Article Figures & Data
Figures
- Figure 1.
Food-maintained operant behavior in M5–/– (white) and M5+/– (gray) mutant mice and their wild-type littermates (black), males and females combined. Abscissas, Concentration of liquid food in water. Ordinates, Food reinforcers earned under the FR1 (reinforcers per hour; left) and the PR (breaking point; right) schedules of reinforcement. The final ratio corresponding to each breaking point is indicated in parentheses for the PR schedule. Data are group means ± SEM of reinforcers earned. Group means were calculated from the average for each mouse of one (FR) or two to three (PR) determinations per concentration evaluated according to a Latin square design. Group sizes are as follows: FR schedule, n = 20–29; PR schedule, n = 10–16. The mutant mice did not differ from their wild-type littermates in food-maintained operant behaviors.
- Figure 2.
Intravenous cocaine self-administration under the FR 1 schedule of reinforcement in male and female M5–/– (white) and M5+/– (gray) mutant mice and their wild-type littermates (black) with previous food-maintained, operant experience. Data from female mice are shown in the left panel, and data from male mice are shown in the right panel. Abscissas, Unit dose of cocaine in saline (Sal) (milligrams per kilogram per infusion; evaluated according to a Latin square design). Ordinates, Cocaine reinforcers earned per hour. Data are group means ± SEM. Group sizes are as follows: females, n = 5–8; males, n = 6–7. Response rates did not differ significantly between genotypes. There was a significant sex by dose interaction (p < 0.01), but doses of 0.10 and 0.32 mg/kg per infusion maintained higher response rates than saline in both sexes (p < 0.05 or p < 0.01 vs saline; Student–Newman–Keuls test).
- Figure 3.
Active and inactive responses during the hole reversal procedure in M5–/– mice, males and females combined. Abscissas, Session number in each phase. Ordinates, Response rate per hour. Active responses were reinforced by 1.0 mg/kg per infusion of cocaine under an FR 1 schedule, and inactive responses had no scheduled consequences. Filled symbols represent responses in the right nose-poke hole (reinforced or inactive), and open symbols represent responses in the left nose-poke hole (reinforced or inactive). The left panel shows responding before reversal (right hole active), the center panel shows responding with the nose-poke holes reversed (left hole active), and the right panel shows responding after the second reversal (right hole active). All points are group means ± SEM. Group size is n = 5. All mice successfully reallocated their behavior to maintain cocaine intake at rates comparable with pre-reversal levels, while decreasing nonreinforced responses over sessions. Results were similar to our previous assessment of the background strain C57BL/6J (see Results).
- Figure 4.
Acquisition of cocaine self-administration behavior in experimentally naive M5–/– (white) and M5+/– (gray) mutant mice and their wild-type littermates (black), males and females combined. Abscissas, Unit dose of cocaine in saline (milligrams per kilogram per infusion). Ordinates, Percentage of mice that acquired self-administration behavior (left) and sessions before criteria were met (right). Group sizes are as follows: n = 6–7 except M5+/– mice at the 0.03 mg/kg per infusion dose, n = 5. Left, Percentage of mice that met criteria for cocaine self-administration. Right, Number of sessions before acquisition criteria were met. Data are group means ± SEM. The reduced acquisition by the mutant mice was reflected by a significant effect of genotype in the number of sessions before acquisition criteria were met at the lowest dose (†p < 0.05, log-rank test). Sex was not a significant factor at any dose.
- Figure 5.
Intravenous cocaine self-administration under the PR schedule of reinforcement in M5–/– (white) and M5+/– (gray) mutant mice and their wild-type littermates (black), males and females combined. Abscissas, Unit dose of cocaine in saline (milligrams per kilogram per infusion). Ordinates, Breaking point (reinforcers earned), with the corresponding final ratio in parentheses. Data are group means ± SEM, calculated from the average for each mouse of two or three determinations per dose evaluated according to a Latin square design. Group sizes were n = 8–12. Sex was not a significant factor. M5–/– mice reached lower breaking points than wild-type mice at doses of 0.03 and 0.32 mg/kg per infusion. †p < 0.05, ††p < 0.01 versus wild type; post hoc t test.
Tables
- Table 1.
