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. 2017 May 1;1662:75-86.
doi: 10.1016/j.brainres.2017.02.027. Epub 2017 Mar 2.

Synergistic Blockade of Alcohol Escalation Drinking in Mice by a Combination of Novel Kappa Opioid Receptor Agonist Mesyl Salvinorin B and Naltrexone

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Synergistic Blockade of Alcohol Escalation Drinking in Mice by a Combination of Novel Kappa Opioid Receptor Agonist Mesyl Salvinorin B and Naltrexone

Yan Zhou et al. Brain Res. .
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Abstract

Mesyl Salvinorin B (MSB) is a potent selective kappa opioid receptor (KOP-r) agonist that has potential for development as an anti-psychostimulant agent with fewer side-effects (e.g., sedation, depression and dysphoria) than classic KOP-r agonists. However, no such study has been done on alcohol. We investigated whether MSB alone or in combination with naltrexone (mu-opioid receptor antagonist) altered voluntary alcohol drinking in both male and female mice. Mice, subjected to 3weeks of chronic escalation drinking (CED) in a two-bottle choice paradigm with 24-h access every other day, developed rapid escalation of alcohol intake and high preference. We found that single, acute administration of MSB dose-dependently reduced alcohol intake and preference in mice after 3-week CED. The effect was specific to alcohol, as shown by the lack of any effect of MSB on sucrose or saccharin intake. We also used the drinking-in-the-dark (DID) model with limited access (4h/day) to evaluate the pharmacological effect of MSB after 3weeks of DID. However, MSB had no effect on alcohol drinking after 3-week DID. Upon investigation of potential synergistic effects between naltrexone and MSB, we found that acute administration of a combination of MSB and naltrexone reduced alcohol intake profoundly after 3-week CED at doses lower than those individual effective doses. Repeated administrations of this combination showed less tolerance development than repeated MSB alone. Our study suggests that the novel KOP-r agonist MSB both alone and in combination with naltrexone shows potential in alcoholism treatment models.

Keywords: Alcohol escalation drinking; Combined therapy; KOP-r; Mesyl Salvinorin B; Naltrexone.

Conflict of interest statement

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

Figures

Figure 1
Figure 1
Effects of single, acute administration of Mesyl Salvinorin B (MSB, 3 mg/kg) or naltrexone (NTN, 2mg/kg) on 15% alcohol intake, water intake, and preference ratio in male and female mice after 3-week chronic escalation drinking (CED). (1) Control groups (n=6–8): males and females received one vehicle injection (1% DMSO for MSB control, or saline for NTN control, i.p.) before the drinking test; (2) MSB groups: males (n=6–8) and females (n=14) received one MSB injection (3 mg/kg in 1% DMSO, i.p.) 30 min before the drinking test; and (3) NTN group: males (n=6) and females (n=8) received one NTN injection (2 mg/kg in saline, i.p.) 10 min before the drinking test. On the test day, alcohol (15%) and water intake values were recorded after 4, 8 and 24 hours of alcohol access. * p<0.05, **p<0.01 and ***p<0.005 vs. control at the same time point (see the statistical analysis in Supporting Information section).
Figure 2
Figure 2
Dose responses of single, acute administration of Mesyl Salvinorin B (MSB, 0, 0.1, 0.3, 1 or 3 mg/kg) alone or combined with naltrexone (NTN, 0, 0.3 or 1 mg/kg) on reducing 15% alcohol intake (A) and alcohol preference (B) in both male and female mice (n=5–8) after 3-week chronic escalation drinking. 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. **p<0.01 vs. control (both MSB and NTN at 0 mg/kg); ## p<0.01 between treatment groups (see the statistical analysis in Supporting Information section).
Figure 3
Figure 3
Effects of single, acute Mesyl Salvinorin B (MSB) administration at 0.3 mg/kg (n=6) or 1 mg/kg (n=8) combined with naltrexone (NTN, 1 mg/kg) on 15% alcohol intake, water intake and preference ratio in female mice after 3-week chronic escalation drinking. Control groups: females received one vehicle (1% DMSO, i.p.) followed by saline before the drinking test in two separate experiments with two different MSB+NTN combinations (Vehicle 1 and Vehicle 2). Test groups: females received one MSB injection (0.3 or 1 mg/kg in 1% DMSO, i.p.) followed by one NTN injection (1 mg/kg, i.p.) before the drinking test. On the test day, 15% alcohol (A) and water intake (B) values were recorded after 4, 8 and 24 hours of alcohol access. Preference ratio is shown (C). * p<0.05; ** p<0.01 and ***p<0.005 vs. control at the same time point (see the statistical analysis in Supporting Information section).
Figure 4
Figure 4
Effects of repeated administration of Mesyl Salvinorin B (MSB, 3 mg/kg) on 15% alcohol intake (A) and preference ratio (B) after 3-week chronic escalation drinking in females (n=6–8). *p<0.05 or **p<0.01 vs. control in the same session (see the statistical analysis in Supporting Information section).
Figure 5
Figure 5
Effects of repeated administration of Mesyl Salvinorin B (0.3 mg/kg) combined with naltrexone (NTN, 1 mg/kg) on 15% alcohol intake (A) and preference ratio (B) after 3-week CED in male (left, n=6) and female mice (right, n=5). *p<0.05 vs. the baseline (see the statistical analysis in Supporting Information section).

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