Reply to Lago, T.R.; Bolognani, F. Comment on “Nazarloo et al. Oxytocin, Vasopressin and Stress: A Hormetic Perspective. Curr. Issues Mol. Biol. 2025, 47, 632”

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript is a well-structured and professional Reply to the Comment by Lago and Bolognani regarding the authors’ previous review on oxytocin, vasopressin, and stress from a hormetic perspective. The response is collegial, coherent, and clearly written, and it successfully addresses the major conceptual points raised by the commentators. Importantly, the Reply provides useful clarification regarding V1a receptor (V1aR) involvement in stress habituation, the predictability of threat (fear vs. anxiety), and the potential translational relevance of V1aR antagonists, thereby strengthening the original biphasic VP–OT framework proposed by the authors.

Strengths:

• Clear structure and logical flow. The Reply is organized into numbered sections that correspond closely to the main issues raised in the Comment (HPA adaptation, threat predictability, clinical implications, receptor integration, and closing remarks), which improves readability and argumentative clarity.
• Strong conceptual integration. The authors reinforce the central framework that vasopressin (VP) and oxytocin (OT) form a dynamic regulatory system supporting catabolic activation and anabolic recovery phases within stress-response hormesis.
• Appropriate use of translational evidence. The discussion of startle paradigms (APS vs. FPS) across anxiety-related disorders, together with references to emerging evidence on V1aR antagonism (including SRX246 studies and fMRI findings), provides meaningful clinical-contextual grounding.
• Balanced clinical interpretation. The authors generally avoid overstatement and frame V1aR antagonism as a plausible modulator of excessive stress activation rather than a simplistic “anti-stress” mechanism.
• Helpful receptor-level clarification. The integration of V1bR (ACTH/HPA axis), V1aR (limbic threat appraisal/habituation/social cognition), and OTR (restorative and anti-inflammatory processes) is clear and supports the biphasic stress-cycle perspective.

Minor weaknesses:

• Some repetition in Section 3 (V1aR antagonists). The core argument is scientifically sound but could be shortened (e.g., by ~20–30%) without loss of content.
• Occasional overly strong phrasing. A few statements could be expressed more cautiously using conditional wording (“may,” “could,” “might”), as some mechanistic interpretations are speculative.
• A slightly stronger closing would be beneficial. Adding 1–2 sentences to highlight the key take-home message and the most testable implications of the model would strengthen the conclusion.

Overall, this Reply fulfills its purpose effectively: it addresses the Comment thoroughly, maintains a constructive academic tone, and adds meaningful receptor-level and translational nuance to the original hormetic stress framework. Only minor language and conciseness improvements are required to reach publication-ready quality.

Comments on the Quality of English Language

Language polishing is needed in a few places. Several sentences are slightly awkward or unclear (e.g., phrasing around “social support follow a stressor…”). A light editorial revision would improve fluency and presentation.

Author Response

Comment 1: Repetition in Section 3 (V1aR antagonists):  Some repetition in Section 3 (V1aR antagonists). The core argument is scientifically sound but could be shortened (e.g., by ~20–30%) without loss of content.             Response:  We agree with this assessment. Section 3 has been condensed by approximately 25% by removing redundant phrasing and tightening the description of V1aR antagonism. Section 3 (shortened ~25% and softened mechanistically).  We replaced our current Section 3 with this streamlined version:           “ The Comment highlights a growing body of evidence indicating that V1aR antagonists reduce anxiety-potentiated startle, modulate amygdala reactivity, and improve social functioning in both clinical and subclinical populations [13-18]. These findings are consistent with vasopressin’s established role in social vigilance and contextual threat processing.

While our original review did not aim to propose specific clinical interventions, these observations align with our conceptual model of VP-OT dynamics. V1aR antagonism may attenuate excessive or prolonged catabolic activation during uncertain threat, thereby facilitating a shift toward oxytocin-mediated recovery. Importantly, this interpretation does not imply suppression of adaptive stress responses, but rather the blunting of V1aR signaling that transitions to a maladaptive state due to excessive or sustained activation. Thus, partial modulation of V1aR signaling may constrain sustained hypervigilance while preserving sufficient VP-OT coupling to support recovery and resilience.

