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. 2018 Jan;42(1):195-205.
doi: 10.1111/acer.13544. Epub 2017 Nov 28.

V1b Receptor Antagonist SSR149415 and Naltrexone Synergistically Decrease Excessive Alcohol Drinking in Male and Female Mice

Yan Zhou  1 , Marcelo Rubinstein  2 , Malcolm J Low  3 , Mary Jeanne Kreek  1
Affiliations

V1b Receptor Antagonist SSR149415 and Naltrexone Synergistically Decrease Excessive Alcohol Drinking in Male and Female Mice

Yan Zhou et al. Alcohol Clin Exp Res. 2018 Jan.

Abstract

Background: A recent clinical trial found that pharmacological blockade of V1b receptors reduces alcohol relapse in alcohol-dependent patients. SSR149415 is a selective V1b receptor antagonist that has potential for development as an alcohol dependency treatment. In this study, we investigated whether SSR149415 alone or in combination with the mu-opioid receptor (MOP-r) antagonist naltrexone (NTN) would alter excessive alcohol drinking in mice.

Methods: Both sexes of C57BL/6J (B6) mice were subjected to a chronic intermittent access (IA) drinking paradigm (2-bottle choice, 24-hour access every other day) for 3 weeks. Sucrose and saccharin drinking were used as controls for alcohol-specific drug effects. Neuronal proopiomelanocortin (POMC) enhancer (nPE) knockout mice with hypothalamic-specific loss of POMC (including beta-endorphin, the main endogenous ligand of MOP-r) were used as a genetic control for the effects of NTN.

Results: Acute administration of SSR149415 (1 to 30 mg/kg) reduced alcohol intake and preference in a dose-dependent manner in both male and female B6 mice after IA. To investigate potential synergistic effects between NTN and SSR149415, we tested 6 different combination doses of SSR149415 and NTN, and found that a combination of SSR149415 (3 mg/kg) and NTN (1 mg/kg) reduced alcohol intake profoundly at doses lower than the individual effective doses in both sexes of B6 mice. We confirmed the effect of SSR149415 on reducing alcohol intake in nPE-/- male mice, consistent with independent mechanisms by which SSR149415 and NTN decrease alcohol drinking.

Conclusions: The combination of V1b antagonist SSR149415 with NTN at individual subthreshold doses shows potential in alcoholism treatment, possibly with less adverse effects.

Keywords: Combined Therapy; Excessive Alcohol Drinking; Naltrexone; SSR149415; V1b Receptor; nPE Knockout Mice.

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Conflict of interest statement

Conflict of interest: All authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
Dose responses of acute administration of SSR149415 (SSR, 0, 1, 3, 10 or 30 mg/kg) alone or combined with naltrexone (NTN, 0, 0.5 or 1 mg/kg) on reducing 15% alcohol intake (A) and alcohol preference (B) after 3-week intermittent access drinking in both male and female B6 mice. Data were collected at the 4-hour time point on the baseline and testing day (24 hours later) and are expressed as a percentage of baseline alcohol intake to account for the differences in baseline that contribute to variation between experiments. n=6–8. *p<0.05 or **p<0.01 vs. control (both SSR and NTN at 0 mg/kg); #p<0.05 or ## p<0.01 between treatment groups.
Figure 2
Figure 2
Effects of acute administration of SSR149415 (SSR, 10 mg/kg) alone or 3 mg/kg SSR combined with naltrexone (NTN, 1 mg/kg) on 15% alcohol intake and preference ratio after 3-week intermittent access drinking in male B6 mice. [A, B] SSR alone: (1) Control group (n=7): males received one vehicle injection (5% DMSO and 5% Cremophor in saline for SSR149415 control, i.p.) before the drinking test; and (2) SSR149415 group (n=8): males received one SSR149415 injection (10 mg/kg, i.p.) before the drinking test; [C, D] SSR + NTN: (1) Control group (n=8): males received one vehicle (5% DMSO and 5% Cremophor in saline for SSR149415 control, i.p.) followed by saline (for NTN control, i.p.) before the drinking test; and (2) SSR149415 + NTN group (n=7): males received one SSR149415 injection (3 mg/kg, i.p.) followed by one NTN injection (1 mg/kg, i.p.) before the drinking test. On the test day, alcohol (15%) intake values were recorded after 4, 8 and 24 hours of alcohol access. * p<0.05, **p<0.01, ***p<0.005 and ****p<0.001 vs. control at the same time point.
Figure 3
Figure 3
Effects of acute administration of SSR149415 (SSR, 10 mg/kg) alone or 3 mg/kg SSR combined with naltrexone (NTN, 1 mg/kg) on 15% alcohol intake and preference ratio after 3-week intermittent access drinking in female B6 mice. [A, B] SSR alone: (1) Control group (n=7): females received one vehicle injection (5% DMSO and 5% Cremophor in saline for SSR149415 control, i.p.) before the drinking test; and (2) SSR149415 group: females (n=7) received one SSR149415 injection (10 mg/kg, i.p.) before the drinking test. [C, D] SSR + NTN: (1) Control group (n=6): females received one vehicle (5% DMSO and 5% Cremophor in saline for SSR149415 control, i.p.) followed by saline (for NTN control, i.p.) before the drinking test; and (2) SSR149415 + NTN group (n=6): females received one SSR149415 injection (3 mg/kg, i.p.) followed by one NTN injection (1 mg/kg, i.p.) before the drinking test. On the test day, alcohol (15%) intake values were recorded after 4, 8 and 24 hours of alcohol access. * p<0.05, **p<0.01, ***p<0.005 and ****p<0.001 vs. control at the same time point.
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