Phenotypic characterization of an alpha 4 neuronal nicotinic acetylcholine receptor subunit knock-out mouse.
Neuronal nicotinic acetylcholine receptors (nAChR) are present in high abundance in the nervous system (Decker et al., 1995). There are a large number of subunits expressed in the brain that combine to form multimeric functional receptors. We have generated an alpha(4) nAChR subunit knock-out line and focus on defining the behavioral role of this receptor subunit. Homozygous mutant mice (Mt) are normal in size, fertility, and home-cage behavior. Spontaneous unconditioned motor behavior revealed an ethogram characterized by significant increases in several topographies of exploratory behavior in Mt relative to wild-type mice (Wt) over the course of habituation to a novel environment. Furthermore, the behavior of Mt in the elevated plus-maze assay was consistent with increased basal levels of anxiety. In response to nicotine, Wt exhibited early reductions in a number of behavioral topographies, under both unhabituated and habituated conditions; conversely, heightened levels of behavioral topographies in Mt were reduced by nicotine in the late phase of the unhabituated condition. Ligand autoradiography confirmed the lack of high-affinity binding to radiolabeled nicotine, cytisine, and epibatidine in the thalamus, cortex, and caudate putamen, although binding to a number of discrete nuclei remained. The study confirms the pivotal role played by the alpha(4) nAChR subunit in the modulation of a number of constituents of the normal mouse ethogram and in anxiety as assessed using the plus-maze. Furthermore, the response of Mt to nicotine administration suggests that persistent nicotine binding sites in the habenulo-interpeduncular system are sufficient to modulate motor activity in actively exploring mice.
Ross
S A
SA
Neurosciences Group, Monash University Department of Medicine and Institute of Reproduction and Development, Monash Medical Centre, Clayton, Victoria, 3168, Australia.
Wong
J Y
JY
Clifford
J J
JJ
Kinsella
A
A
Massalas
J S
JS
Horne
M K
MK
Scheffer
I E
IE
Kola
I
I
Waddington
J L
JL
Berkovic
S F
SF
Drago
J
J
D000374:Aggression / Q000187:drug effects; D000470:Alkaloids / Q000493:pharmacokinetics; D000818:Animals; D001345:Autoradiography; D001392:Azocines; D001483:Base Sequence; D001824:Body Constitution; D001921:Brain / Q000502:physiology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics; D002038:Bungarotoxins / Q000493:pharmacokinetics; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D005298:Fertility; D006185:Habituation, Psychophysiologic; D006720:Homozygote; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000502:physiology*; D009538:Nicotine / Q000493:pharmacokinetics / Q000494:pharmacology; D015345:Oligonucleotide Probes; D010641:Phenotype; D011725:Pyridines / Q000493:pharmacokinetics; D011807:Quinolizines; D011978:Receptors, Nicotinic / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015183:Restriction Mapping; D012919:Social Behavior; D014316:Tritium; D000093843:Quinolizidine Alkaloids
D000470:Alkaloids; D001392:Azocines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002038:Bungarotoxins; D009538:Nicotine; D015345:Oligonucleotide Probes; D011725:Pyridines; D011807:Quinolizines; D011978:Receptors, Nicotinic; D014316:Tritium; C004712:cytisine; D000093843:Quinolizidine Alkaloids; C082748:epibatidine