Journal of Neural Transmission

, Volume 115, Issue 1, pp 117–125 | Cite as

Appearance of antidepressant-like effect by sildenafil in rats after central muscarinic receptor blockade: evidence from behavioural and neuro-receptor studies

  • C. B. BrinkEmail author
  • J. D. Clapton
  • B. E. Eagar
  • B. H. Harvey


The phosphodiesterase (PDE) 5 inhibitor sildenafil has been shown to display psychotropic actions in humans and animals, and has been used for the treatment of antidepressant-associated erectile dysfunction. However, its effects on the neurobiology of depression are unknown. Nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) inhibition is anti-depressant in animals, and increasing cGMP with sildenafil is anxiogenic in rodents. Substantial cholinergic-nitrergic interaction exists in the brain, while sildenafil shows modulatory actions on cholinergic transmission. Depression is also associated with increased cholinergic drive. Here we report that sildenafil increases muscarinic acetylcholine receptor (mAChR) signaling in human neuroblastoma cells. We also show that fluoxetine (20 mg/kg/day × 7 days), as well as a combination of sildenafil (10 mg/kg/day × 7 days) plus the antimuscarinic atropine (1 mg/kg/day × 7 days) demonstrates significant, comparable antidepressant-like effects in the rat forced swim test (FST) and also reduces cortical β-adrenergic receptor (β-AR) density, while sildenafil or atropine alone did not. Importantly, sildenafil did not modify fluoxetine’s response. Sildenafil thus demonstrates antidepressant-like effects but only after central muscarinic receptor blockade, providing evidence for cholinergic-nitrergic interactions in the neurobiology of depression.

Keywords: Sildenafil; phosphodiesterase type 5 inhibitor; antidepressant, cyclic GMP; nitric oxide; cholinergic; muscarinic acetylcholine receptor; rat 


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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • C. B. Brink
    • 1
    Email author
  • J. D. Clapton
    • 1
  • B. E. Eagar
    • 1
  • B. H. Harvey
    • 1
  1. 1.Unit for Drug Research and Development, Division of PharmacologyNorth-West University (PUK)PotchefstroomSouth Africa

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