Additive interaction between scopolamine and nitric oxide agents on immobility in the forced swim test but not exploratory activity in the hole-board

  • Mohammad Nasehi
  • Mohammad-Hossein Mohammadi-Mahdiabadi-Hasani
  • Mohaddeseh Ebrahimi-GhiriEmail author
  • Mohammad-Reza Zarrindast
Original Investigation



The muscarinic cholinergic antagonist scopolamine has received an attention due to its unique antidepressant effects. However, the considerable adverse effects on nervous system limit the use of scopolamine as a psychiatric drug.


In order to overcome the limitations and increase the therapeutic effects of scopolamine, we decided to examine the effects of joint administration of sub-effective dose of scopolamine and the sub-effective dose of a nitric oxide (NO) precursor l-Arginine or a non-selective nitric oxide synthase (NOS) inhibitor l-NAME on depression- and anxiety-related behaviors in male NMRI mice.


To this aim, animal behavior was assessed in the forced swim test (FST) and hole-board apparatus.


Scopolamine (0.05 mg/kg) significantly decreased immobility time in the FST, suggesting an antidepressant-like effect. Moreover, l-Arginine (50 mg/kg) produced an antidepressant-like response in the FST and decreased head-dip counts in the hole-board apparatus, indicating an anxiety-like effect. The same doses of scopolamine and l-Arginine decreased the locomotor activity in mice. Joint administration of sub-effective dose of scopolamine (0.01 mg/kg) with a low dose of l-Arginine (25 mg/kg) or l-NAME (1 mg/kg) induced a profound antidepressant-like effect in the FST. These drug combinations did not influence on anxiety-related behaviors. Meanwhile, l-NAME alone did not alter the performance of mice in the FST and hole-board. Isobolographic analysis revealed an additive effect for scopolamine and l-Arginine or l-NAME.


Data suggests that NO agents could positively impact the therapeutic profile of scopolamine, because they might be useful for inducing antidepressant-like effect associated to scopolamine.


Scopolamine l-Arginine l-NAME Depression- and anxiety-related behaviors Mice 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

213_2019_5294_MOESM1_ESM.pdf (380 kb)
ESM 1 (PDF 379 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Mohammad Nasehi
    • 1
  • Mohammad-Hossein Mohammadi-Mahdiabadi-Hasani
    • 2
  • Mohaddeseh Ebrahimi-Ghiri
    • 3
    Email author
  • Mohammad-Reza Zarrindast
    • 2
    • 4
    • 5
    • 6
  1. 1.Cognitive and Neuroscience Research Center (CNRC), Tehran Medical Sciences, Amir-Almomenin HospitalIslamic Azad UniversityTehranIran
  2. 2.Institute for Cognitive Science Studies (ICSS)TehranIran
  3. 3.Department of Biology, Faculty of SciencesUniversity of ZanjanZanjanIran
  4. 4.Department of Pharmacology School of MedicineTehran University of Medical SciencesTehranIran
  5. 5.Iranian National Center for Addiction StudiesTehran University of Medical SciencesTehranIran
  6. 6.Department of Neuroendocrinology, Endocrinology, and Metabolism Research InstituteTehran University of Medical SciencesTehranIran

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