What Is the Relationship Between Panic Attacks and the Amygdala?

Panic disorder is a feature of panicattacks that repetitively manifests significant autonomic symptoms such as palpitations, sweating, and tremors, accompanied by a strong sense of dying or loss of control and fear of unfortunate consequences Acute Anxiety Disorder.

Panic disorder

Panic disorder is short for panic disorder.

Panic disorder, also called acute anxiety attack, is a manifestation of anxiety.

The typical panic disorder is intermittent and may not show any special symptoms when the patient is in a break. However, the patient's attack was not limited to any situation, and there were no special triggers. So the onset of panic disorder is also unpredictable. The onset of panic disorder usually begins with sudden fear, with obvious cardiovascular and respiratory symptoms, which can be accompanied by tremors, dizziness and other symptoms.

Strong fear and fear can make the patient's heart beat faster, and even palpitations, chest discomfort, fast and shallow breathing, cold or fever on the surface, urgency, tremor, nausea, dizziness, etc. Most patients are paralyzed on the sofa, and some patients exclaim for help and run to someone's room. This symptom lasts for several minutes or half an hour, and it is rare to occur for a long time. After the attack, the mood gradually eases. But after the attack, you can still feel nervous, top-heavy, bedridden, and weak.

In the early stages of a patient's illness, the patient may think that he is about to die, may be worried about a heart attack or stroke, or he may be crazy. Even if the patient has had phobias several times and clearly knows that he will be safe after the attacks, but also because of this strong discomfort, there is a fear of dying. In fact, patients with severe panic attacks sometimes have only mild attacks, or milder or shorter duration attacks.

Some patients often experience a rapid increase in heart rate while resting, and symptoms of hyperventilation are common. Even some patients may develop hypocapnia before the onset of phobia, which indicates that The patient may have chronic hyperventilation. Excessive ventilation in some patients can be a pre-existing manifestation of a panic attack, followed by a complete panic attack. But most patients have panic disorder before hyperventilation. ^[1]

This disease is one of the most active fields in modern research, and can be summarized in the following aspects:

1,

The disease often has no obvious inducement. Sudden onset of a variety of autonomic symptoms, especially palpitations, tightness of breath, dizziness, sweating, etc. are the most prominent; the symptoms develop rapidly to a peak in a short period of time with strong fear; the duration is short, and it will relieve itself intermittently. In addition to the expected anxiety and fear of recurrence, there may be no symptoms of discomfort. Intervals often repeated may be short or long. Frequent attacks and expected anxiety easily misdiagnosed as widespread anxiety disorder

The purpose is to control early

Introduction to Molecular Genetics

Panic disorder is a type of recurrent severe anxiety. There are many hypotheses explaining its etiology mechanism. The hypotheses of neurobiochemistry include the classical neurotransmitter GABA, 5-HT, DA and Ach and other abnormal functional hypotheses, and the neuropeptide CCK and DA imbalance hypothesis. Genetic factors may also play a role in the occurrence of panic disorders, because in the investigation of the ethnic family of the stove, it was found that the incidence of this disease among close relatives of patients with anxiety disorders is 15%, which is three times that of ordinary residents [1 ]; The survey of twins found that the monosexual twins had the same disease rate of 50% and the anxiety quality was 65%, while the twins twins had the same disease rate only 4% and the anxiety quality was only 13% [1]; these Studies have shown that panic disorder has a clear genetic predisposition, and its cause is at least partially genetic.

With the development of molecular genetics technology, many studies have been conducted on the etiology of panic disorder at the genetic level.

GABAA receptor gene

GABA receptors are divided into two subtypes, GABAA and GABAB. The GABAA subtype receptor forms a complex with the chloride value and stability receptors. The complex is a tetramer composed of , , , and subunits, and is gated by the chloride value. The subunit has a stable binding point; the subunit has a GABA binding point; the subunit cannot bind to benzodiazepines or GABA, but it is when the oligomeric receptor and benzodiazepine have high affinity Necessary; there is no binding site on the delta subunit and its function is unclear. The peptide chains of the , , , and subunits all cross the cell membrane 4 times [2, 3].

