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. 2002 Jun 25;99(13):9026-30.
doi: 10.1073/pnas.142039099.

Cocaine sensitization and reward are under the influence of circadian genes and rhythm

Carolina Abarca  1 , Urs Albrecht, Rainer Spanagel
Affiliations

Cocaine sensitization and reward are under the influence of circadian genes and rhythm

Carolina Abarca et al. Proc Natl Acad Sci U S A. .

Abstract

Investigations using the fruit fly Drosophila melanogaster have shown that the circadian clock gene period (Per) can influence behavioral responses to cocaine. Here we show that the mouse homologues of the Drosophila Per gene, mPer1 and mPer2, modulate cocaine sensitization and reward, two phenomena extensively studied in humans and animals because of their importance for drug abuse. In response to an acute cocaine injection mPer1 and mPer2 mutant mice as well as wild-type mice exhibited an approximately 5-fold increase in activity compared with saline control levels, showing that there is no initial difference in sensitivity to acute cocaine administration in Per mutants. After repeated cocaine injections wild-type mice exhibited a sensitized behavioral response that was absent in mPer1 knockout mice. In contrast, mPer2 mutant mice exhibited a hypersensitized response to cocaine. Conditioned place preference experiments revealed similar behavioral reactions: mPer1 knockout mice showed a complete lack of cocaine reward whereas mPer2 mutants showed a strong cocaine-induced place preference. In another set of experiments, we tested C57/BL6J mice at different Zeitgeber times and found that cocaine-induced behavioral sensitization and place preference are under the control of the circadian clock. In conclusion, we demonstrate that processes involved in cocaine addiction depend on the circadian rhythm and are modulated in an opposing manner by mPer1 and mPer2 genes.

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Figures

Figure 1
Figure 1
Basal locomotor activity and acute cocaine response in Per mutants. Locomotor responses to saline and single cocaine injections in wild-type (wt) mice or mice carrying a mutation in mPer1 or mPer2 genes are shown. (A) The graph shows the activity after saline and acute cocaine injections (* indicates a significant difference to saline treatment P < 0.05). (Inset) The basal locomotor response during a period of 30 min [F(2,36) = 1.38. P = 0.26]. (B) The increase in locomotor activity after an acute cocaine injection was also calculated as percentage difference in activity to a saline injection. One-way ANOVA did not show statistical differences between the three genotypes [F(2,39) = 0.046, P = 0.9]. All data are presented as mean ± SEM.
Figure 2
Figure 2
Short-term sensitization in Per mutants. Locomotor responses to acute and repeated saline/cocaine injections in wild-type (wt) mice or mice carrying a mutation in mPer1 or mPer2 genes after a 3-day withdrawal period are shown. (A) Mean locomotor activity ± SEM after acute cocaine and repeated cocaine injections (wt, n = 13–16; Per1 mutant, n = 9–10; and Per2 mutant, n = 14–15). Two-way ANOVA revealed that cocaine sensitization differed significantly for the different genotypes (see text). Further statistical comparisons between acute and repeated treatment showed the following differences for each genotype: wt, P = 0.04; Per1 mutant, P = 0.78; and Per2 mutant, P = 0.002. * indicates a significant difference to acute cocaine P < 0.05; **, P < 0.01. (B) The increase in locomotor activity after repeated cocaine injections was also calculated as percentage difference in activity to acute cocaine injection. The dashed line indicates mean activity after acute cocaine injection. One-way ANOVA revealed a genotype effect [F(2,36) = 9.5, P = 0.005]. * indicates a significant difference to wt mice, P < 0.05.
Figure 3
Figure 3
Long-term sensitization in Per mutants. Locomotor responses to acute and repeated saline/cocaine injections in wild-type (wt) mice or mice carrying a mutation in mPer1 and mPer2 genes after a withdrawal period of 3 weeks are shown. (A) Mean locomotor activity ± SEM after acute and repeated cocaine injections. Two-way ANOVA revealed that cocaine sensitization differed significantly for the different genotypes (see text). Further statistical comparison between acute and repeated (long-term) treatment for each genotype showed the following differences: wt, P = 0.37; Per1 mutant, P = 0.44; and Per2 mutant, P = 0.007. * indicates a significant difference to acute cocaine P < 0.01. (B) The increase in locomotor activity after repeated cocaine injections was also calculated as percentage difference in activity to acute cocaine injection. One-way ANOVA revealed a genotype effect [F(2,16) = 7.15, P = 0.007]. * indicates a significant difference to wt mice, P < 0.05.
Figure 4
Figure 4
CPP in wild-type (wt) mice or mice carrying a mutation in mPer1 and mPer2 genes. Cocaine-induced place conditioning engendered opposite responses in Per1 mutant and Per2 mutant mice. Data are given as mean ± SEM of difference between time on cocaine-paired and saline-paired side. One-way ANOVA revealed significant differences for the factor genotype: F(2,63) = 5.65, P = 0.005. Post hoc analysis showed differences between wt and Per1 mutant (P = 0.029) and no difference between wt vs. Per2 mutant (P = 0.45), Per1 mutant vs. Per2 mutant P = 0.026. * indicates a significant difference to wt mice, P < 0.05.
Figure 5
Figure 5
Diurnal differences in cocaine-induced behavioral sensitization and reward. (A) Locomotor activity was measured at different time points (ZT4 and ZT12) in C57/BL6J mice (n = 15 per group) after acute and repeated cocaine injections. The increase in locomotor activity after repeated cocaine injections was calculated as percentage difference in activity to acute cocaine injection. The dashed line indicates mean activity after acute cocaine injection. Unpaired t test reveals significant decrease in behavioral sensitization at the end of the light phase in comparison to sensitization at ZT4, P = 0.0001. (B) Cocaine-induced place preference measured at two different time points. At ZT4 place preference was significantly different from cocaine-induced place preference at ZT12, P = 0.028. * indicates significant difference to ZT4, P < 0.05.
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