Biological Background of Anxiety Attacks in Agoraphobia

Abstract

Anxiety is characterized as either a state of mind, lacking a thick spatial depth, or otherwise conceived as something that individuals undergo alone. Anxiety can be in different shapes and levels of severity; this paper will describe its biological background in cases of Agoraphobia. It will touch the base of such biological influence as overactivity of the nucleus locus coeruleus and changes in the level of activity of this enzyme MAO activity. GABA levels fluctuation may be another reason for causing pathological anxiety, as well as experimental evidence, suggests that overactivity of serotonergic pathways, particularly the ascending dorsal raphe system may contribute to the production of pathological anxiety, studies also have demonstrated both decreased and increased dopamine turnover in response to stress. Lastly, activation of the right frontal hemisphere appears to portray activation of an avoidance-withdrawal system and seems to be correlated with negative emotions; several observations suggest that panic disorder should be characterized by right frontal hyperactivation.

Keywords: agoraphobia, anxiety, panic attacks, biological background

Biological Background of Anxiety Attacks in Agoraphobia

Agoraphobia is defined by in DSM-5 (American Psychiatric Association, 2013) as anxiety about being in places or situations in which escape might be intricate, or help might not be available in the event of having a panic attack or panic-like symptoms. (Panic Disorder and Agoraphobia. (n.d.). Retrieved from https://www.stjoes.ca/health-services/mental-health-addiction-services/mental-health-services/anxiety-treatment-and-research-clinic-atrc-/definitions-and-useful-links/panic-disorder-and-agoraphobia.). There is a mistaken belief that the term agoraphobia refers to a fear of open location. This is not true; most people with agoraphobia are much more fearful of enclosed spaces, such as tunnels, small rooms, and elevators. About 30 to 50% of people with agoraphobia also have panic disorder, and about 2% of women and 1% of men have agoraphobia during any 12 months. (Barnhill, J. W., By, Barnhill, J. W., & Last full review/revision October 2018 by John W. Barnhill. (n.d.). Agoraphobia - Mental Health Disorders. Retrieved from https://www.msdmanuals.com/en-sg/home/mental-health-disorders/anxiety-and-stress-related-disorders/agoraphobia.).

Overactivity of the nucleus coeruleus . The occurrence of anxiety attacks can depend on overactivity of the nucleus locus coeruleus (the system responsible for attention regulation) and the ascending noradrenergic systems. The noradrenergic systems (noradrenergic neurons in the brain form a neurotransmitter system when triggered, apply influence on large areas of the brain, the effects diffuses on alertness, arousal, and readiness for action) originate in the pons and medulla oblongata. The principal noradrenaline is containing a nucleus, and the nucleus locus coeruleus provides noradrenergic innervations to the cerebral and cerebellar cortices, the limbic system, brainstem and spinal cord. P-receptors and Y-receptors mediate the effects of noradrenaline (they are in the brain). Cortical P-receptors (Substance P (SP) is one of the most abundant peptides in the central nervous system and has been suspected in a range of physiological and pathophysiological processes including stress regulation, as well as active and anxiety-related behaviour (Ebner, K., & Singewald, N. (2006). The role of substance P in stress and anxiety responses. Amino Acids, 31(3), 251–272. doi: 10.1007/s00726-006-0335-9)) are most responsive to changes in noradrenaline activity (release of norepinephrine, increasing heart rate and blood pressure). Cortical Y-receptors, an endogenous anticonvulsant in the central nervous system, plays an essential role in the regulation of neuronal excitability are confined to post-synaptic locations. Presynaptic receptors may be autoreceptors, react to adrenergic agonists by decreasing neuronal firing.

Anxiety may be the result of alterations in peripheral autonomic mechanisms rather than central receptor abnormalities. Studies of heart rate, blood flow and skin conductance have shown evidence of increased peripheral arousal in patients with pathological anxiety (Judd, F., Burrows, G., & Norman, T. (1985). The Biological Basis of Anxiety An Overview . Journal of Affective Disorders, 271–284). Many features of spontaneous panic attacks are consistent with P-receptor stimulation. This may be due either to increased receptor sensitivity or to increased stimulation of the 3-adrenergic system (adrenergic system plays an essential role in the regulation of cardiovascular structure and function).

Symptoms resulting from P-receptor stimulation may occur secondary to CNS events. If P-receptor stimulation is the primary event increased peripheral arousal should consistently precede anxiety, panic and fear of panic.

Monoamine oxidase (MAO) . Monoamine oxidase (MAO) is an enzyme crucial to the degradation of biogenic amines (the bioactive amine neurotransmitters; includes the catecholamines (epinephrine, norepinephrine, dopamine), serotonin, and histamine.). If the enzyme activity is inhibited endogenous amines accumulate. Changes in the level of activity of this enzyme notably lowered MAO activity, have been reported in association with many psychiatric illnesses. Altered function of MAO may be directly or indirectly related to the production of panic anxiety. In the brain, MAO preferentially oxidises noradrenaline and 5HT (5-hydroxytryptamine receptors or 5-HT receptors are a group of G protein-coupled receptor found in the central and peripheral nervous systems.) After relaxation therapy, MAO elevated platelet in patients with chronic anxiety and agoraphobia would decrease. It is unlikely that increased platelet MAO levels are a primary factor in the genesis of anxiety. Most probably change in MAO activity is an adaptive response to repeated surges of catecholamine secretion (Pavarati, S., & Warrington, S. (2019). Physiology, Catecholamines. StatPearls.).

Gamma-aminobutyric acid (GABA) . Gamma-aminobutyric acid (GABA) is the most prevalent inhibitory neurotransmitter in the brain ( Judd, F., Burrows, G., & Norman, T. (1985). The Biological Basis of Anxiety An Overview . Journal of Affectrcx Disorders, 271–284). GABA levels fluctuation may be the reason for causing pathological anxiety.

Benzodiazepine receptors are widely distributed in the CNS. They are found in highest concentrations in the cerebral cortex, cerebellum and amygdala and less in the hippocampus, striatum and spinal cord (Griffin, C., Kaye, A., Bueno, F., & Kaye, A. (2013). Benzodiazepine Pharmacology and Central Nervous System–Mediated Effects. The Ochsner Journal, 214–223). There is a possible functional link between GABA and benzodiazepines. Benzodiazepines are active anxiolytic agents and enhance GABA transmission. Benzodiazepines also reduce the turnover of noradrenaline, dopamine, serotonin and acetylcholine. Thus the behavioural actions of benzodiazepines may result directly from changes in GABA transmission or GABA inhibition of other neurotransmitters.

Tribulin, a low-molecular-weight compound found in normal human urine, also binds specifically to benzodiazepine receptors and inhibits monoamine oxidase activity (Glover, V. (1998). Function of endogenous monoamine oxidase inhibitors (tribulin). MAO — The Mother of All Amine Oxidases Journal of Neural Transmission. Supplement, 307–313. doi: 10.1007/978-3-7091-6499-0_31). Preliminary studies have shown that patients with a generalised anxiety disorder and panic disorder and agoraphobia have increased urinary output of tribulin. Benzodiazepine-dependent patients withdrawn from anxiolytic medication have raised tribulin levels coincident with the occurrence of severe anxiety symptoms.

Serotonin . Experimental evidence suggests that overactivity of serotonergic pathways, particularly the ascending dorsal raphe system may contribute to the production of pathological anxiety (Hale, M. W., Shekhar, A., & Lowry, C. A. (2012). Stress-related Serotonergic Systems: Implications for Symptomatology of Anxiety and Affective Disorders. Cellular and Molecular Neurobiology, 32 (5), 695–708. doi: 10.1007/s10571-012-9827-1). Inhibitors of serotonin synthesis produce anxiolytic effects in animal tests which are reversed by injection of the serotonin precursor 5-hydroxytryptophan (Sachs, B. D., Jacobsen, J. P. R., Thomas, T. L., Siesser, W. B., Roberts, W. L., & Caron, M. G. (2013). The effects of congenital brain serotonin deficiency on responses to chronic fluoxetine. Translational Psychiatry, 3 (8). doi: 10.1038/tp.2013.65). Carbachol stimulation of the dorsal raphe produces an anxiety response which is reversed with benzodiazepines. The efficacy of antidepressants in alleviating panic may be due to their actions on serotonergic pathways (Harmer, C. J., Duman, R. S., & Cowen, P. J. (2017). How do antidepressants work? New perspectives for refining future treatment approaches. The Lancet Psychiatry, 4 (5), 409–418. doi: 10.1016/s2215-0366(17)30015-9). Long-term administration of tricyclic antidepressants leads to a reduction in the number of 5-HT, receptors, which means clomipramine and zimelidine, relatively selective 5-HT uptake blockers have been reported to be useful in the treatment of panic attacks (Celada, P., Puig, V., Bosch, M. A., Adell, A., & Artigas, F. (2004). The therapeutic role of 5-HT1A and 5-HT2A receptors in depression. Journal of Psychiatry and Neuroscience, (29), 250–265.).