The GABAA receptor-chlorine channel-stable receptor complex plays an important role in anxiety resistance; GABAA receptors are coupled to chloride channels and gate the chloride channels. GABAA receptor agonists (such as GABA) can activate GABAA receptors Body, open the chloride channel, increase the extracellular CI-influx and increase the chloride conductance, cause hyperpolarization of the post-synaptic membrane, produce an inhibitory effect on neurons, and thus produce an anxiolytic effect; benzodiazepine anxiolytic drugs ( (Such as diazepam, etc.) acting on diazepam receptors can up-regulate GABAA receptors, which in turn increases the affinity of GABAA receptors for GABA and increases the binding to GABA, thereby increasing the frequency of GABAA receptors opening chloride channels and enhancing GABA. The post-synaptic inhibitory effect of anthrax shows an anxiolytic effect; barbiturates directly act on the chloride channel, which prolongs the opening time of the chloride channel, and also has an anxiolytic effect. In short, GABAA receptor agonists, stability receptor agonists, and barbiturates have anxiolytic effects because they act on GABAA receptors, stability receptors, and chloride channels, respectively. In contrast, diazepam binding inhibitor (DBI) is an endogenous stable binding inhibitor, which can down-regulate GABAA receptors, reduce the binding of GABAA to ligands, and cause anxiety; -carbolin and stable stabilizers Body binding, weakening the effect of GABA, can also cause anxiety; Azadirachtin can close chlorine channels, antagonize the effect of GABA, can cause convulsions. Therefore, the GABAA receptor-chlorine channel-stable receptor complex plays a very important role in the occurrence and treatment of anxiety [2].

The subunits of the GABAA receptor-chlorine channel-stable receptor complex have great polymorphisms. There are 13 variants of the human GAGAA receptor complex subunits, of which there are 7 variants of the subunit (1 7) ), There are 3 variants of subunit (1 3), 2 variants of subunit (1 2), and no variants have been found in the subunit [3]. There is a hypothesis that the susceptibility to panic disorder and the responsiveness to drug treatment are related to the different GAGAA receptor complex subunit variants, and because each subunit variant is encoded by a unique gene and its corresponding mRNA Therefore, the hypothesis further suggests that the susceptibility to panic disorder and the responsiveness to drug treatment are related to GAGAA receptor complex gene polymorphisms and mRNA levels. Tanay (1996) [4] found that chronic administration of anti-frightening drugs imipramine, phenelzine, and metazolam to rats can change the mRNA levels of 1, 2, and 2 subunits in the brainstem GABAA receptor complex. In addition, the expression of subunits of specific GABAA receptor complexes is changed, and the changes in the expression of these genes are different from those caused by non-anti-panic anxiolytic drugs (buspirone), which strongly supports the above hypothesis. . Crowe (1997) [5] further tested the genes (1 5, 1, 3, 2) encoding the 8 subunit variants of the GABAA receptor complex. In 104 strictly defined panic disorder patients, 134 generalized Patients with panic disorder or sub-syndrome panic disorder were linked between the above genes, but the results showed that there was a linkage, which does not support the above hypothesis. It is believed that panic disorder is not caused by any of the eight GABAA receptor complex subunit genes tested. Gene mutation.

5-HT1D receptor gene

The anti-anxiety effect of the drug also involves other transmitter systems, such as the NE system, especially the central blue spot, which is the expected dangerous arousal center; the DA system may be related to emotional behavior and anxiety performance; the 5-HT system is particularly in the dorsal nucleus , Inhibit the adaptive behavior of anxiety. The above-mentioned transmitter systems work together at different levels in the brain [6].

