Characterization of behavioral response to amphetamine, tyrosine hydroxylase levels, and dopamine receptor levels in neurokinin 3 receptor knockout mice.
The neurokinin 3 (NK3) receptor is a novel target under investigation for improvement of symptoms of schizophrenia, because of its ability to modulate dopaminergic signaling. To further understanding of the function of this receptor, sensitivity to dopaminergic stimuli and levels of dopaminergic receptors and tyrosine hydroxylase in NK3 receptor knockout mice were studied. Knockout of the receptor was confirmed by lack of NK3 protein and lack of electrophysiological responsivity of presumed dopaminergic neurons to senktide. NK3 receptor knockout mice showed mild hyperlocomotion and deficits on the rotarod. NK3 receptor knockout mice did not show significant differences in sensitivity to locomotor effects of acute amphetamine (0.3, 1, and 3 mg/kg subcutaneously) or significant alterations in sensitization to locomotor effects of amphetamine, but did show nonsignificant hyperreactivity to 1 mg/kg amphetamine and a nonsignificantly increased propensity to develop sensitization. A small decrease in D1 receptor binding was seen in the dorsal striatum and olfactory tubercle, and a small decrease of in tyrosine hydroxylase in the olfactory tubercle, but no change was seen in D2 receptor binding. Together, these results support a role for the NK3 receptor in reactivity to dopaminergic stimuli, but the lack of robust changes indicates that the sensitivity to dopamine may be activity-dependent or benign in nature.
Nordquist
Rebecca E
RE
F. Hoffmann-La Roche Ltd., PRBD-N, Psychiatry Disease Area, CH-4070 Basel, Switzerland. r.e.nordquist@uu.nl
Savignac
Helene
H
Pauly-Evers
Meike
M
Walker
Gaby
G
Knoflach
Fred
F
Borroni
Edilio
E
Glaentzlin
Patricia
P
Bohrmann
Bernd
B
Messer
Jurg
J
Ozmen
Laurence
L
Albientz
Anita
A
Spooren
Will
W
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D010446:Peptide Fragments / Q000494:pharmacology; D004856:Postural Balance / Q000187:drug effects / Q000235:genetics; D011954:Receptors, Dopamine / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000378:metabolism; D018042:Receptors, Neurokinin-3 / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
D010446:Peptide Fragments; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D018042:Receptors, Neurokinin-3; C054724:senktide; D013373:Substance P; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine