Anxiety is one of the most comorbid conditions with major depressive disorder (MDD). Depression-associated anxiety often stems from the dysfunctional hypothalamic-pituitary-adrenal (HPA) axis and its altered regulation by the amygdala. Furthermore, MDD is associated with altered glutamatergic processing leading to anxiety and impaired regulation of the HPA axis. Recent studies have demonstrated that N-acetyl cysteine (NAC), a pleiotropic drug, exerts antidepressant-like effect by modulation of hippocampal functions, periterminal release of glutamate, and/or redox systems. However, the effects of NAC on depression-associated anxiety, HPA axis hyperactivity, and amygdalar dysfunctions are relatively unknown.
Accordingly, we evaluated the effect of NAC on neonatal clomipramine (CLI)-induced adulthood anxiety and accompanying changes in plasma corticosterone levels, amygdalar volumes, neuronal/glial densities, levels of monoamines, and their metabolites in the amygdalar complex.
We found that chronic treatment with NAC reverses CLI-induced anhedonia and enhanced anxiety. Interestingly, attenuation of CLI-associated anxiety in NAC-treated rats were accompanied by a reversal of adrenal and spleen hypertrophy, and normalization of enhanced plasma corticosterone levels, indicating improved HPA axis functioning. Furthermore, NAC treatment was sufficient to reverse volumetric hypertrophy of basolateral amygdala (BLA), and altered noradrenaline (NA) metabolism in the amygdalar complex. The effects of NAC in the reversal of CLI-induced impairments were similar to that of fluoxetine (FLX).
We suggest that beneficial effects of NAC on antidepressive- and antianxiety-like behaviors are at least in part mediated via restoration of amygdalar and HPA axis functioning. Our results support the hypothesis that NAC might be evolved as a therapeutic strategy for reversal of amygdalar dysfunction in depression.
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Basolateral nucleus of amygdala
Central nucleus of amygdala
Flinders sensitive line
- HPA axis:
Lateral nucleus of amygdala
Major depressive disorder
Novelty-suppressed feeding test
Sucrose preference test
Vogel’s conflict test
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Suwarna Chakraborty was supported by a Senior Research Fellowship from Indian Council of Medical Research (ICMR; 3/1/2/74/Neuro/2018-NCD-I), New Delhi, India. Sunil Jamuna Tripathi was supported by Research Associate Fellowship (45/04/2018-ANA-BMS) from the ICMR, New Delhi, India. We received financial support from the Department of Biotechnology (DBT), Government of India, New Delhi, and the National Institute of Mental Health and Neuro Sciences (NIMHANS), Bengaluru, India. Funding agencies have no role in study design, collection, analysis, and interpretation of data and writing the reports.
All experiments comply with the guidelines of the Committee for the Purpose of Control and Supervision of Experiments on Animals, Government of India.
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Chakraborty, S., Tripathi, S.J., Raju, T.R. et al. Mechanisms underlying remediation of depression-associated anxiety by chronic N-acetyl cysteine treatment. Psychopharmacology 237, 2967–2981 (2020). https://doi.org/10.1007/s00213-020-05585-x
- N-acetyl cysteine (NAC)
- Hypothalamic-pituitary-adrenal (HPA) axis dysfunctions
- Basolateral amygdalar hypertrophy