A Mouse Model for Binge-Level Methamphetamine Use

Abstract

Binge/crash cycles of methamphetamine (MA) use are frequently reported by individuals suffering from MA use disorders. A MA binge is self-reported as multiple daily doses that commonly accumulate to 800 mg/day (~10 mg/kg/day for a 170 pound human). A genetic animal model with a similar vulnerability to binge-level MA intake is missing. We used selectively bred MA high drinking (MAHDR) and low drinking (MALDR) mouse lines to determine whether several procedural variations would result in binge-level MA intake. Data were also collected in two progenitor populations of the MA drinking lines, the DBA/2J (D2) strain and the F2 cross of the D2 and C57BL/6J strains. The impact of 3 factors was examined: (1) concentration of MA in the two-bottle choice procedure used for selective breeding; (2) ratio of bottles containing MA vs. water, and (3) length of the withdrawal (or abstinence) period between MA drinking sessions. When MA concentration was progressively increased every 4 days in 20 mg/l amounts from 20 to 140 mg/l, maximum intake in MALDR mice was 1.1 mg/kg, whereas MAHDR mice consumed as much as 14.6 mg/kg. When these concentrations were tested in a multiple bottle choice procedure, the highest ratio of MA to water bottles (3:1) was associated with escalated MA intake of up to 29.1 mg/kg in MAHDR mice and 12.0 mg/kg in F2 mice; MALDR mice did not show a ratio-dependent escalation in MA intake. Finally, MAHDR and D2 mice were offered 3 bottles of MA vs. water at increasing concentrations from 20 to 80 mg/l, and tested under an intermittent 6-h withdrawal period, which was lengthened to 30 h (D2 mice) or to 30 or 78 h (MAHDR). D2 and MAHDR mice initially consumed similar amounts of 14-16 mg/kg MA, but D2 mice reduced their MA intake 3-fold after introduction of 30-h abstinence periods, whereas MAHDR mice retained their high level of intake regardless of withdrawal period. MAHDR mice provide a genetic model of binge-level MA intake appropriate for the study of associated MA-induced neurobiological changes and pharmaceutical treatments.

Keywords: MAHDR; MALDR; abstinence; genetic; selected line; self-administration; voluntary consumption; withdrawal.

Figure 1

Design for Experiment 4. The control group had access to 4 water bottles (not shown), whereas the MA group had access to 3 MA bottles and 1 water bottle.

Figure 2

Design for Experiment 5. The control group had access to 4 water bottles (not shown), whereas the MA group had access to 3 MA bottles and 1 water bottle.

Figure 3

Increasing concentration of MA leads to binge-level MA intake in selectively bred MA high drinking (MAHDR) mice. (A) mean (± SEM) mg/kg/18 h MA consumed for MA concentrations offered for 4 days each and for each mouse line; B: mean (± SEM) total fluid consumed during the same 18-h periods for each MA concentration and mouse line. ⁺p <0.001 for the difference between MAHDR and MALDR at each concentration; ^**p <0.01 compared to the next lower MA concentration.

Figure 4

A high MA bottle to water (H₂O) bottle ratio (3MA:1H₂O) increased MA intake in MAHDR, but not MALDR, mice. (A,B) Mean (±SEM) mg/kg/18 h MA consumed for each MA concentration, mouse line, and group; (C,D): Mean (±SEM) total fluid consumed during the same 18-h periods for each MA concentration, mouse line, and group. ⁺p <0.01 compared to Group 4 at each MA concentration; ^*p <0.05, ^**p <0.01, ^***p <0.001 compared to the next lower MA concentration for Group 4 only.

Figure 5

A high MA bottle to H₂O bottle ratio (3MA:1H₂O) increased MA intake in B6D2F2 (F2) mice. (A) Mean (±SEM) mg/kg/18 h MA consumed for each MA concentration and group; (B) Mean (±SEM) total fluid consumed during the same 18-h period for each MA concentration and group. ^*, #, and & indicate p <0.05 for Group 4 compared to Group 1, 2, or 3, respectively.

Figure 6

MA intake is reduced in D2 mice when the intermittent MA withdrawal period is lengthened from 6 to 30 h. (A) Mean (±SEM) mg/kg/18 h MA consumed during the MA drinking acquisition period; (B) Mean (±SEM) mg/kg/18 h MA consumed when access to 80 mg/l MA was separated by 30-h withdrawal (abstinence) periods; (C,D) Corresponding mean (±SEM) total fluid consumption for the MA and water only control groups. ^***p <0.001, compared to the next lower MA concentration; ###p <0.001 for the main effect of Day.

Figure 7

MA intake remains high in MAHDR mice under multiple intermittent MA withdrawal periods. (A) Mean (±SEM) mg/kg/18 h MA consumed for each MA concentration and group, during the MA drinking acquisition period; (B) Mean (±SEM) mg/kg/18 h MA consumed when access to 80 mg/l MA was separated by 6-, 30-, or 78-h withdrawal (abstinence) periods; (C, D) Corresponding mean (±SEM) total fluid consumed. Note: Group 1, 6 h (□) is water control group. The MA drinking group 2–4 designations are based on the variable withdrawal length after day 12. See Figure 1 for group information. ^***p <0.001, compared to the next lower MA concentration; ⁺⁺⁺p <0.001, Group 2–4 compared to Group 1.

Figure 8

MAHDR mice are variable in their peak MA intake and MA intake patterns across time. (A) Frequency of animals in bins of 5 mg/kg/18 h, with peak 80 mg/l MA intake level ≥ the value along the x-axis. The inset shows the distribution for D2 mice from Experiment 4 for comparison; (B) MA drinking patterns of 4 MAHDR mice from Group 2 of Experiment 5 illustrating variability in patterns of peaks and troughs in binge-level MA intake. Patterns for Group 2 animals are shown, because they were given daily MA access, whereas the other groups were given MA access every other day or every 3 days.