The increase in plasma corticosteroids can accelerate the T-HT renewal rate and excessive 5-HT functional activity, which may be related to the occurrence of anxiety [7]; 5-HT can also promote the secretion of ACTH, thereby regulating and Affects anxiety and emotional response [1]. Anxiolytics benzodiazepines can reduce 5-HT activity, inhibit the renewal rate of 5-HT in the brain, and slow down the rate of 5-HT consumption, which may be related to its anxiolytic effect [1-7]; anxiolytics Buspirone can reduce the vitality of 5-HT energy neurons, and its anxiolytic effect is also related to this [8]. In short, the 5-HT system is closely related to the occurrence and treatment of anxiety disorders, and the 5-HT receptor gene has therefore become one of the candidate genes for panic disorder.

5-HT is divided into 14 training subtypes, in which 5-HT1D receptor can be further subdivided into 5-HT1D receptor gene at the 1080th base of C and T can be converted to form a 080 polymorphism [9 ]; The 276th base of the gene encoding the 5HT1D receptor can undergo A and C conversion to form the A276G polymorphism [9]; these two polymorphisms are static polymorphisms and do not directly change the encoded amino acid structure However, they may indirectly affect the expression level of 5-HT1D receptors, which in turn affects the susceptibility to panic disorder. Therefore, Ohara (1996) [9] studied a group of panic disorder patients and normal controls, and sequenced their 5-HT1D and receptor genes, but found that the above two polymorphisms were not significant between the two groups. The differences do not support the argument that 5-HT1D receptor genes affect panic disorder susceptibility.

D4 receptor gene

Dopamine D4 receptors are mainly distributed in the frontal cortex. Because the genes encoding D4 receptors are highly polymorphic, these polymorphisms may affect the function of D4 receptors, making this gene one of the candidate genes for evaluating panic disorder. . Ten polymorphisms were found in the D4 receptor gene, including three static polymorphisms and seven dynamic polymorphisms. The first 31 base C on the 11th codon upstream of the start codon of the D4 receptor gene can be converted to T, thereby forming a polymorphism C-31T, the allele A1 (that is, the first 31 base is C) The frequency is 0.93 and the frequency of A2 is 0.07 [10]; the 31st base G in the 11th codon downstream of the start codon of the D4 receptor gene can be converted to C, so that the encoded 11th amino acid Gly on the D4 receptor Substitution with the amino acid Arg to form the polymorphism Gly11Arg, the frequency of the allele A1 (that is, the 31st base G) is 0.99, and the frequency of A2 is 0.11 [10]; the D4 receptor gene is 21bp above the 36th to 42th codons The long base sequence can be deleted, the polymorphic allele A1 has no 21bp deletion, and the allele A1 has 21bp deletion [10]. Cichon (1995) [10] studied 148 normal Germans, 256 schizophrenics, 99 patients with emotional disorders and a group of panic disorders, and found that the polymorphisms C-31T, Gly11Arg of all patients were not significantly different from those of normal people The difference is that no 21bp deletion was found in patients with schizophrenia, affective disorders and normal people, but this rare mutation was found in one panic disorder patient, which may mean that the deletion mutation is involved in the occurrence of panic disorder. But it can also be an opportunistic false positive result.

CHRNA4 gene

The central neurotransmitter NE responds to the hypothalamic-pituitary-adrenal response induced by stress, and acetylcholine (Ach) can promote ACTH secretion, which can then regulate and affect the emotional response to anxiety [1]; another study found that anxiety Cholinesterase activity is significantly lower in patients with dysfunction, which suggests that anxiety is related to lower cholinesterase activity [1]. In short, the Ach energy system is closely related to the occurrence of anxiety.

Ach receptors are divided into N and M subtypes. N-type Ach receptors (nicotinic acetylcholine receptor (CHRN)) are widely distributed in the central nervous system, and are found in the hippocampus, amygdala, and striatum of the cerebral cortex and limbic system. distributed. The CHRN receptor is composed of four subgenes, and the subunits are named , , , and . Each subunit is a transmembrane glycoprotein with a molecular weight of about 55kD. They form the CHRN receptor according to the ratio of 2. The total molecular weight is about 275kD; the five subunits are arranged in a pentagonal shape, and together form the wall of the ion channel of the CHRN receptor. They are generally asymmetric dumbbell-shaped. On the glutamic acid residues at positions 192 and 193 of the subunit, they have the ability to recognize and bind Ach; when the Ach ion (mainly Na +) enters the cell through the ion channel, the post-synaptic membrane undergoes a potential change, Produce physiological effects [3].

