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.

Trace amine-associated receptor 1 regulation of methamphetamine-induced neurotoxicity

“…Initially developed as an animal model of differential genetic risk for MA intake, mice were bidirectionally selectively bred for voluntary MA consumption from the F2 cross of C57BL/6J (B6) and DBA2/J (D2) mice, using a two-bottle choice task, generating the MA high drinking (MAHDR) and MA low drinking (MALDR) lines (Wheeler et al , 2009). It was later discovered that D2 mice possess a non-synonymous single-nucleotide polymorphism (SNP) that encodes a present, but non-functional TAAR1 and MAHDR mice were homozygous for the D2 allele, whereas MALDR mice were either hetero- or homozygous for the dominant B6 allele that encodes a functional TAAR1 (Harkness et al , 2015;Shabani et al , 2016). Besides differential MA consumption, MAHDR mice expressing the non-functional D2 Taar1 allele exhibit MA-conditioned place preference (CPP), but are insensitive to MA-conditioned taste aversion (CTA), whereas MALDR mice expressing the functional B6 allele lack MA-induced CPP and exhibit high sensitivity to MA-induced CTA (Wheeler et al , 2009;Shabani et al , 2012).…”

Depression‐like symptoms of withdrawal in a genetic mouse model of binge methamphetamine intake

“…6,11,12 MA has dose-dependent negative subjective effects such as anxiety and dysphoria, particularly after 2 to 3 days of abstinence. 20 Furthermore, MA intake was sustained in MAHDR mice after each of several forced abstinence periods of 30 hours in duration. [14][15][16] Unknown is the relationship between the magnitude of symptoms occurring after MA is withdrawn and genetic risk for MA consumption.…”

“…13 Sensitivity to initial positive psychostimulant drug effects has some predictive value for future intake in human and nonhuman subjects. 20 One of the two progenitors of the selected lines, the DBA/2J (D2) strain, but not the other progenitor, the C57BL/6J (B6) strain, voluntarily consumes MA. However, greater sensitivity to the initial negative subjective effects of MA may reduce subsequent MA use in humans, 14 and greater sensitivity to conditioned aversive effects of MA is genetically associated with reduced MA intake in mice.…”

Parallel Effects of Methamphetamine on Anxiety and CCL3 in Humans and a Genetic Mouse Model of High Methamphetamine Intake

“…Plasma levels of CCL3 had not recovered as long as 6 months after MA abuse, though a within-subject examination of CCL3 levels during recovery from MA abuse is needed. Our studies using a different animal model (low-dose MA treatment) found an increase in plasma and hippocampal CCL3 within 72 h of MA treatment and recovery of CCL3 levels after 3 weeks of abstinence [57]; however, it would be exciting to study this in our model of binge-level voluntary MA use [11]. In previous work, 4 h after a single 2 mg/kg dose of MA, the oppositely selectively bred low MA drinking MALDR mice exhibited reduced expression of ccl3 in the nucleus accumbens, as compared to saline-treated MALDR mice [18].…”

“…MAHDR mice voluntarily consume MA in a 2-bottle choice procedure and operantly self-administer MA orally and intracerebroventricularly to a larger extent than MA low drinking (MALDR) mice [10]. Furthermore, the MAHDR line consumes binge-like levels of MA under conditions of high MA availability [11], making them a good model for human MA addiction.…”