Overactivity of serotonergic pathways, particularly the ascending dorsal raphe system may contribute to the production of pathological anxiety. Inhibitors of serotonin synthesis produce anxiolytic effects in animal tests which are reversed by injection of the serotonin precursor 5-hydroxytryptophan (Mecawi, A., Fonseca, F., Araujo, I. D., & Reis, L. (2013). Serotonergic Autoinhibition within Dorsal Raphe Nucleus Modulates Sodium Appetite. Neurobiology of Body Fluid Homeostasis Frontiers in Neuroscience, 161–178. doi: 10.1201/b15544-12). Carbachol stimulation of the dorsal raphe produces an anxiety response which is reversed with benzodiazepines. The efficacy of antidepressants in alleviating panic may be due to their actions on serotonergic pathways (Bystritsky, A., Khalsa, S., Cameron, M., & Schiffman, J. (2013). Current Diagnosis and Treatment of Anxiety Disorders. Pharmacy & Therapeutics, (38), 30–57.). Long-term administration of tricyclic antidepressants leads to a reduction in the number of 5-HT, receptors (Cassano, G., Rossi, N., & Pini, S. (202AD). Psychopharmacology of anxiety disorders. Dialogues Clinical Neuroscience, (4), 271–285.). Clomipramine and zimelidine, relatively selective 5-HT uptake blockers have been reported to be useful in the treatment of panic attacks.

Dopamine . The role of dopamine in the production of anxiety is unknown and has been less studied than other neurotransmitters. Animal studies have demonstrated both decreased and increased dopamine turnover in response to stress (Kleinridders, A., Cai, W., Cappellucci, L., Ghazarian, A., Collins, W. R., Vienberg, S. G., Kahn, C. R. (2015). Insulin resistance in brain alters dopamine turnover and causes behavioral disorders. Proceedings of the National Academy of Sciences, 112 (11), 3463–3468. doi: 10.1073/pnas.1500877112). By measuring dopamine and homothallic acid levels in the brain, and by blocking dopamine synthesis in the brain, it was possible to show that severe stresses such as footshock and immobilisation, which induce both emotional and motor responses, do increase dopamine metabolism (Bliss, E. L., & Ailion, J. (1971). Relationship of stress and activity to brain dopamine and homovanillic acid. Life Sciences, 10(20), 1161–1169. doi: 10.1016/0024-3205(71)90276-1). This may suggest a more specific role for dopamine in the aetiology of anxiety. No studies in patients with panic disorder have yet been conducted.

Right Frontal Lobe . Activation of the right frontal hemisphere appears to portray activation of an avoidance-withdrawal system and seems to be correlated with negative emotions. Since both negative emotions and avoidance-withdrawal behaviour identify patients with panic disorder, it is predicted that patients with panic disorder, agoraphobia and anxiety problems will display greater right than left frontal hemisphere activation (Bruder, G. E., Fong, R., Tenke, C. E., Leite, P., Towey, J. P., Stewart, J. E., Quitkin, F. M. (1997). Regional brain asymmetries in major depression with or without an anxiety disorder: A quantitative electroencephalographic study. Biological Psychiatry, 41(9), 939–948. doi: 10.1016/s0006-3223(96)00260-0). The electroencephalograph measures frontal Brain asymmetry (FBA). Increased activation in right anterior regions is associated with negative effect, whereas higher activation in the left frontal hemisphere is associated with positive effect (Davidson, R., & Tomarken, A. (1989). Laterality and emotion: an electrophysiological approach. Handbook of Neuropsychology, 3, 419–441). Frontal brain asymmetry reflects the activation of specialized systems for avoidance-withdrawal behaviour in the right frontal hemisphere.

Panic disorder should be characterized by right frontal hyperactivation, the right hemisphere predominantly controls and processes autonomic changes and interoceptive perceptions, both crucial factors in the development and maintenance of the panic disorder (Katkin, E. S., Cestaro, V. L., & Weitkunat, R. (1991). Individual Differences in Cortical Evoked Potentials as a Function of Heartbeat Detection Ability. International Journal of Neuroscience, 61(3-4), 269–276. doi: 10.3109/00207459108990745). Most patients with panic disorder are characterized by avoidance-withdrawal behaviour, which seems to be controlled by the right frontal brain.

Depression consistently is associated with FBA with decreased left frontal hemisphere activation (Henriques, J. B., & Davidson, R. J. (1990). Regional brain electrical asymmetries discriminate between previously depressed and healthy control subjects. Journal of Abnormal Psychology, 99(1), 22-31). Regarding anxiety, FBA with a right frontal hyperactivation during rest in anxious, depressed patients, while an inverse FBA was found in anxious undergraduate students (Bruder, G. E., Fong, R., Tenke, C. E., Leite, P., Towey, J. P., Stewart, J. E., Quitkin, F. M. (1997). Regional brain asymmetries in major depression with or without an anxiety disorder: A quantitative electroencephalographic study. Biological Psychiatry, 41(9), 939–948. doi: 10.1016/s0006-3223(96)00260-0)(Heller, W., Nitschke, J. B., Etienne, M. A., & Miller, G. A. (1997). Patterns of regional brain activity differentiate types of anxiety. Journal of Abnormal Psychology, 106(3), 376-385). Both studies also found relatively greater right than left parietal activation in anxious, depressed patients and anxious undergraduates during phases of arousal. These posterior asymmetries are in line with the idea that anxious arousal, including panic, should be associated with a relatively increased right parietal-temporal activation, while anxious apprehension should be associated with a relatively increased left parietal activation.

