial hypothalamus of the cat. Brain Res 1998;796: 27-37.

47.

Lm H , Chandler S , Beitz AJ , Shipley MT , Behbehani MM. Charactenzation of the effect of cholecystokinin (CCK) on neurons in the penaqueductal gray of the rat: immunocytochemical and in vivo and in vitro electrophysiological studies. Brain Res 1994, 642:83-94.

48.

Redgrave P , Dean P. Does the PAG learn about emergencies from the superior colliculus? In: Depaulis A , Bandler R , editors. The midbrain penaqueductal gray matter. New York: Plenum Press ; 1991. p. 199-209.

49.

Brandao ML , de Aguiar JC , Graeff FG. GABA mediation of the antiaversive action of the minor tranquilizers . Pharmacol Biochem Behav 1982;16:397-402

50.

Schenberg LC , Graeff FG. Role of the penaqueductal gray substance in the antianxiety action of benzodiazepines. Pharmacol Biochem Behav 1978;9:287-295.

51.

Depaulis A , Vergnes M. Elicitation of intraspecific defensive behavior in the rat by microinjections of picrotoxin, a γ-aminobutync antagonist, into the midbrain periaqueductal gray matter. Brain Res 1986,367:87-95.

52.

Sandkuhler J , Herdegen T.

Distinct patterns of activated neurons throughout the rat midbrain penaqueductal gray induced by chemical stimulation within its subdivisions

J Comp Neurol 1995;351:546-53

53.

Ottersen OP , Storm-Mathisen J. Glutamate and GABA-contammg neurons in the mouse brain, as demonstrated with a new immunocytochemical technique . J Comp Neurol 1984;229:374-92.

54.

Reichling DB. GABAergic neuronal circuitary in the penaqueductal gray matter. In: Depaulis A , Bandler R , editors. The midbram penaqueductal gray matter. New York: Plenum Press; 1991. p. 329-44.

55.

Lovick TA , Paul NL. Co-localization of GABA with mcotmamide adenine dinucleotide phosphate-dependent diaphorase in neurones in the dorsolateral periaqueductal grey matter of the rat. Neurosci Lett 1999;272:167-70.

56.

Bowery NG , Hudson AL , Pnce GW. GABAA and GABAB receptor distribution in the rat central nervous system. Neuroscience 1987;20:364-83.

57.

Margeta-Mitrovic M , Mitrovic I , Riley RC , Jan LY , Basbaum AI. Immunohistochemical locahzation of GABAB receptors in the rat central nervous system. J Comp Neurol 1999;405.299-321.

58.

Barbaresi P , Gazzanelli G , Malatesta M. GABA transporter-1 (GAT-1) immunoreactivity in the cat penaqueductal gray matter. Neurosci Lett 1998;250:123-6.

59.

Onstott D , Mayer B , Beitz AJ. Nitric oxide synthase immunoreactive neurons anatomically define a longitudinal dorsolateral column within the midbrain periaqueductal grey of the rat: analysis using laser confocal microscopy. Brain Res 1993;610:317-24.

60.

Chiavegatto S , Scavone C , Canteras NS. Nitric oxide synthase activity in the dorsal periaqueductal gray in rats expressing innate fear responses. Neuroreport 1998;9:571-6.

61.

Guimaraes FS , de Aguiar JC , Del Bel EA , Ballejo G. Anxiolytic effect of nitric oxide synthase inhibitors microinjected into dorsal central gray. Neuroreport 1994;5:1919-32.

62.

Hall, CW , Behbeham MM. The medial preoptic nucleus of the hypothalamus modulates activity of nitric oxide sensitive neurons in the midbrain penaqueductal gray. Brain Res 1997;765:208-17.

63.

Lovick TA.

Role of nitric oxide in medullary raphe-evoked m-hibition of neuronal activity in the periaqueductal grey matter

Neuroscience 1996;75:1203-9.

64.

Lovick TA , Key BJ.

Inhibitory effect of nitric-oxide on neuronal activity in the periaqueductal grey matter of the rat

Exp Brain Res 1996; 108:382-8.

65.

