Morphine intake and the effects of naltrexone and buprenorphine on the acquisition of methamphetamine intake

Abstract

Some common genetic factors appear to influence risk for drug dependence across multiple drugs of abuse. In previous research, mice that were selectively bred for higher amounts of methamphetamine consumption, using a two-bottle choice methamphetamine drinking procedure, were found to be less sensitive to the locomotor stimulant effects of morphine and of the more selective μ-opioid receptor agonist fentanyl, compared to mice that were bred for low methamphetamine consumption. This suggested that μ-opioid receptor-mediated pathways may influence genetic risk for methamphetamine consumption. We hypothesized that these differences in opioid sensitivity would impact opioid intake in the methamphetamine drinking lines and that drugs with μ-opioid receptor activity would impact methamphetamine intake. Consumption of morphine was examined in 2, two-bottle choice studies, one that compared morphine to quinine consumption and another that used a saccharin fading procedure. Next, naltrexone (0, 0.5, 1, 2, 5, 10 and 20 mg/kg), a μ-opioid receptor antagonist, and buprenorphine (0, 1, 2 or 4 mg/kg), a μ-opioid receptor partial agonist, were each examined for their effects on the acquisition of methamphetamine consumption. Low methamphetamine drinking mice consumed more morphine compared to high methamphetamine drinking mice. Naltrexone did not alter methamphetamine consumption in either selected line; however, buprenorphine reduced methamphetamine intake in the high methamphetamine drinking line. These data show that greater sensitivity to opioids is associated with greater opioid intake and warrant further investigation of drugs with μ-opioid receptor-specific agonist activity in genetically determined differences in methamphetamine consumption.

Keywords: addiction; amphetamine; opioid; psychostimulant; quinine; reward; saccharin; selective breeding; two-bottle choice drinking; μ-Opioid receptor.

Figure 1. Consumption of morphine and quinine in MADR mice, when offered as alternative solutions in a two-bottle choice study

Shown in panel (a),(b) and (c) are mean ± SEM morphine, quinine, and total volume consumed, for 0.3 and 0.7 mg/ml concentrations of morphine (in 0.2% saccharin) vs 0.2 and 0.4 mg/ml concentrations of quinine (in 0.2% saccharin) in a 24-h, two-bottle choice preference test. Panels (d), (e) and (f) show similar data for 0.3 and 1.0 mg/ml morphine (in 0.2% saccharin) vs 0.2 and 0.55 mg/ml quinine (in 0.2% saccharin) concentrations, and total volume consumed. Each bar is a two-day average for days 2 and 4 of a 4-day drinking period. #p<.05, ##p<.01, for the line difference at the indicated concentration; +p<.05 for the main effect of line. Final N=8–14/sex/line.

Figure 2. Consumption of morphine by MADR mice in a saccharin fading study

(a) shows mean ± SEM morphine consumed when offered at increasing concentrations in a fixed concentration of saccharin and then in a fixed concentration at decreasing saccharin concentrations. (b) shows mean ± SEM total volume consumed. Each data point is a two-day average for days 2 and 4 of a 4-day drinking period. #p<.05, ##p<.01, ###p<.001 for the line difference at the indicated concentration. Final N=9–13/sex/line.

Figure 3. Pretreatment with naltrexone does not alter MA drinking in MADR mice

(a) and (b) show mean ± SEM 20 mg/l and 40 mg/l MA consumed, when offered vs water in a 6-h limited access procedure during the beginning of the dark phase of the light : dark cycle. (c) shows mean ± SEM total volume intake. Mice were treated with saline or one of several doses of naltrexone 30 min prior to MA drinking tube access. Each data point is a two-day average for days 2 and 4 of a 4-day drinking period. +++p<.001 for the main effect of line. Final N=6/sex/line/dose.

Figure 4. Pretreatment with higher doses of naltrexone does not alter MA drinking in MADR mice

(a) and (b) show mean ± SEM 20 mg/l and 40 mg/l MA consumed, when offered vs water in a 6-h limited access procedure during the beginning of the dark phase of the light : dark cycle. (c) shows mean ± SEM total volume intake. Mice were treated with saline or one of several doses of naltrexone 30 min prior to MA drinking tube access. Each data point is a two-day average for days 2 and 4 of a 4-day drinking period. ++p<.01; +++p<.001 for the main effect of line. Final N=8/sex/line/dose.

Figure 5. Lower doses of BUP reduce MA intake

Shown are mean ± SEM 20 and 40 mg/l MA consumption and total volume intake for the first (a–c), second (d–f) and third (g–i) 2-h periods of a 6-h MA vs water access period. The legend in panel a applies to panels a, b, d, e, g and h; the legend in panel c applies to panels c, f and i. Mice were treated with saline or one of several doses of BUP 30 min prior to the 6-h access period during the dark phase of the light : dark cycle. Each data point is a two-day average for days 2 and 4 of a 4-day drinking period. #p<.05, ##p<.01, ###p<.001, for the line difference at the indicated dose. *p<.05 for the difference between the saline and BUP mean at the indicated dose. +++p<.001 for the main effect of line. Final N=6/sex/line/dose.