The subunits that make up the CHRN receptor have multiple variants [3], of which the alpha subunit has 6 variants (2 to 7) and the beta subunit has 3 variants (2 to 4), and these variants can be changed For the function of the CHRN receptor, each variant is uniquely encoded, in which the gene encoding the 4 subunit (CHRNA4 gene) is located at the 20q13.3 locus [11]. Previous studies have found that anxiety disorder is associated with low-voltage EEG (LVEEG), and about 1/3 of VLEEG cases are linked to the locus 20q13.3 [1], so there is a hypothesis that the susceptibility to panic disorder may also be related to the CHRNA4 receptor. In order to explore the relationship between the two, Steinlein (1997) [11] tested the allele frequencies of three different CHRA4 gene polymorphisms in a group of panic disorder patients and normal people, and found no significant difference. The study does not support the association between the CHRNA4 gene and panic disorder.

CCKB gene

Cholecystokinin (CCK) is a neuropeptide, which is mainly synthesized in cells. Its precursor is composed of 130 amino acids. After translation, it can produce active peptide fragments such as CCK39, CCK33, CCK8, and CCK4 [ 12]. Low doses of CCK4 can induce panic attacks in patients with panic disorder [13], so CCK may be involved in the occurrence of panic disorder.

CCK receptors are divided into two subtypes, namely CCKA and CCKB receptors. CCKA receptors are distributed in the periphery, while CCKB receptors are distributed in the cerebral cortex and striatum. [12] Therefore, the genes encoding CCKB receptors are panic disorders. Candidate genes. Kato (1996) [13] screened mutations in the CCKB gene of probands in 22 panic disorder families using the SSCP method and found two polymorphisms: introns between exons 4 and 5 in 10 patients A polymorphism was found on 2491C A, and a missense mutation (1550G A, Val125 Ile) was found on the extracellular loop of exon 2 of a proband; in 34 other unrelated panic disorders This missense mutation was detected in patients and 112 normal controls, and it was found in 8.8% (3/34) of patients and 4.4% (5/112) of normal people. However, the differences between these mutations in patients and normal people were not significant, so it is believed that these mutations have no pathophysiological significance in panic disorders.

Conclusion

Many molecular genetic studies on panic disorder have been carried out, mainly focusing on the relationship between panic disorder and GABAA, 5-HT1D, D4, CHRNA4 receptor genes and CCKB genes. Except that a 21 bp deletion mutation in the D4 receptor gene may be involved in the occurrence of panic disorder in these studies, the rest of the studies were negative. However, this does not make us lose confidence in finding susceptible genes for panic disorder, because there are still inadequacies in previous studies: The investigation of the subtypes and polymorphic types of candidate genes is incomplete: for example, the GABAA receptor Of the 13 subunit genes, only 8 have been investigated, and 5 have not yet been investigated. Of the 14 subtypes of 5-HT receptor genes, only 1 has been investigated, and 13 have not been investigated. 10 types of D4 receptor genes have been investigated. Only 3 polymorphisms were investigated, and 7 were not investigated; only 1 of the 11 subunit genes of CHRN receptor was investigated, and 10 were not investigated. Small sample size: Panic disorder may be a genetic heterogeneous disease that is caused by the superposition of the small genetic effects of multiple genes. Therefore, to investigate the relationship between each gene and panic disorder, a large sample is often required. Only in the previous study, the sample size was not large, it is difficult to rule out the possibility of false negative results, and the only study that found positive results may also be because the sample size is too small, it is difficult to rule out false positive results caused by chance. Therefore, the molecular genetics research on panic disorder is equivalent to further expanding the sample size and conducting in-depth and comprehensive research.