Disruption of the neurokinin-3 receptor (NK3) in mice leads to cognitive deficits.
BACKGROUND
The structurally related neuropeptides, substance P, neurokinin A, and neurokinin B, belong to a family of molecules termed tachykinins and are widely distributed in the central and peripheral nervous systems. These peptides mediate their effects through three G protein coupled receptor subtypes, the neurokinin-1, neurokinin-2 and neurokinin-3 receptors, respectively.


OBJECTIVE
To study the physiological functions of NK3, a line of NK3 knockout mice were generated and characterized in a broad spectrum of well-established behavioral tests.


RESULTS
In several tests, including spontaneous locomotor activity, elevated plus maze, forced swim, and hot plate, wild-type and knockout mice performed similarly. However, in several cognition tests, including passive avoidance, acquisition of conditioned avoidance responding (CAR), and the Morris water maze, NK3 knockout mice displayed deficits compared to wild-type mice. Although NK3 wild-type and knockout mice performed similarly in the training phase of the passive avoidance test, knockout mice had shorter latencies to enter the dark compartment on days 3 and 4, suggesting impaired retention. In the acquisition phase of the conditioned avoidance responding assay, NK3 knockout mice acquired the CAR task at a slower rate than wild-type mice. Once the CAR test was acquired, both NK3 wild-type and knockout mice responded similarly to clozapine and risperidone, drugs which suppress responding in this test. In the Morris water maze, NK3 knockout mice showed increased latencies to find the escape platform on day 3 of training, suggesting a modest, but significant delay in acquisition compared to wild-type mice.


CONCLUSIONS
These studies suggest a role for NK3 in learning and memory in mice.
Siuciak
Judith A
JA
CNS Discovery, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. judith.siuciak@gmail.com
McCarthy
Sheryl A
SA
Martin
A N
AN
Chapin
D S
DS
Stock
J
J
Nadeau
D M
DM
Kantesaria
S
S
Bryce-Pritt
D
D
McLean
S
S
D000367:Age Factors; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology*; D001522:Behavior, Animal / Q000187:drug effects; D003024:Clozapine / Q000494:pharmacology; D003072:Cognition Disorders / Q000503:physiopathology*; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D015870:Gene Expression; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D018042:Receptors, Neurokinin-3 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018967:Risperidone / Q000494:pharmacology; D013550:Swimming; D013997:Time Factors; D015430:Weight Gain / Q000187:drug effects
D014150:Antipsychotic Agents; D018042:Receptors, Neurokinin-3; D003024:Clozapine; D018967:Risperidone