Sex differences in the effect of bupropion and naltrexone combination on alcohol drinking in mice

Abstract

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.

Effects of naltrexone on alcohol, sucrose, and saccharin binge-like drinking in C57BL/6J mice: a study with a multiple bottle choice procedure

“…To the best of our knowledge, the current study presents the first data showing that NTX reduces saccharin intake using a DID procedure. A combination of bupropion 10 mg/kg + NTX 1 mg/kg, capable of reducing 4% sucrose intake, did not affect 0.1% saccharin DID consumption (Zhou et al, 2019). However, previous research using non-DID procedures has found that opioid receptor antagonism can reduce saccharin intake (Lynch and Libby, 1983;Chow et al, 1997;Biggs and Myers, 1998).…”

“…NTX is known for its efficacy in reducing high alcohol drinking in relapsing patients (Volpicelli et al, 1992;Kiefer et al, 2003;Jonas et al, 2014). NTX, alone or in combination with other drugs, has been shown to reduce EtOH intake using DID methodology (Kamdar et al, 2007;Tarragón et al, 2012;Ripley et al, 2015;Zhou et al, 2019;Navarro et al, 2019). These results add to an extensive list of studies indicating that NTX reduces EtOH consumption using a variety of methodologies and animal models (Davidson and Amit, 1997;Sharpe and Samson 2001;Fachin-Scheit et al, 2006), including genetically predisposed EtOH-preferring strains of rodents such as B6 mice (Le et al, 1993, Phillips et al, 1997Middaugh et al, 2003;Dhaher et al, 2012).…”

“…This intake was significantly higher than what has been previously reported with other DID experiments that used lower concentrations. Using 0.1% saccharin, Zhou et al (2019) found intakes around 0.1 g/kg in 4 h (male B6), while Kamens et al (2018) showed drinking up to ∼0.02 g/kg in 2 h (adolescent male and female B6; 0.033% saccharin). Our animals preferred the concentration of 1.06%.…”

“…The opioid receptor antagonist naltrexone (NTX), a compound with high affinity for mu-opioid receptors, is used to treat alcoholism (Volpicelli et al, 1992;Kiefer et al, 2003;Jonas et al, 2014), and in combination with bupropion (marketed as Contrave™) has recently been approved for the treatment of binge-eating disorder and weight-loss management. With B6 mice and a dose range of 2-8 mg/kg, previous data have shown that NTX can reduce EtOH binge-like intake using the DID model, although some sex differences have been reported (Kamdar et al, 2007;Tarragón et al, 2012;Zhou et al, 2019;Navarro et al, 2019). It is important to mention, however, that doses of NTX as high as 10 mg/kg have failed to reduce EtOH intake in mice selected for high blood EtOH levels (HDID lines) obtained using the DID model (Crabbe et al, 2017).…”

Restricted immunological and cellular pathways are shared by murine models of chronic alcohol consumption

“…For this reason, a comparison of 4 weeks MC model with 4 weeks LD diet potentially decreases the duration of alcohol exposure effect but increases more the differences between the amount of alcohol consumed by the mice in each model. Third of all, to increase the sensitivity of our analysis we used in our experiments only female mice as is pretty well known that the effect of alcohol is sex dependent in mice and humans 55,[60][61][62][63][64] . Actually, our ongoing current work in the lab is focused on specific cellular immune effects present only in females and not observed in male mice (data not presented, manuscript in preparation).…”