Psychopharmacology

, Volume 211, Issue 4, pp 367–375

Suppression of alcohol self-administration and reinstatement of alcohol seeking by melanin-concentrating hormone receptor 1 (MCH1-R) antagonism in Wistar rats

  • Andrea Cippitelli
  • Camilla Karlsson
  • Janice L. Shaw
  • Annika Thorsell
  • Donald R. Gehlert
  • Markus Heilig
original investigation

DOI: 10.1007/s00213-010-1891-y

Cite this article as:
Cippitelli, A., Karlsson, C., Shaw, J.L. et al. Psychopharmacology (2010) 211: 367. doi:10.1007/s00213-010-1891-y

Abstract

Rationale

Melanin-concentrating hormone (MCH) is involved in regulation of appetitive behaviors as well as emotional reactivity and reward, behavioral domains relevant to alcohol addiction.

Materials and 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.

Conclusion

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.

Keywords

FootshockReinstatementAlcoholSeekingSaccharinMCH1-R

Supplementary material

213_2010_1891_MOESM1_ESM.doc (176 kb)
ESM Table 1GW803430 did not exhibit activity below 100 nM as shown in a panel of common and non-common drug targets used to evaluate the MCH-1 receptor antagonism selectivity. (DOC 175 kb)

Copyright information

© US Government 2010

Authors and Affiliations

  • Andrea Cippitelli
    • 1
  • Camilla Karlsson
    • 1
  • Janice L. Shaw
    • 2
  • Annika Thorsell
    • 1
  • Donald R. Gehlert
    • 2
  • Markus Heilig
    • 1
  1. 1.Laboratory of Clinical and Translational StudiesNational Institute of Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH)BethesdaUSA
  2. 2.Neuroscience and Endocrine Discovery Research, Lilly Research Laboratories, a Division of Eli Lilly and CompanyIndianapolisUSA