Antisense knockdown of the rat alpha7 nicotinic acetylcholine receptor produces spatial memory impairment.
Selective and brain penetrating pharmacological antagonists for use in clarifying a role of alpha7 nicotinic acetylcholine receptors (nAChR) in behavioral paradigms are presently unavailable. Studies in alpha7 knock-out mice (KO) have not revealed convincing changes in behavioral phenotype, in particular measures of cognition that include contextual fear conditioning and spatial memory, which may be due to compensatory developmental changes. Therefore, an antisense oligonucleotide (aON) targeted toward the 3'- and 5'-UTR coding regions of the rat alpha7 nicotinic acetylcholine receptor was used. Following central injection of aON into the lateral ventricle of Long Evans rats for 6 days, treated rats exhibited a significant 42% and 25% decrease in alpha7 nAChR densities in hippocampus and cortex, respectively, as measured by [(3)H]-methyllycaconitine (MLA) binding. There was no change in alpha4beta2 densities measured by [(3)H]-cytisine binding. Acquisition of Morris Water Maze (MWM) performance, a measure of spatial memory, was impaired in aON-treated rats. In addition, a reduction in target platform crossings during a subsequent probe-trial was observed. These data demonstrate the ability of this aON to reduce hippocampal and cortical alpha7 nicotinic receptor densities associated with impaired MWM performance and support the specific involvement of the alpha7 nAChR in spatial learning and memory, a phenotype not affected in alpha7 KO mice.
Curzon
Peter
P
Neuroscience Research, Abbott Laboratories GPRD, Abbott Park, IL 60064-6115, United States. peter.curzon@abbott.com
Anderson
David J
DJ
Nikkel
Arthur L
AL
Fox
Gerard B
GB
Gopalakrishnan
Murali
M
Decker
Michael W
MW
Bitner
Robert S
RS
D000157:Aconitine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001392:Azocines / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006624:Hippocampus / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced* / Q000503:physiopathology; D018733:Nicotinic Antagonists / Q000493:pharmacokinetics; D020319:Oligodeoxyribonucleotides, Antisense / Q000009:adverse effects*; D011485:Protein Binding / Q000187:drug effects; D011807:Quinolizines / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013028:Space Perception / Q000187:drug effects*; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000093843:Quinolizidine Alkaloids
D000157:Aconitine; D000470:Alkaloids; D001392:Azocines; D018733:Nicotinic Antagonists; D020319:Oligodeoxyribonucleotides, Antisense; D011807:Quinolizines; D011978:Receptors, Nicotinic; D014316:Tritium; D064569:alpha7 Nicotinic Acetylcholine Receptor; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; C054634:methyllycaconitine; C004712:cytisine; D000093843:Quinolizidine Alkaloids