Conclusion

The occurrence of anxiety attacks in agoraphobia can depend on overactivity of the nucleus locus coeruleus, the ascending noradrenergic systems, changes in the level of activity of MAO activity, GABA levels fluctuation, decreased and increased dopamine turnover in response to stress and activation of the right frontal hemisphere.

Activation of P-receptors and Y-receptors. P-receptors and Y-receptors mediate the effects of noradrenaline in the brain, noradrenergic neurons in the brain form a neurotransmitter system when triggered. If P-receptor stimulation increases, peripheral arousal should consistently precede anxiety, panic and fear of panic.

Changes in the level of activity of this enzyme, notably lower MAO activity is an association with many psychiatric illnesses. Altered function of MAO may be directly or indirectly related to the production of panic anxiety. As after relaxation therapy, MAO elevated platelets in patients with chronic anxiety and agoraphobia would decrease.

There is also a possible functional link between GABA and benzodiazepines. Benzodiazepines reduce the turnover of noradrenaline, dopamine, serotonin and acetylcholine. Thus the behavioural actions of benzodiazepines may result directly from changes in GABA transmission or GABA inhibition of other neurotransmitters. Carbachol stimulation of the dorsal raphe produces an anxiety response which is reversed with benzodiazepines. The efficacy of antidepressants in alleviating panic may be due to their actions on serotonergic pathways. Experimental evidence suggests that overactivity of serotonergic pathways, particularly the ascending dorsal raphe system may contribute to the production of pathological anxiety.

By measuring dopamine and homothallic acid levels in the brain, and by blocking dopamine synthesis in the brain, it can be shown that severe stresses such as footshock and immobilisation which induce both emotional and motor responses do increase dopamine metabolism. This may suggest a more specific role for dopamine in the aetiology of anxiety. No studies in patients with panic disorder have yet been conducted.

Activation of the right frontal hemisphere appears to portray activation of an avoidance-withdrawal system and seems to be correlated with negative emotions. Both studies also found relatively higher right than left parietal activation in anxious patients and distressed undergraduates during stressful times of anxious arousal. These posterior asymmetries are in course with the idea that anxious arousal, including panic, should be associated with a relatively increased right parietal-temporal activation, while anxious apprehension should be associated with a relatively increased left parietal activation.

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Hale, M. W., Shekhar, A., & Lowry, C. A. (2012). Stress-related Serotonergic Systems: Implications for Symptomatology of Anxiety and Affective Disorders. Cellular and Molecular Neurobiology, 32 (5), 695–708. doi: 10.1007/s10571-012-9827-1

Sachs, B. D., Jacobsen, J. P. R., Thomas, T. L., Siesser, W. B., Roberts, W. L., & Caron, M. G. (2013). The effects of congenital brain serotonin deficiency on responses to chronic fluoxetine. Translational Psychiatry, 3 (8). doi: 10.1038/tp.2013.65

Celada, P., Puig, V., Bosch, M. A., Adell, A., & Artigas, F. (2004). The therapeutic role of 5-HT1A and 5-HT2A receptors in depression. Journal of Psychiatry and Neuroscience, (29), 250–265.

Harmer, C. J., Duman, R. S., & Cowen, P. J. (2017). How do antidepressants work? New perspectives for refining future treatment approaches. The Lancet Psychiatry, 4 (5), 409–418. doi: 10.1016/s2215-0366(17)30015-9

Mecawi, A., Fonseca, F., Araujo, I. D., & Reis, L. (2013). Serotonergic Autoinhibition within Dorsal Raphe Nucleus Modulates Sodium Appetite. Neurobiology of Body Fluid Homeostasis Frontiers in Neuroscience, 161–178. doi: 10.1201/b15544-12

Bystritsky, A., Khalsa, S., Cameron, M., & Schiffman, J. (2013). Current Diagnosis and Treatment of Anxiety Disorders. Pharmacy & Therapeutics, (38), 30–57.

Cassano, G., Rossi, N., & Pini, S. (202AD). Psychopharmacology of anxiety disorders. Dialogues Clinical Neuroscience, (4), 271–285.

Kleinridders, A., Cai, W., Cappellucci, L., Ghazarian, A., Collins, W. R., Vienberg, S. G., Kahn, C. R. (2015). Insulin resistance in brain alters dopamine turnover and causes behavioral disorders. Proceedings of the National Academy of Sciences, 112(11), 3463–3468. doi: 10.1073/pnas.1500877112

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