From a hormetic perspective, stress responses are beneficial when appropriately scaled in intensity and duration. Therapeutic effects of V1aR antagonism may therefore arise from limiting prolonged uncertainty-driven activation within limbic circuits such as the bed nucleus of the stria terminalis and extended amygdala, rather than abolishing stress responsiveness altogether. These receptor-targeted approaches may be particularly relevant for disorders characterized by heightened sensitivity to unpredictable threat. ”

Comment 2: Overly strong phrasing and speculative mechanisms:  A few statements could be expressed more cautiously using conditional wording (“may,” “could,” “might”), as some mechanistic interpretations are speculative.

Response: We appreciate this suggestion and have revised several statements throughout the manuscript to adopt more conditional language. Specifically, mechanistic interpretations regarding V1aR modulation, stress-phase transitions, and therapeutic implications have been reframed using “may,” “could,” and “likely,” to better reflect the inferential and hypothesis-generating nature of these interpretations.

Comment 3: Language clarity and awkward phrasing:  Several sentences are slightly awkward or unclear (e.g., phrasing around “social support follow a stressor…”).

Response:  We have revised the identified sentence and performed a light editorial pass throughout the manuscript to improve clarity, grammar, and flow. For example:  Original sentence: We believe social support follow a stressor (unpredictable or predictable) may one of the most important factors for hormetic processes and resilience.

Replaced with: “ We suggest that the post-stressor environment, particularly the presence of social support, may be among the most important modulators of hormetic adaptation and resilience following both predictable and unpredictable stressors. ”

Similar adjustments were made elsewhere to improve readability and precision.

We replaced the surrounding paragraph with this refined version:

“ This distinction is both clinically and mechanistically relevant. Hormetic processes can follow both predictable and unpredictable stressors, and predictability alone may not be a prerequisite for resilience. Where it may matter most is in how long VP-driven anxiety persists and how readily the system shifts into OT-mediated recovery, which may depend more on the environment after the stressor (post-stressor context) than on the stressor itself. We suggest that the post-stressor environment, particularly the presence of social support, may be among the most important modulators of hormetic adaptation and resilience following both predictable and unpredictable stressors, as the presence of others can provide feelings of “safety” to facilitate hormetic restorative processes. Unpredictable threats tend to prolong vasopressin-mediated vigilance, impair habituation, and increase allostatic load, whereas predictable stressors may more reliably permit adaptive calibration of stress responses. Thus, the emphasis on threat predictability adds important nuance to the proposed VP-OT hormetic framework.”

Comment 4: Strengthening the closing remarks:  A slightly stronger closing would be beneficial. Adding 1–2 sentences to highlight the key take-home message and the most testable implications of the model would strengthen…..

Response: We have replaced the closing remarks by following two sentences that explicitly highlight the central take-home message and outline testable implications of the proposed VP-OT hormetic framework. Replace your current Closing Remarks with:

“ We thank Lago and Bolognani for their collegial and insightful contribution. Their Comment advances the discussion of vasopressin receptor dynamics and illustrates how neuroendocrine models of stress adaptation can inform translational research. 

Taken together, these perspectives support a biphasic framework in which vasopressin and oxytocin coordinate mobilization and recovery across stress phases, with V1aR playing a potential role in calibrating responses to uncertainty and social context. This model yields testable predictions: specifically, that modulation of V1aR signaling should differentially affect habituation, threat predictability, and the transition from activation to recovery. Clarifying these mechanisms may help guide the development of targeted interventions for stress-related disorders characterized by dysregulated uncertainty processing. ”

Comment 5: Overall comment on English quality:  Language polishing is needed in a few places.

Response: We thank the reviewer for noting that only minor language and conciseness improvements were required. We have implemented these revisions throughout the manuscript and believe the current version better reflects the clarity and tone appropriate for publication.

Once again, we thank Reviewer for their thoughtful and constructive feedback, which has strengthened both the clarity and precision of this Reply.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

We thank the authors for their insightful and constructive Comment, which thoughtfully expands the discussion on vasopressin receptor subtypes and stress habituation. We particularly appreciate the emphasis on threat predictability and V1aR-mediated mechanisms, which adds important nuance and translational relevance to the proposed hormesis framework.

Author Response

Comments and Suggestions for Authors

We thank the authors for their insightful and constructive Comment, which thoughtfully expands the discussion on vasopressin receptor subtypes and stress habituation. We particularly appreciate the emphasis on threat predictability and V1aR-mediated mechanisms, which adds important nuance and translational relevance to the proposed hormesis framework.

Response:  We sincerely thank Reviewer for their positive and supportive evaluation of our Reply manuscript. We appreciate the reviewer’s recognition of the conceptual value of emphasizing threat predictability and V1aR-mediated mechanisms, and for noting the translational relevance of these points within the proposed hormesis framework.