title: Investigating the role of protein kinase-G in the antidepressant-like response of sildenafil in combination with muscarinic acetylcholine receptor antagonism.
abstract: The cGMP/PK-G pathway plays a crucial role in neuroprotection and neurotrophin support, and is possibly involved in antidepressant action. Recently we reported on a novel antidepressant-like response following simultaneous administration of sildenafil (phosphodiesterase 5 (PDE5) inhibitor, thereby increasing cGMP levels), and atropine (muscarinic acetylcholine receptor antagonist) in the rat forced swim test (FST). However, it is unclear whether the antidepressant-like activity of sildenafil+atropine is mediated via the activation of PK-G, an important down-stream effector for cGMP, and whether this may target known pathways in antidepressant action. We investigated whether the antidepressant-like response of sildenafil+/-atropine could be reversed by Rp-8-Br-PET-cGMP, a PK-G inhibitor, and also whether a combination of 8-Br-cGMP (PK-G activator)+/-atropine would likewise be active in the FST, and whether this combination could be attenuated by a PK-G inhibitor. 8-Br-cGMP alone, but not sildenafil alone, reduced immobility and selectively increased swimming in the FST. The antidepressant-like action of sildenafil was only evident following co-administration of atropine, and selectively increased climbing behaviour. Importantly, PK-G inhibition prevented the antidepressant-like effects of both 8-Br-cGMP and the sildenafil/atropine combination. These results confirm cholinergic-cGMP-PK-G interactions in the antidepressant-like effects of sildenafil, putatively acting via noradrenergic mechanisms, whereas direct PK-G activation induces antidepressant-like effects that are associated with enhancement of serotonergic neurotransmission.
authors.affiliation: School of Pharmacy, North-West University, Potchefstroom, South Africa.
authors.forename: Nico
authors.initials: N
authors.lastname: Liebenberg
authors.forename: Gregers
authors.initials: G
authors.lastname: Wegener
authors.forename: Brian Herbert
authors.initials: BH
authors.lastname: Harvey
authors.forename: Christiaan Beyers
authors.initials: CB
authors.lastname: Brink
mesh_terms: D000818:Animals; D001285:Atropine / Q000494:pharmacology* / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D003863:Depression / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D004347:Drug Interactions / Q000502:physiology; D004359:Drug Therapy, Combination; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate; D018709:Statistics, Nonparametric; D013450:Sulfones / Q000494:pharmacology* / Q000627:therapeutic use; D013550:Swimming / Q000523:psychology; D013873:Thionucleotides / Q000494:pharmacology
chemical_list: D018727:Muscarinic Antagonists; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D013873:Thionucleotides; C083763:8-bromoguanosino-3',5'-cyclic monophosphorothioate; C098740:8-bromo-beta-phenyl-1,N(2)-ethenoguanosine 3',5'-cyclic monophosphorothioate; D001285:Atropine; D000068677:Sildenafil Citrate; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP