Selective breeding for magnitude of methamphetamine-induced sensitization alters methamphetamine consumption

Abstract

Rationale: Genetically determined differences in susceptibility to drug-induced sensitization could be related to risk for drug consumption.

Objectives: Studies were performed to determine whether selective breeding could be used to create lines of mice with different magnitudes of locomotor sensitization to methamphetamine (MA). MA sensitization (MASENS) lines were also examined for genetically correlated responses to MA.

Methods: Beginning with the F2 cross of C57BL/6J and DBA/2J strains, mice were tested for locomotor sensitization to repeated injections of 1 mg/kg MA and bred based on magnitude of sensitization. Five selected offspring generations were tested. All generations were also tested for MA consumption, and some were tested for dose-dependent locomotor-stimulant responses to MA, consumption of saccharin, quinine, and potassium chloride as a measure of taste sensitivity, and MA clearance after acute and repeated MA.

Results: Selective breeding resulted in creation of two lines [MA high sensitization (MAHSENS) and MA low sensitization (MALSENS)] that differed in magnitude of MA-induced sensitization. Initially, greater MA consumption in MAHSENS mice reversed over the course of selection so that MALSENS mice consumed more MA. MAHSENS mice exhibited greater sensitivity to the acute stimulant effects of MA, but there were no significant differences between the lines in MA clearance from blood.

Conclusions: Genetic factors influence magnitude of MA-induced locomotor sensitization and some of the genes involved in magnitude of this response also influence MA sensitivity and consumption. Genetic factors leading to greater MA-induced sensitization may serve a protective role against high levels of MA consumption.

Fig. 1

Locomotor sensitization to MA is a heritable trait. Shown are the sensitization score (day 11–day 3) means (±SEM) for the F2 population (n=57–60 per sex; total N=117; age=64±1 days), for the parents (n=13 per sex and line) selected to produce offspring for each selection generation and for the offspring of each generation (n=66–128 mice per generation; age=63±1 days old on the first day of testing). The dose of MA administered on all test days was 1 mg/kg. ^*Main effect of line in S1 [F(1,100)=6.1, p<0.02]; S2 [F(1,65)=12.9, p<0.001], S3 [F(1,62)=15.2, p<0.001], S4 [F(1,124)=8.6, p<0.01], and S5 [F(1,113)=11.9, p<0.001]

Fig. 2

Acute locomotor stimulation to MA is genetically correlated with magnitude of MA-induced sensitization. Main figure: Shown are the acute stimulant score (day 3–day 2) means (±SEM) for the same F2 population and selected line offspring whose sensitization scores are shown in Fig. 1. The dose of MA given on day 3 was 1 mg/kg. ^†Statistical trend for a main effect of line in S1 [F(1,100)=2.8, p= 0.09], S2 [F(1,65)=3.0, p=0.09], and S5 [F(1,113)=2.9, p=0.09]. ^*Main effect of line in S3 [F(1,62)=5.5, p<0.05] and S4 [F(1,124)= 5.2, p<0.05]. Inset: Mean (±SEM) acute stimulant scores for the parents shown in Fig. 1

Fig. 3

Activity levels on saline treatment days of MAHSENS and MALSENS mice across selection generations. Shown is mean (±SEM) distance traveled in cm for the same F2 population and selected line offspring whose sensitization and acute MA scores are shown in Figs. 1 and 2. ^*p<0.05 for the comparison of MAHSENS and MALSENS mice of that selection generation

Fig. 4

MAHSENS mice exhibit greater sensitivity to the acute stimulant effects of MA compared to MALSENS mice. Shown are mean (±SEM) acute stimulant scores for S5 MAHSENS and MALSENS mice (n=7–12 per selected line, sex, and dose; total N= 198; age=84±1 days) that were tested after saline on 2 consecutive days and then after saline or several doses of MA on day 3. ^*p<0.05 for the comparison of MAHSENS and MALSENS mice of the same sex. ^**p < 0.001 for the comparison of MAHSENS and MALSENS mice of the same sex. ^ap < 0.05 for the comparison of the effect of that MA dose to the saline group (0 mg/kg) of the same line and sex

Fig. 5

Line differences in the amount of MA consumed reverse over the course of selection for magnitude of MA-induced sensitization. Shown are mean (±SEM) MA consumption (a, b) and preference (c, d) values for a 20 and 40 mg/l solution of MA offered vs. tap water for MAHSENS and MALSENS mice tested in each selection generation (n=8–12 per line and sex in each generation; 75±1 days old). Panels e and f show total volume of fluid consumed from both the MA- and water-containing tubes during the 18-h period when the 20 and 40 mg/l MA solutions were offered, respectively. Mice had ad libitum access to water during the remaining 6-h period. ^*p<0.05 for the main effect of line

Fig. 6

Consumption of novel tastants in S2 and S5G6 MASENS mice. Shown are mean (±SEM) saccharin (a, b), quinine (c, d), and potassium chloride (e, f) consumed in generation S2 (n=10–11 per line and sex) and S5G6 (n=7–18 per line and sex) MALSENS and MAHSENS mice, when each tastant solution was offered vs. tap water. ^**p<0.01 for the main effect of line in panels a and c and for the effect of line within females only in panel b