Assessment of the aversive consequences of acute and chronic administration of the melanocortin agonist, MTII.
BACKGROUND
The synthetic melanocortin (MC) agonist, melanotan-II (MTII), reduces food intake and body weight for hours to days after administration. One early report on the effect of MTII suggested that part of its anorexic action may be mediated by aversive consequences. In that experiment, MTII was found to support a mild conditioned taste aversion (CTA).


OBJECTIVE
The present experiments replicate and extend those findings in two additional CTA paradigms to further characterize the aversive effects of MTII in rats.


METHODS
Experiment 1 simultaneously assessed the ability of MTII to support CTA and reduce food intake, using a small oral infusion of a novel taste as the conditioned stimulus. Experiment 2 assessed the aversive consequences of chronic MTII administration. To accomplish this, we paired implantation of lithium chloride (LiCl)-, MTII- or saline-containing osmotic minipumps with a constantly available novel flavor. After 7 days, rats received a choice test between the minipump-paired flavor and a previously available neutral flavor.


RESULTS
Rats with saline minipumps exhibited no preference for either flavor. By contrast, rats in both the LiCl and MTII minipump groups significantly preferred the neutral flavor, indicating the development of a CTA. Additionally, CTA produced by administration of MTII was found to be more resistant to extinction than that produced by LiCl.


CONCLUSIONS
The reduction in food intake caused by MTII is accompanied by aversive consequences regardless of route of administration. These results present difficulties for the development of MCs-based therapies for obesity.
Benoit
S C
SC
Department of Psychiatry, University of Cincinnati Medical Center, Cincinnati, OH 5267, USA. stephen.benoit@uc.edu
Sheldon
R J
RJ
Air
E L
EL
Messerschmidt
P
P
Wilmer
K A
KA
Hodge
K M B
KM
Jones
M B
MB
Eckstein
D M M
DM
McOsker
C C
CC
Woods
S C
SC
Seeley
R J
RJ
D000818:Animals; D001362:Avoidance Learning; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D008297:Male; D051379:Mice; D009765:Obesity / Q000188:drug therapy*; D051381:Rats; D013651:Taste Disorders / Q000139:chemically induced; D000521:alpha-MSH / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives*
C081720:alpha-MSH (4-10)amide, Ac-Nle(4)-cyclo(Asp(5)-Phe(7)-Lys(10))-; D000521:alpha-MSH