Suppression of alcohol self-administration and reinstatement of alcohol seeking by melanin-concentrating hormone receptor 1 (MCH1-R) antagonism in Wistar rats.
BACKGROUND
Melanin-concentrating hormone (MCH) is involved in regulation of appetitive behaviors as well as emotional reactivity and reward, behavioral domains relevant to alcohol addiction.


METHODS
We evaluated the effects of the non-peptide MCH1 receptor antagonist, GW803430 [6-(4-chloro-phenyl)-3-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3H-thieno[3,2-d]pyrimidin-4-one; 3-30 mg/kg, i.p.] on alcohol-related behaviors in Wistar rats.


RESULTS
Ex vivo binding experiments demonstrated that the GW803430 dose range used resulted in high central MCH1 receptor occupancy. Alcohol self-administration was dose-dependently and potently suppressed, by approximately 80% at the highest dose. Reinstatement of alcohol-seeking induced by alcohol-associated cues was essentially eliminated. In contrast, reinstatement induced by footshock stress was not significantly altered. Taste preference for a quinine/saccharin solution, locomotor activity, and alcohol elimination were unaffected.


CONCLUSIONS
Together, these observations support a specific involvement of the MCH system in mediating alcohol reward and cue-induced relapse to alcohol seeking. MCH1-R antagonism may constitute an attractive treatment target for alcohol use disorders.
Cippitelli
Andrea
A
Laboratory of Clinical and Translational Studies, National Institute of Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), 10 Center Dr., 1/5330, Bethesda, MD 20892-1108, USA.
Karlsson
Camilla
C
Shaw
Janice L
JL
Thorsell
Annika
A
Gehlert
Donald R
DR
Heilig
Markus
M
D000428:Alcohol Drinking / Q000517:prevention & control*; D000818:Animals; D019440:Anti-Obesity Agents / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D011744:Pyrimidinones / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D012201:Reward; D055502:Secondary Prevention; D012646:Self Administration; D013649:Taste / Q000187:drug effects; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology*
C540748:6-(4-chlorophenyl)-3-(3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl)-3H-thieno(3,2-d)pyrimidin-4-one; D019440:Anti-Obesity Agents; C491208:MCHR1 protein, rat; D011744:Pyrimidinones; D017481:Receptors, Somatostatin; D013876:Thiophenes