Bupropion, Alone and in Combination with Naltrexone, Blunts Binge‐Like Ethanol Drinking and Intake Following Chronic Intermittent Access to Ethanol in Male C57<scp>BL</scp>/6J Mice

Navarro, Montserrat; Luhn, Kendall L.; Kampov‐Polevoy, Alexey B.; Garbutt, James C.; Thiele, Todd E.

doi:10.1111/acer.13992

Cited by 18 publications

(10 citation statements)

References 52 publications

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“…This is especially important for the current and coming experiments because our preclinical research is testing the two pharmacologically active components of the FDA approved drug Contrave® for its potential use in alcohol treatment. Our results support the potential use of the combinations of BPP+NTX to reduce alcohol consumption in a phase II clinical trial experiment [Navarro et al, 2019], with clear consideration of gender differences. A similar reduction observed with sucrose intake may indicate an off-target effect of the combinations.…”

Section: Discussionsupporting

confidence: 77%

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

Zhou

Leri

Low

et al. 2019

Pharmacology Biochemistry and Behavior

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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.

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Section: Discussionsupporting

confidence: 77%

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

Zhou

Leri

Low

et al. 2019

Pharmacology Biochemistry and Behavior

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“…In line with our data, DAGL inhibition by DO34 has been previously shown to reduce operant responding for alcohol (43). The magnitude of effect on EtOH intake observed after DAGL inhibition is comparable to or greater than those observed with clinically available treatments such as Naltrexone (44)(45)(46) and Acomprasate (46,47) in similar rodent models. Moreover, pharmacological DAGL inhibition did not affect sucrose preference, suggesting a lack of generalized effect to natural reward, although female DAGL KO mice do exhibit reductions in sucrose preference under some conditions (23).…”

Section: Discussionsupporting

confidence: 90%

Targeting diacylglycerol lipase reduces alcohol consumption in preclinical models

Winters¹,

Bedse²,

Astafyev³

et al. 2021

Journal of Clinical Investigation

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Alcohol use disorder (AUD) is associated with substantial morbidity, mortality, and societal cost, and pharmacological treatment options for AUD are limited. The endogenous cannabinoid (eCB) signaling system is critically involved in reward processing and alcohol intake is positively correlated with release of the eCB ligand 2-Arachidonoylglycerol (2-AG) within reward neurocircuitry. Here we show that genetic and pharmacological inhibition of diacylglycerol lipase (DAGL), the rate limiting enzyme in the synthesis of 2-AG, reduces alcohol consumption in a variety of preclinical models ranging from a voluntary free-access model to aversion resistant-drinking and dependence-like drinking induced via chronic intermittent ethanol vapor exposure in mice. DAGL inhibition during either chronic alcohol consumption or protracted withdrawal was devoid of anxiogenic and depressive-like behavioral effects. Lastly, DAGL inhibition also prevented ethanolinduced suppression of GABAergic transmission onto midbrain dopamine neurons, providing mechanistic insight into how DAGL inhibition could affect alcohol reward. These data suggest reducing 2-AG signaling via inhibition of DAGL could represent an effective approach to reduce alcohol consumption across the spectrum of AUD severity.

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“…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).…”

Section: ! 12mentioning

confidence: 77%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Morales

Rodríguez-Borillo

Font

et al. 2020

Behavioural Pharmacology

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Chronic alcohol (EtOH) binging has been associated with long-term neural adaptations that lead to the development of addiction. Many of the neurobiological features of EtOH abuse are shared with other forms of binging, like pathological feeding. The drinkingin-the-dark paradigm (DID) has been used extensively to study the neurobiology of EtOH binge-like drinking due to its ability to promote high intakes relevant to human behavior. DID can also generate high consumption of other tastants, but this procedure has not been fully adapted to study forms of binging behavior that are not alcohol-driven. In the present study we used a modified version of DID that uses multiple bottle availability to promote even higher levels of EtOH drinking in male C57BL/6J mice and allows a thorough investigation of tastant preferences. We assessed whether administration of systemic naltrexone (NTX) could reduce binging on EtOH, sucrose, and saccharin separately as well as in combination. Our multiple bottle DID procedure resulted in heightened levels of consumption compared to previously reported data using this task. We found that administration of the opioid receptor antagonist NTX reduced intakes of preferred, highly concentrated EtOH, sucrose, and saccharin. We also report that NTX was able to reduce overall intakes when animals were allowed to self-administer EtOH, sucrose, or saccharin in combination. Our modified DID procedure provides a novel approach to study binging behavior that extends beyond EtOH to other tastants (i.e., sucrose and artificial sweeteners), and has implications for the study of the neuropharmacology of binge drinking.

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Bupropion, Alone and in Combination with Naltrexone, Blunts Binge‐Like Ethanol Drinking and Intake Following Chronic Intermittent Access to Ethanol in Male C57BL/6J Mice

Cited by 18 publications

References 52 publications

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

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

Targeting diacylglycerol lipase reduces alcohol consumption in preclinical models

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

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