Mechanisms underlying remediation of depression-associated anxiety by chronic N-acetyl cysteine treatment

Abstract

Rationale

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.

Objectives

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.

Results

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).

Conclusions

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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Data accessibility

This study includes original data. Authors have full access to all data and take responsibility for the integrity of the data and the accuracy of the data analysis. The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

5-HIAA:

5-Hydroxyindoleacetic acid

5-HT:

5-Hydroxytryptamine (serotonin)

5-HTT:

Serotonin transporter

BLA:

Basolateral nucleus of amygdala

CeA:

Central nucleus of amygdala

CLI:

Clomipramine

DA:

Dopamine

DOPAC:

3,4-Dihydroxyphenylacetic acid

FLX:

Fluoxetine

FSL:

Flinders sensitive line

HPA axis:

Hypothalamic-pituitary-adrenal axis

HVA:

Homovanillic acid

LA:

Lateral nucleus of amygdala

LC:

Locus coeruleus

MDD:

Major depressive disorder

MHPG:

3-Methoxy-4-hydroxyphenylglycol

NA:

Noradrenaline

NAC:

N-acetyl cysteine

NSFT:

Novelty-suppressed feeding test

PFC:

Prefrontal cortex

PVN:

Paraventricular nucleus

SPT:

Sucrose preference test

VCT:

Vogel’s conflict test

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Funding

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.

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SC, TRR, and BSSR conceptualized and designed the experiments; SC and SJT performed the experiments and analyzed the data; SC, SJT, TRR, and BSSR wrote the manuscript.

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Correspondence to B.S. Shankaranarayana Rao.

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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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The authors declare that they have no conflict of interest.

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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 (2020). https://doi.org/10.1007/s00213-020-05585-x

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Keywords

  • N-acetyl cysteine (NAC)
  • Anxiety
  • Depression
  • Hypothalamic-pituitary-adrenal (HPA) axis dysfunctions
  • Basolateral amygdalar hypertrophy