A fixed dose combination of bupropion (BPP) and naltrexone (NTX), Contrave®, is 
an FDA approved pharmacotherapy for the treatment of obesity. A recent study 
found that combining BPP with low-dose NTX reduced alcohol drinking in 
alcohol-preferring male rats. To explore potential pharmacological effects of 
the BPP + NTX combination on alcohol drinking, both male and female C57Bl/6J 
mice were tested on one-week drinking-in-the dark (DID) and three-week 
intermittent access (IA) models. Neuronal proopiomelanocortin (POMC) enhancer 
knockout (nPE-/-) mice with hypothalamic-specific deficiency of POMC, and its 
bioactive peptides melanocyte stimulating hormone and beta-endorphin, were used 
as a genetic control for the effects of the BPP + NTX. A single administration 
of BPP + NTX (10 mg/kg + 1 mg/kg) decreased alcohol intake after DID in C57Bl/6J 
males, but not females. Also in C57Bl/6J males, BPP + NTX reduced intake of the 
caloric reinforcer sucrose, but not the non-caloric reinforcer saccharin. In 
contrast, BPP + NTX had no effect on alcohol DID in nPE-/- males. Pretreatment 
with the selective melanocortin 4 receptor (MC4R) antagonist HS014 reversed the 
anti-dipsogenic effect of BPP + NTX on alcohol DID in C57Bl/6J males. In the 
3-week chronic IA model, single or repeated administrations for four days of 
BPP + NTX reduced alcohol intake and preference in C57Bl/6J males only. The 
behavioral measures observed in C57Bl/6J mice provide clear evidence that 
BPP + NTX profoundly reduced alcohol drinking in males, but the doses tested 
were not effective in females. Furthermore, our results suggest a hypothalamic 
POMC/MC4R-dependent mechanism for the observed BPP + NTX effects on alcohol 
drinking in male mice.