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, 216 (3), 367-78

Increased Cocaine Self-Administration in M4 Muscarinic Acetylcholine Receptor Knockout Mice

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Increased Cocaine Self-Administration in M4 Muscarinic Acetylcholine Receptor Knockout Mice

Lene S Schmidt et al. Psychopharmacology (Berl).

Abstract

Rationale: The reinforcing effects of cocaine are mediated by the mesolimbic dopamine system. Behavioral and neurochemical studies have shown that the cholinergic muscarinic M(4) receptor subtype plays an important role in regulation of dopaminergic neurotransmission.

Objectives: Here we investigated for the first time the involvement of M(4) receptors in the reinforcing effects of cocaine using chronic intravenous cocaine self-administration in extensively backcrossed M(4) receptor knockout (M(4) (-/-)) mice.

Methods: We evaluated acquisition of cocaine self-administration in experimentally naïve mice. Both cocaine self-administration and food-maintained operant behavior were evaluated under fixed ratio 1 (FR 1) and progressive ratio (PR) schedules of reinforcement. In addition, cocaine-induced dopamine release and cocaine-induced hyperactivity were evaluated.

Results: M(4) (-/-) mice earned significantly more cocaine reinforcers and reached higher breaking points than their wild-type littermates (M(4) (+/+)) at intermediate doses of cocaine under both FR 1 and PR schedules of reinforcement. Under the PR schedule, M(4) (-/-) mice exhibited significantly higher response rates at the lowest liquid food concentration. In accordance with these results, cocaine-induced dopamine efflux in the nucleus accumbens and hyperlocomotion were increased in M(4) (-/-) mice compared to M(4) (+/+) mice.

Conclusions: Our data suggest that M(4) receptors play an important role in regulation of the reward circuitry and may serve as a new target in the medical treatment of drug addiction.

Figures

Fig 1
Fig 1
Acquisition of cocaine self-administration behavior in experimentally naïve M4−/− mice (white) and M4+/+ mice (black). a: Number of sessions before acquisition criteria were met. b: Percentage of mice that met criteria for cocaine self-administration. Abscissas: Unit dose of cocaine (mg/kg/infusion). Ordinates: Sessions before criteria were met (a) and percentage of mice that acquired self-administration behavior (b). Group sizes: n = 8-9. The M4−/− mice did not differ from their wildtype littermates in acquisition of cocaine self-administration behavior.
Fig 2
Fig 2
Intravenous cocaine self-administration under the FR 1 (a) and the PR (b) schedule of reinforcement in M4−/− mice (white) and wildtype littermates (black). Abscissas: Unit dose of cocaine in saline (mg/kg/infusion). Ordinates: Reinforcers earned under the FR 1 (reinforcers per hour, a) and under the PR (breaking point, b) schedule of reinforcement. The final ratio corresponding to each breaking point is indicated in parentheses for the PR schedule. Group means were calculated from the average for each mouse of two determinations per dose evaluated according to a Latin square design. Group sizes: FR 1 schedule: n = 10-13; PR schedule: n = 8. A significant main effect of genotype was found under both FR 1 and PR schedules of reinforcement. M4−/− mice exhibited higher response rates than wildtype mice at doses of 0.3 and 1.0 mg/kg/infusion under the FR 1 schedule. Under the PR schedule of reinforcement, M4−/− mice reached higher breaking points than wildtype mice at the 1.0 mg/kg per infusion dose. *p < 0.05, **p < 0.01, ***p < 0.001 vs. wildtype; post-hoc t-test following overall significant genotype effect in two-way ANOVA.
Fig 3
Fig 3
Food-maintained operant behavior under the FR 1 (a) and the PR (b) schedule of reinforcement in M4−/− mice (white) and wildtype littermates (black). Abscissas: Concentration of liquid food in water. Ordinates: Reinforcers earned under the FR 1 (reinforcers per hour, a) and under the PR (breaking point, b) schedule of reinforcement. The final ratio corresponding to each breaking point is indicated in parentheses for the PR schedule. Group means were calculated from the average for each mouse of two determinations per concentration evaluated according to a Latin square design. Group sizes: FR 1 schedule: n = 10-13; PR schedule: n = 9-10. The M4−/− mice did not differ from their wildtype littermates in food-maintained responding under the FR 1 schedule. Under the PR schedule of reinforcement M4−/− mice reached higher breaking points at a concentration of 3% liquid food. **p < 0.01 vs. wildtype; post-hoc t-test following overall significant genotype effect in two-way ANOVA.
None
Fig 4
Time course of extracellular NAc dopamine efflux in response to cocaine in M4−/− (white) and M4+/+ (black) mice, n=4-7. Cocaine 30 mg/kg (circle) significantly increased extracellular dopamine in M4−/− mice (samples 20 min to 140 min, p<0.001). This response was significantly enhanced in M4−/− mice compared to M4+/+ mice (***p<0.001, **p<0.01 and *p<0.05). Figure 4. Insert shows cocaine induced dopamine efflux as AUC from 20-80 min. Both genotypes; M4−/− and M4+/+ mice show both a significant dose- and genotype-dependent increase in dopamine efflux (***p<0.001 and **p<0.01).
Fig 5
Fig 5
Effects of cocaine on locomotor activity in naive M4−/− mice (white) and M4+/+ mice (black). M4−/− mice and control littermates (n=5-10) were injected subcutaneously with the indicated doses of cocaine. Locomotor activity was assessed during a 1 h test period. *p<0.05 vs. control; post-hoc t-test following overall significant genotype effect in two-way ANOVA.
Fig 6
Fig 6
Pseudocolored autoradiograms showing 3[H]SCH23390 binding to D1 receptors (A-C) and 3[H]raclopride binding to D2 receptors (D-F) at the level of the caudate-putamen (CPu), nucleus accumbens (NAc) and olfactory tubercle (TO) (color order blue, green, yellow, and red indicate progressively increased binding levels, respectively). A: Non-specific binding in M4+/+ mouse brain. B: Total D1 binding in M4+/+ mouse brain. C: Total D1 binding in M4−/− mouse brain. D: Non-specific binding in M4+/+ mouse brain. E: Total D2 binding in M4+/+ mouse brain. F: Total D2 binding in M4−/− mouse brain. The density of D1 and D2 receptors did not differ between M4−/− and M4+/+ mice (see Table 2 for quantitative data). Scale bar = 1 mm.

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