Localisation of NMU1R and NMU2R in human and rat central nervous system and effects of neuromedin-U following central administration in rats.
BACKGROUND
Neuromedin-U (NmU) is an agonist at NMU1R and NMU2R. The brain distribution of NmU and its receptors, in particular NMU2R, suggests widespread central roles for NmU. In agreement, centrally administered NmU affects feeding behaviour, energy expenditure and pituitary output. Further central nervous system (CNS) roles for NmU warrant investigation.


OBJECTIVE
To investigate the CNS role of NmU by mapping NMU1R and NMU2R mRNA and measuring the behavioural, endocrine, neurochemical and c-fos response to intracerebroventricular (i.c.v.) NmU.


METHODS
Binding affinity and functional potency of rat NmU was determined at human NMU1R and NMU2R. Expression of NMU1R and NMU2R mRNA in rat and human tissue was determined using semi-quantitative reverse-transcription polymerase chain reaction. In in-vivo studies, NmU was administered i.c.v. to male Sprague-Dawley rats, and changes in grooming, motor activity and pre-pulse inhibition (PPI) were assessed. In further studies, plasma endocrine hormones, [DOPAC + HVA]/[dopamine] and [5-HIAA]/[5-HT] ratios and levels of Fos-like immunoreactivity (FLI) were measured 20 min post-NmU (i.c.v.).


RESULTS
NmU bound to NMU1R ( K(I), 0.11+/-0.02 nM) and NMU2R ( K(I), 0.21+/-0.05 nM) with equal affinity and was equally active at NMU1R (EC(50), 1.25+/-0.05 nM) and NMU2R (EC(50), 1.10+/-0.20 nM) in a functional assay. NMU2R mRNA expression was found at the highest levels in the CNS regions of both rat and human tissues. NMU1R mRNA expression was restricted to the periphery of both species with the exception of the rat amygdala. NmU caused a marked increase in grooming and motor activity but did not affect PPI. Further, NmU decreased plasma prolactin but did not affect levels of corticosterone, luteinising hormone or thyroid stimulating hormone. NmU elevated levels of 5-HT in the frontal cortex and hypothalamus, with decreased levels of its metabolites in the hippocampus and hypothalamus, but did not affect dopamine function. NmU markedly increased FLI in the nucleus accumbens, frontal cortex and central amygdala.


CONCLUSIONS
These data provide further evidence for widespread roles for NmU and its receptors in the brain.
Gartlon
Jane
J
Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline plc, New Frontiers Science Park, Third Avenue, Harlow, CM19 5AW, Essex, United Kingdom. jane.gartlon@gsk.com
Szekeres
Philip
P
Pullen
Mark
M
Sarau
Henry M
HM
Aiyar
Nambi
N
Shabon
Usman
U
Michalovich
David
D
Steplewski
Klaudia
K
Ellis
Cathy
C
Elshourbagy
Nabil
N
Duxon
Mark
M
Ashmeade
Tracey E
TE
Harrison
David C
DC
Murdock
Paul
P
Wilson
Shelagh
S
Ennaceur
Abdel
A
Atkins
Alan
A
Heidbreder
Christian
C
Hagan
Jim J
JJ
Hunter
A Jackie
AJ
Jones
Declan N C
DN
D000818:Animals; D002460:Cell Line; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007276:Injections, Intraventricular; D008565:Membrane Proteins / Q000819:agonists* / Q000378:metabolism*; D009479:Neuropeptides / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017981:Receptors, Neurotransmitter / Q000819:agonists* / Q000378:metabolism*; D013552:Swine
D008565:Membrane Proteins; D009479:Neuropeptides; D017981:Receptors, Neurotransmitter; C082444:neuromedin U receptor; C056900:neuromedin U