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Central norepinephrine transmission is required for stress-induced repetitive behavior in two rodent models of obsessive-compulsive disorder

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Abstract

Rationale

Obsessive-compulsive disorder (OCD) is characterized by repetitive behaviors exacerbated by stress. Many OCD patients do not respond to available pharmacotherapies, but neurosurgical ablation of the anterior cingulate cortex (ACC) can provide symptomatic relief. Although the ACC receives noradrenergic innervation and expresses adrenergic receptors (ARs), the involvement of norepinephrine (NE) in OCD has not been investigated.

Objective

To determine the effects of genetic or pharmacological disruption of NE neurotransmission on marble burying (MB) and nestlet shredding (NS), two animal models of OCD.

Methods

We assessed NE-deficient (Dbh −/−) mice and NE-competent (Dbh +/−) controls in MB and NS tasks. We also measured the effects of anti-adrenergic drugs on NS and MB in control mice and the effects of pharmacological restoration of central NE in Dbh −/− mice. Finally, we compared c-fos induction in the locus coeruleus (LC) and ACC of Dbh −/− and control mice following both tasks.

Results

Dbh −/− mice virtually lacked MB and NS behaviors seen in control mice but did not differ in the elevated zero maze (EZM) model of general anxiety-like behavior. Pharmacological restoration of central NE synthesis in Dbh −/− mice completely rescued NS behavior, while NS and MB were suppressed in control mice by anti-adrenergic drugs. Expression of c-fos in the ACC was attenuated in Dbh −/− mice after MB and NS.

Conclusion

These findings support a role for NE transmission to the ACC in the expression of stress-induced compulsive behaviors and suggest further evaluation of anti-adrenergic drugs for OCD is warranted.

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Acknowledgments

We thank Lundbeck for providing the DOPS, Synosia Therapeutics for providing the nepicastat, and C. Strauss for helpful editing of the manuscript.

Funding

This work was supported by the National Institutes of Health (AG061175, NS102306, and DA038453 to DW; GM8602-22 to DL; MH116622 to RPT).

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Authors and Affiliations

  1. Department of Human Genetics, Emory University School of Medicine, 615 Michael St., Whitehead 301, Atlanta, GA, 30322, USA

    Daniel Lustberg, Alexa F. Iannitelli, Rachel P. Tillage, L. Cameron Liles & David Weinshenker

  2. University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Molly Pruitt

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  1. Daniel Lustberg
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Correspondence to David Weinshenker.

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DW is co-inventor on a patent concerning the use of selective dopamine β-hydroxylase inhibitors for the treatment of cocaine dependence (US-2010-0105748-A1; “Methods and Compositions for Treatment of Drug Addiction”). The other authors declare no conflicts of interest.

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Lustberg, D., Iannitelli, A.F., Tillage, R.P. et al. Central norepinephrine transmission is required for stress-induced repetitive behavior in two rodent models of obsessive-compulsive disorder. Psychopharmacology 237, 1973–1987 (2020). https://doi.org/10.1007/s00213-020-05512-0

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