General health, sensorimotor, and behavioral characteristics of female and male M5+/+, M5+/–, and M5–/– mice
+/+ Females +/- Females -/- Females +/+ Males +/- Males -/- Males Parameter (n = 15) (n = 13) (n = 13) (n = 14) (n = 13) (n = 13) General health Body weight (g) 21.0 ± 0.3 20.5 ± 0.2 20.7 ± 0.3 24.9 ± 0.5 25.3 ± 0.6 24.8 ± 0.5 Fur mattinga 0 0 0 0.07 ± 0.07 0 0.31 ± 0.13 Baldinga 0 0 0 0 0 0 Soresa 0 0 0 0 0 0.15 ± 0.15 Whiskersa 0 0 0 0 0 0 Home-cage behaviora Sleep 8:00 A.M. 2.00 ± 1.15 1.33 ± 1.33 3.33 ± 0.67 1.33 ± 1.33 2.67 ± 1.33 4.00 ± 0.00 2:00 P.M. 2.67 ± 10.33 1.33 ± 1.33 4.00 ± 0.00 3.33 ± 0.67 4.00 ± 0.00 2.67 ± 0.67 8:00 P.M. 0 0 0 0 0 0 Huddled 8:00 A.M. 2.33 ± 1.20 2.33 ± 1.20 4.00 ± 0.00 2.67 ± 0.67 4.00 ± 0.00 4.00 ± 0.00 2:00 P.M. 2.67 ± 1.33 2.67 ± 1.33 4.00 ± 0.00 3.33 ± 0.67 4.00 ± 0.00 3.00 ± 0.58 8:00 P.M. 0 0 0 0 0 0 In “igloo” 8:00 A.M. 3.00 ± 1.00 2.33 ± 1.20 4.00 ± 0.00 2.67 ± 0.67 4.00 ± 0.00 3.33 ± 0.67 2:00 P.M. 0.33 ± 0.33 2.67 ± 1.33 4.00 ± 0.00 3.33 ± 0.67 4.00 ± 0.00 3.00 ± 0.58 8:00 P.M. 0 0.33 ± 0.33 0.33 ± 0.33 0.33 ± 0.33 0 1.00 ± 0.00 Fighting 0 0 0 0.33 ± 0.33 0.33 ± 0.33 2.00 ± 058 Wounds from fighting 0.13 ± 0.09 0 0 0 0 0.69 ± 0.24 Reaction to handlinga Escape 0 0.08 ± 0.08 0.23 ± 017 0 0 0 Biting 0 0 0 0 0 0 Sensorimotorb Eye blink test 15/15 13/13 13/13 14/14 12/13 12/13 Ear twitch 15/15 13/13 13/13 14/14 13/13 13/13 Whisker orientation 14/15 13/13 11/13 14/14 13/13 13/13 Righting reflex 15/15 13/13 13/13 14/14 13/13 13/13 Vision test 15/15 13/13 13/13 14/14 13/13 13/13 Motor skills Hanging wire test (s) 58.13 ± 1.87 59.46 ± 0.54 55.85 ± 2.81 55.50 ± 2.30 57.62 ± 2.07 54.54 ± 3.20 Footprint pattern SL (mm) 52.95 ± 1.15 52.36 ± 1.34 51.17 ± 1.25 55.82 ± 1.30 57.19 ± 1.10 56.12 ± 1.07 Difference in SL (mm) 18.85 ± 1.03 18.88 ± 1.49 16.38 ± 1.30 20.26 ± 1.35 19.91 ± 1.34 17.42 ± 1.35 Base of support (mm) 24.09 ± 0.38 24.49 ± 0.57 24.28 ± 0.60 24.72 ± 0.50 25.47 ± 0.41 24.51 ± 0.30 -
The male M5-/- mice showed significantly higher scores than all other genotype/sex groups in incidence of fighting in the home cage, presence of wounds from fighting (bite wounds on tails and rumps), and fur matting (all p < 0.01). Regardless of genotype, female mice had lower body weight and shorter stride length than male mice (both p < 0.001). All other measures were similar between genotypes and sexes. SL, Stride length.
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↵ a Scores 0 – 4 (0, none; 4, as much as ever observed).
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↵ b Number of mice testing “normal”/total mice.
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- Table 2.
Mean number of sessions to criteria in food-trained M5+/+, M5+/–, and M5–/– mice (males and females combined)
Genotype Sessions to criteria +/+ +/- -/- Food FR 1 acquisition 3.17 ± 0.56 (23) 2.66 ± 0.11 (29) 2.80 ± 0.28 (20) Food FR 1 extinction 1.35 ± 0.13 (23) 1.31 ± 0.12 (29) 1.75 ± 0.28 (20) Food PR baseline 5.38 ± 0.69 (13) 5.25 ± 0.86 (16) 5.10 ± 0.71 (10) Food PR extinction 2.92 ± 0.37 (13) 2.88 ± 0.92 (16) 1.20 ± 0.13 (10) Cocaine FR 1 baseline 3.39 ± 0.88 (18) 2.71 ± 0.28 (24) 2.80 ± 0.39 (15) Cocaine FR 1 extinction 5.22 ± 1.15 (18) 5.21 ± 1.28 (24) 3.27 ± 0.56 (15) -
Data are group means ± SEM, with n in parentheses. All mice were trained with liquid food under an FR 1 schedule of reinforcement, and a randomly chosen subset was subsequently tested under a PR schedule. After recovery from the catheter implantation surgery, 1.0 mg/kg per infusion of cocaine was made available as the reinforcer. Some attrition occurred during or shortly after surgery. There was no significant effect of genotype or of sex in any of the measures.
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