Effect of subchronic galantamine treatment on neuronal nicotinic and muscarinic receptor subtypes in transgenic mice overexpressing human acetylcholinesterase.
Overexpression of acetylcholinesterase (AChE) in mice causes cholinergic deficits with memory impairment. In this study, AChE overexpressing (hAChE-Tg) and control (FVB/N) mice were treated with the AChE inhibitor (AChEI) galantamine (4 mg/kg/day) for 10 days. The concentration of galantamine in plasma was 75-80 ng/ml. The inhibition of AChE was 20% in red blood cells (RBC) and 30% in brain cortical tissue. A significant increase in [(3)H]cytisine (alpha4 nicotinic receptor) binding was measured in the CA1 and CA3 area of the hippocampus of FVB/N mice following galantamine treatment. Similarly, a significant increase in [(125)I]alphabungarotoxin (alpha7 nicotinic receptor) binding was found in the frontal cortex, retrosplenial gr. cortex, motor cortex and thalamus in galantamine treated FVB/N compared to saline treated mice. No significant changes in nicotinic receptor binding sites were observed in galantamine treated hAChE-Tg mice. Significant decreases in the muscarinic receptors measured by [(3)H]AF-DX-384 (M2 muscarinic receptor) and [(3)H]pirenzepine (M1 muscarinic receptor) were observed in several brain regions of galantamine treated FVB/N and hAChE-Tg mice. This study shows regional and receptor subtype specific changes in the nicotinic receptor subtypes compared to the muscarinic receptors following galantamine treatment in FVB/N and hAChE-Tg mice.
Svedberg
Marie M
MM
Division of Molecular Neuropharmacology, Department of Neurotec, Karolinska Institutet, Huddinge University Hospital B84, S-141 86 Stockholm, Sweden.
Bednar
Ivan
I
Nordberg
Agneta
A
D000110:Acetylcholinesterase / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D005260:Female; D005702:Galantamine / Q000008:administration & dosage*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D021122:Protein Subunits / Q000096:biosynthesis; D011976:Receptors, Muscarinic / Q000096:biosynthesis*; D011978:Receptors, Nicotinic / Q000096:biosynthesis*
D002800:Cholinesterase Inhibitors; D021122:Protein Subunits; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D005702:Galantamine; D000110:Acetylcholinesterase