Phosphodiesterase inhibition by sildenafil citrate attenuates the learning impairment induced by blockade of cholinergic muscarinic receptors in rats.
We examined whether treatment with sildenafil citrate (the active compound of Viagra), a cyclic nucleotide phosphodiesterase type 5 inhibitor (PDE5), would reverse the learning impairment induced by cholinergic muscarinic (mACh) receptor blockade [0.75 mg/kg scopolamine HCl, intraperitoneal (i.p.) injections]. Rats were pretrained in a one-way active avoidance of foot shock in a straight runway and the next day received 15 training trials in a 14-unit T-maze. Performance in this maze paradigm requires accurate responding to avoid mild foot shock and has been shown to be sensitive to aging and to impairment in central cholinergic systems. Intraperitoneal (i.p.) injections of scopolamine or saline and sildenafil or vehicle were given 30 and 15 min before training, respectively. The combined treatment conditions were as follows: saline+vehicle (control), scopolamine (0.75 mg/kg)+vehicle, and scopolamine (0.75 mg/kg)+sildenafil (1.5, 3.0, or 4.5 mg/kg). Behavioral measures of performance included deviations from the correct pathway (errors), run time from start to goal, shock frequency, and duration. Statistical analysis revealed that scopolamine impaired maze performance and that sildenafil (3.0 mg/kg) significantly attenuated this impairment in a dose-dependent manner. These results suggest that sildenafil citrate may serve as a cognitive enhancer for therapeutic treatment of cholinergic dysfunction in age-related cognitive decline and Alzheimer's dementia (AD).
Devan
Bryan D
BD
Behavioral Neuroscience Section, Laboratory of Experimental Gerontology, Gerontology Research Center, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD, 21224, USA. DevanBr@grc.nia.nih.gov
Sierra-Mercado
Demetrio
D
Jimenez
Mariana
M
Bowker
Jonna L
JL
Duffy
Kara B
KB
Spangler
Edward L
EL
Ingram
Donald K
DK
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000502:physiology; D000818:Animals; D008297:Male; D018782:Maze Learning / Q000187:drug effects* / Q000502:physiology; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines; D051381:Rats; D011916:Rats, Inbred F344; D011976:Receptors, Muscarinic / Q000502:physiology*; D000068677:Sildenafil Citrate; D013450:Sulfones
D018727:Muscarinic Antagonists; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D011976:Receptors, Muscarinic; D013450:Sulfones; D000068677:Sildenafil Citrate; D015106:3',5'-Cyclic-GMP Phosphodiesterases