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Relationship: 3645

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

A1AR Antagonism leads to Increased cortisol

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

A1AR Antagonism

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Increased cortisol

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Binding of Alpha 1-Adrenergics to Antagonists Leading to Depression	adjacent	Moderate	Moderate	LUANA GOMES (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
mouse	Mus musculus	High	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Unspecific	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
All life stages	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Alpha-1-adrenergic receptors are involved in the regulation of corticotropin-releasing factor (CRF) secretion in the hypothalamic paraventricular nucleus (PVN). Activation of these receptors by norepinephrine stimulates CRF gene expression and release, thereby promoting HPA axis activation (Itoi et al., 1994). In contrast, pharmacological blockade of α1 receptors with antagonists such as prazosin inhibits this pathway, resulting in a reduction of stress-induced CRF release (Kiss & Aguilera, 1992) and attenuating the increase in CRF mRNA observed during repeated or prolonged stimulation (Kiss & Aguilera, 2000). Thus, α1-adrenergic receptor antagonism decreases noradrenergic drive on CRF neurons, leading to reduced production and secretion of this neuropeptide, providing biological plausibility for the relationship between α1 antagonism and CRF reduction.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

The evidence supporting this KER was collected through systematic searches in PubMed and Web of Science using the keywords “α1-adrenergic receptor,” “antagonist,” “CRF,” and “corticotropin-releasing factor,” combined with the Boolean operators AND/OR. Both in vivo and in vitro experimental studies in rodents were included, along with relevant review articles describing CRF regulatory mechanisms. Studies lacking direct measurements of CRF or appropriate experimental controls were excluded. The selected studies were evaluated for relevance, methodological quality, and consistency of findings to provide empirical support for the causal relationship between α1-adrenergic receptor antagonism and reduced CRF.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

The biological plausibility supporting the relationship between α1 receptor antagonism and CRF reduction is based on evidence showing that pharmacological blockade of these receptors with antagonists, such as prazosin, inhibits the excitatory noradrenergic pathway acting on CRF neurons. Therefore, α1 receptor antagonism leads to decreased CRF production and secretion.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

In a study with conscious rats, norepinephrine (NE) was bilaterally microinjected into the hypothalamic paraventricular nucleus (PVH) to assess its effects on CRF expression and release. Administration of NE (5–50 nmol/side) produced a dose-dependent increase in plasma ACTH levels, peaking at 30 minutes and returning to baseline after 90 minutes. This stimulatory effect of NE was completely blocked by intracerebroventricular pretreatment with prazosin, an α1-adrenergic receptor antagonist, while propranolol had no significant effect. These findings indicate that NE activates the hypothalamic–pituitary–adrenal axis by stimulating CRF gene expression and release in the PVH, and that this response is specifically mediated by α1-adrenergic receptors (ITOI et al., 1994).
In experiments using electrophysiological recordings and Ca²⁺ imaging in corticotropin-releasing hormone (CRH)-producing neurons, exposure to norepinephrine significantly increased neuronal excitability. Much of this activation was mediated by α1-adrenergic receptors, demonstrating that stimulation of these receptors can enhance CRH release (GOUWS et al., 2022).
Blockade of α1-adrenergic receptors reduces the activity of CRF neurons and CRF release, attenuating stress-related behavioral responses. In contrast, activation of these receptors increases noradrenergic excitability and elevates CRF expression and secretion, enhancing both behavioral and physiological responses to stress. (Gresack Et Al; 2013).
Experimental studies indicate that α1-adrenergic receptors are critical for the regulation of CRF in the prefrontal cortex. Blockade of these receptors with prazosin completely abolished the anxiolytic effects of CRF, suggesting that α1 activation is necessary for maintaining CRF activity in this region. These findings, supported by previous studies showing that prazosin also reduces the anxiolytic effects of other drugs and increases anxiety-like behaviors in PTSD models, indicate that inhibition of α1 receptors can lead to decreased CRF expression and release in the prefrontal cortex. The high density of α1 receptors in layer V pyramidal neurons and the dense noradrenergic innervation further support the plausibility of a functional interaction between CRF and noradrenaline, mediated by CRFR1 and α1 receptors, which explains these effects. (CECCHI Et Al; 2002).
The α-adrenergic agonist phenylephrine rapidly and robustly increases ACTH levels in ovariectomized rats, with a peak at 5 minutes and elevated levels lasting at least 2 hours. This effect is almost completely blocked by the α1-adrenergic antagonist prazosin, indicating it is mediated specifically by α1 receptors. Dexamethasone pretreatment also prevents the ACTH increase, confirming involvement of the anterior pituitary. Levels of α-MSH are minimally affected. These results indicate that phenylephrine directly stimulates ACTH secretion via α1 receptors on pituitary corticotrophs, supporting the role of epinephrine and norepinephrine as physiological CRF-releasing factors. (Proulx-Ferland, Breault & Côté, 1982)

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

References

List of the literature that was cited for this KER description. More help

Itoi K, Suda T, Tozawa F, et al. 1994. Microinjeção de norepinefrina no núcleo paraventricular do hipotálamo estimula a expressão gênica do fator liberador de corticotropina em ratos conscientes. Endocrinologia 135:2177–2182.
Kiss A, Aguilera G. 1992. Participação dos receptores adrenérgicos α-1 na secreção do hormônio liberador de corticotropina hipotalâmico durante o estresse. Neuroendocrinologia 56:153–160.
Kiss A, Aguilera G. 2000. Papel dos receptores α-1-adrenérgicos na regulação do mRNA do hormônio liberador de corticotropina no núcleo paraventricular durante o estresse. Neurobiologia Celular e Molecular 20:683–694.
Aguilera G. 2011. Responsividade do eixo HPA ao estresse: implicações para o envelhecimento saudável. Gerontologia Experimental 46:90–95.
Itoi, K., Suda, T., Tozawa, F., Dobashi, I., Ohmori, N., Sakai, Y., Abe, K., & Demura, H. (1994). Microinjeção de norepinefrina no núcleo paraventricular do hipotálamo estimula a expressão gênica do fator liberador de corticotropina em ratos conscientes. Endocrinologia, 135 (5), 2177–2182. https://doi.org/10.1210/endo.135.5.7956940.
Gouws, JM, Sherrington, A., Zheng, S., Kim, JS, & Iremonger, KJ (2022). Regulação da atividade da rede neuronal do hormônio liberador de corticotropina por sinais de estresse noradrenérgico. The Journal of Physiology, 600 (19), 4347–4359. https://doi.org/10.1113/jp283328 .
Gresack, J. E.; Risbrough, V. B. Corticotropin-releasing factor and noradrenergic signalling exert reciprocal control over startle reactivity. The International Journal of Neuropsychopharmacology, 14(9), 1179–1194, 2010. Oxford University Press. https://doi.org/10.1017/s1461145710001409
Cecchi, M.; Khoshbouei, H.; Morilak, D. A. Modulatory effects of norepinephrine, acting on alpha1 receptors in the central nucleus of the amygdala, on behavioral and neuroendocrine responses to acute immobilization stress. Neuropharmacology, 43(7), 1139–1147, 2002. Elsevier. https://doi.org/10.1016/s0028-3908(02)00292-7
Proulx-Ferland, L.; Breault, M.; Côté, J. Alpha1-adrenergic stimulation of ACTH secretion in vivo in the rat. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 6(4-6), 433–438, 1982. Elsevier. https://doi.org/10.1016/s0278-5846(82)80123-1