Effects of protein kinase A and G inhibitors on hippocampal cholinergic markers expressions in rolipram- and sildenafil-induced spatial memory improvement.
Although there are number of studies showing that phosphodiesterase (PDE) 4 and 5 inhibitors affect different kinds of memory, their effects on spatial memory consolidation in conjunction with the cholinergic activity in the hippocampus have not been studied before. In the present study firstly, rats were evaluated for the effects of different doses of the PDE4 inhibitor rolipram and the PDE5 inhibitor sildenafil on spatial memory consolidation in the water maze task. Rolipram or sildenafil was daily administered intraperitoneally 3 or 0 h after the last trial of training, respectively. Then in a separate related experiment the effect of the most efficient doses of rolipram or sildenafil accompanied by an intrahippocampally injected protein kinase A (PKA) or protein kinase G (PKG) inhibitor, respectively, was examined. Finally for determination of the hippocampal cholinergic activity the protein expression of hippocampal vesicular acetylcholine transporter (VAChT) and cholineacetyltransferase (ChAT) was measured. Rolipram at 0.03 mg/kg as well as sildenafil at 3 mg/kg increased spatial memory and their enhancing effect was completely blocked following inhibition of PKA and PKG, respectively. Furthermore, none of the treatments had a significant effect on the hippocampal ChAT and VAChT levels. Our data showed that rolipram and sildenafil enhanced spatial memory consolidation in an inverted U-shaped dose-response curve. This effect is dependent on the activity of cAMP/PKA- and cGMP/PKG-mediated pathways, respectively in the hippocampus. However, we did not find evidence for a chronic increase of cholinergic activity in the observed PDE inhibitor-induced memory improvement.
Department of Pharmacology, Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
Ali
A
Hosseini-Sharifabad
Mohammad Hossein
MH
Ghahremani
Omid
O
Sabzevari
Naser
N
Naghdi
Mohammad
M
Abdollahi
Cordian
C
Beyer
Eva
E
Bollen
Jos
J
Prickaerts
Ali
A
Roghani
Mohammad
M
Sharifzadeh
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D004347:Drug Interactions; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects*; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020889:Rolipram / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage / Q000494:pharmacology*; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism
D058988:Phosphodiesterase 4 Inhibitors; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011687:Purines; C493461:Slc18a3 protein, rat; D013450:Sulfones; D050494:Vesicular Acetylcholine Transport Proteins; D000068677:Sildenafil Citrate; D002795:Choline O-Acetyltransferase; D017868:Cyclic AMP-Dependent Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D020889:Rolipram; D000109:Acetylcholine