Hall CW , Behbeham MM. Synaptic effects of nitric oxide on enkephalinergic, GABAergic and glutamatergic networks of the rat penaqueductal gray. Brain Res 1998;805:69-87.

66.

Getting SJ , Segieth J , Ahmad S , Biggs CS , Whitton PS Biphasic modulation of GABA release by nitric oxide in the hippocampus in freely moving rats. Brain Res 1996;717:196-68.

67.

Guevara-Guzman R , Emson PC , Kendrick KM. Modulation of in vivo striate transmitter release by nitric oxide and cyclic GMP. J Neurochem 1994;62:807-10.

68.

Lonart G , Wang J , Johnson KM Nitric oxide induces neurotransmitter release from hippocampal slices. Eur J Pharmacol 1992; 220:271-2

69.

Ohkuma S , Katsura M , Chen DZ , Narihara H , Kunyama K. Nitnc oxide-evoked [3H]α-ammobutyric acid release is mediated by two distinct mechanisms. Mol Brain Res 1996;36:137-44

70.

Fukami S , Uchida I , Mashimo T , Takenoshita M , Yoshiya I. Gamma subunit dependent modulation by nitric oxide (NO) in recombmant GABAA receptor. Neuroreport 1998;9:1089-93.

71.

Verdoorn TA , Draguhn A , Ymer S , Seeburg PH , Sakmann B. Functional properties of recombinant GABAA receptors depend upon subunit composition. Neuron 1990;4:919-28.

72.

Fntschy JM , Mohler H. GABAA-receptor heterogeneity in the adult rat brain. differential regional and cellular distribution of seven major subunits. J Comp Neurol 1995;359:154-94.

73.

Hämälämen MM , Lovick TA. Involvement of nitric oxide and serotonin in modulation of antinociception and pressor responses evoked by stimulation in the dorsolateral region of the periaqueductal gray matter in the rat. Neuroscience 1997;80:821-7.

74.

Kiser RS , Lebovitz M. Monoaminergic mechanisms in aversive brain stimulation. Physiol Behav 1975;15:47-53

75.

Schutz MT , de Aguiar JC , Graeff FG. Anti-aversive role of serotomn in the periaqueductal grey matter. Psychopharmacology (Berl) 1985;85:340-5.

76.

Shlik J , Aluoja A , Vasar V , Vasar E , Podar T , Bradwejn J Effects of citalopram treatment on behavioural, cardiovascular and neuroendocnne response to cholecystokmm tetrapeptide challenge in patients with panic disorder. J Psychiatry Neurosci 1997; 22:332-40

77.

van Megen HJ , Westenberg HG , den Boer JA , Slaap B , Scheepmakers A. Effect of the selective serotonin reuptake m-hibitor fluvoxamme on CCK-4 induced panic attacks. Psychopharmacology (Berl) 1997;129:357-64.

78.

Bertani A , Perna G , Arancio CC , Caldivola D , Bellodi L. Pharmacological effect of imipramine, paroxetme and sertraline on 35% carbon dioxide hypersensitivity in panic patients a double-blind, random, placebo-controlled study. J Clin Psychopharmacol 1997;17:97-101.

79.

Bradwejn J , Koszycki D. Imipramine antagonism of the pamcogemc effects of cholecystokinin tetrapeptide in panic disorder patients. Am J Psychiatry 1994;151:261-3.

80.

Beitz AJ , Clements JR , Mullett MA , Ecklund LJ. Differential origin of bramstem serotonergic projections to the midbrain periaqueductal gray and superior colliculus in the rat. J Comp Neurol 1986;250:498-509.

81.

Schenberg LC , Lovick TA. Attenuation of the midbrain-evoked defense reaction by selective stimulation of medullary raphe neurons in rats. Am J Physiol 1995;269:R1378-9.

82.

Lovick TA.

Serotonergic influence from nucleus raphe obscurus on neurones in the periaqueductal grey matter in the rat

Brain Res 1993;606:92-8.

83.

Lovick TA. Influence of the dorsal and median raphe on neurones in the periaqueductal grey matter: role of 5-hydroxytryptamme. Neuroscience 1994 ;59:993-1000.

84.

Beckett SR , Lawrence AJ , Marsden CA , Marshall PW. Attenuation of chemically-induced defense response by 5-HT(1) receptor agonist administered into the periaqueductal gray. Psychopharmacology (Berl) 1992;108:110-4

85.

Mongeau R , Marsden CA. Effect of imipramine treatments on the 5-HTlA-receptor-mediated inhibition of panic-like behaviours in rats. Psychopharmacology (Berl) 1997;131:321-8.

86.

Behbehani MM , Lm H , Jiang M , Pun RY , Shipley MT. Activation of serotonin 1A receptors inhibits midbrain periaqueductal gray neurons m the rat. Brain Res 1993;612:56-60.

87.

Brandao ML , Lopez-Garcia JA , Graeff FG , Roberts MH. Electrophysiological evidence for excitatory 5HT2 and depressant 5HT1 receptors on neurones of the rat midbrain tectum. Brain Res 1991;556:259-66.

88.

Jenck F , Moreau JL , Berendsen HH. Antiaversive effects of 5HT(2C) receptor agonists and fluoxetine in a model of panic-like anxiety in rats. Eur Neuropsychopharmacol 1998;8:161-8.

89.

Nogueira RL , Graeff FG. Role of 5-HT receptors in the modulation of dorsal penaqueductal gray generated aversion. Pharmacol Biochem Behav 1995;52:1-6.

90.

Stezhka VV , Lovick TA. Inhibitory serotonergic influence on neurones in the dorsolateral penaqueductal grey matter involves nitric oxide. J Physiol (Lond) 1998;509:160P.

91.

Clements JR , Beitz AJ , Fletcher TF , Mullett MA. Immunocytochemical localization of serotonin in the rat penaqueductal gray: a quantitative light and electron microscopic study. J Comp Neurol 1985,236:60-70

92.

Lorram DS , Hull EM. Nitnc oxide increases dopamme and serotonm release in the medial preoptic area. Neuroreport 1993 ;5: 87-9.

93.

Pogun S , Kuhar MJ. Regulation of neurotransmitter reuptake by nitric oxide. Ann NY Acad Sci 1994;34:305-15.

94.

Parry DM , Paul NL , Lumb BM , Lovick TA. Ultrastructural relationship between serotonergic and nitric oxide synthase (NOS)-contammg neurones in the rat periaqueductal grey matter. Soc Neurosci Abst 1999;25:1675.

95.

Kow LM , Pfaff DW. Mapping of neural and signal transduction pathways for lordosis in search of estrogen actions on the central nervous system . Behav Brain Res 1998;92:169-80.

96.

Smith SS , Gong QH , Hsu FC , Markowitz RS , ffrench-Mullen JM , Li X. GABA A receptor α4 subunit expression prevents withdrawal properties of an endogenous steroid. Nature 1997;392: 926-30.

97.

Breslow MF , Fankhauser MP , Potter RL , Meredith KE , Misiaszek J , Hope DG Jr. Role of γ-aminobutyric acid in anti-panic drug efficacy. Am J Psychiatry 1989;146:353-6.

98.

Lader M , Mathews A. Physiological changes during spontaneous panic attacks. J Psychosom Res 1970;14:377-82.

99.

Lovick TA. Integrated activity of cardiovascular and pain regulatory systems: role m adaptive behavioural responses. Prog Neurobiol 1993;40:631-44.

100.

Lovick TA , Drew S. Stimulation in nucleus raphe obscurus is cardioprotective against ischemic changes evoked by stimulation in the periaqueductal gray matter. J Physiol (Lond) 1998:511P: 112P.

101.

Nashold BS Jr , Wilson WP , Slaughter DG. Sensations evoked by stimulation in the midbrain of man. J Neurosurg 1969;30.14-24.

102.

Richardson DE , Akil H. Pain reduction by electrical brain stimulation in man Part 1. acute administration in penaqueductal and penventricular sites . J Neurosurg 1977;47:178-83.

103.

Young RF.

Brain and spinal stimulation: how and to whom!

Clin Neurosurg 1989;35:429-47