The role of acid-sensitive ion channels in panic disorder: a systematic review of animal studies and meta-analysis of human studies

Abstract

Acid-sensitive ion channels, such as amiloride-sensitive cation channel (ACCN), transient receptor potential vanilloid-1 (TRPV1), and T-cell death-associated gene 8 (TDAG8) are highly related to the expression of fear and are expressed in several regions of the brain. These molecules can detect acidosis and maintain brain homeostasis. An important role of pH homeostasis has been suggested in the physiology of panic disorder (PD), with acidosis as an interoceptive trigger for panic attacks. To examine the effect of acid-sensitive channels on PD symptoms, we conducted a systematic review and meta-analysis of these chemosensors in rodents and humans. Following PRISMA guidelines, we systematically searched the Web of Science, Medline/Pubmed, Scopus, Science Direct, and SciELO databases. The review included original research in PD patients and animal models of PD that investigated acid-sensitive channels and PD symptoms. Studies without a control group, studies involving patients with a comorbid psychiatric diagnosis, and in vitro studies were excluded. Eleven articles met the inclusion criteria for the systematic review. The majority of the studies showed an association between panic symptoms and acid-sensitive channels. PD patients appear to display polymorphisms in the ACCN gene and elevated levels of TDAG8 mRNA. The results showed a decrease in panic-like symptoms after acid channel blockade in animal models. Despite the relatively limited data on this topic in the literature, our review identified evidence linking acid-sensitive channels to PD in humans and preclinical models. Future research should explore possible underlying mechanisms of this association, attempt to replicate the existing findings in larger populations, and develop new therapeutic strategies based on these biological features.

Understanding rat emotional responses to CO2

“…Several behavioral studies indicate that carbon dioxide (CO 2 ) elicits negative responses and is aversive to rats [1][2][3][4][5][6][7][8] although not all studies agree 9,10 . Rat exposure to CO 2 is a well-accepted translational model for the understanding of fear, anxiety, dyspnea (feeling of breathlessness), and panic in humans 11 .…”

Panic disorder respiratory subtype: psychopathology and challenge tests – an update

“…2,38,39,77 Alterations in the neural circuitry that involves the brainstem and fear network and impairments in the pH chemosensory system may be the main mechanisms involved in the respiratory abnormalities observed in PD patients. [78][79][80][81] Individuals diagnosed with PD generally have a high perception of danger or threat. 82 To assess a situation as threatening and mount an anxiety-like response, an individual must first detect environmental stimuli through sensory systems and then identify them as aversive or potentially dangerous.…”

“… 2 , 38 , 39 , 77 Alterations in the neural circuitry that involves the brainstem and fear network and impairments in the pH chemosensory system may be the main mechanisms involved in the respiratory abnormalities observed in PD patients. 78 - 81 …”

Animal Models for Panic Disorder

“…Using dynamic T1ρ relaxation imaging, which corresponds to an acidosis in the regions assessed, Magnotta et al (2014) found a greater activity-evoked T1ρ response in the visual cortex of PD patients. From a molecular point of view, acidosis-related responses have been implicated as risk factors for PD (Quagliato, Freire, & Nardi, 2018). The rs9915774 SNP of the ACCN1 gene (the human homologue of acid-sensing ion channel 2) has been found to be associated with PD in genome-wide association analysis (Gregersen et al, 2012).…”

“…The rs9915774 SNP of the ACCN1 gene (the human homologue of acid-sensing ion channel 2) has been found to be associated with PD in genome-wide association analysis (Gregersen et al, 2012). In a metanalysis of four studies on the relationship between rs685012 SNP of the ACCN2 gene, which codes the neuronal amiloride-sensitive cation channel 2, Quagliato et al (2018) found that the 4/21 Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 22 April 2019 doi:10.20944/preprints201808.0494.v2…”