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Cocaine-and-Amphetamine Regulated Transcript (CART) peptide attenuates dopamine- and cocaine-mediated locomotor activity in both male and female rats: lack of sex differences - PubMed

Cocaine-and-Amphetamine Regulated Transcript (CART) peptide attenuates dopamine- and cocaine-mediated locomotor activity in both male and female rats: lack of sex differences

Martin O Job et al. Neuropeptides. 2014 Apr.

Abstract

Cocaine-and-Amphetamine Regulated Transcript peptide (CART peptide) is known for having an inhibitory effect on dopamine (DA)- and cocaine-mediated actions and is postulated to be a homeostatic, regulatory factor in the nucleus accumbens (NAc). Some sex differences in cocaine-mediated locomotor activity (LMA) and in the expression and function of CART peptide have been reported. However, it is not known if the inhibitory effect of CART peptide on cocaine-mediated LMA is sexually dimorphic. In this study, the effects of CART 55-102 on LMA due to intra-NAc DA and i.p. cocaine were determined in male and female Sprague-Dawley rats. The results show that CART 55-102 blunted or reduced both the DA- and cocaine-induced LMA in both males and females. In conclusion, CART peptide is effective in blunting DA- and cocaine-mediated LMA in both males and females.

Keywords: CART55-102; Cocaine; Dopamine; Locomotion; Nucleus accumbens; Phrases Cocaine-and-Amphetamine Regulated Transcript peptide; Sex differences.

Copyright © 2014 Elsevier Ltd. All rights reserved.

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Conflict of interest statement

Conflict of Interest

The authors have no conflicts of interest.

Figures

Fig. 1
Fig. 1. The effect of CART peptide on the LMA due to different doses of cocaine in male and female rats (cocaine dose-response)

CART55-102 (2.5 ug) or saline was administered directly into the NAc of male and female rats immediately before an ip injection of different doses of cocaine (0, 5, 7.5, 10 and 15 mg/kg ip) and LMA was measured. The groups and number of animals/group are shown in Table 1. The y-axis represents total distance traveled in 90 mins and the detailed time courses of LMA after treatment are not shown. The experiments were done in counterbalanced design such that for each cocaine dose, all animals had both saline and CART peptide treatments. The statistical analysis procedure was done as described in the Methods section. For within subject effects (repeated measures design), there was a significant CART effect (F1, 35 = 32.509, ***P<0.0001), a significant CART x cocaine dose effect (F4, 35 = 7.822, ***P<0.0001), no significant CART x sex interaction (F1, 35 = 1.941, P = 0.171) and no significant CART x sex x cocaine dose interaction (F4, 35 = 1.073, P = 0.385). Between subjects, ANOVA showed a significant difference in sex (F1, 35 = 8.988, ***P = 0.005), cocaine dose (F4, 35 = 27.369, ***P<0.0001), but no sex x cocaine dose interaction (F4, 35 = 2.197, P = 0.09). Bonferroni post hoc tests showed that for both sexes, cocaine 10 mg/kg ip and cocaine 15 mg/kg ip increased LMA compared to saline and CART blunted cocaine 10- and cocaine 15-mediated LMA. Bonferroni post hoc tests showed that females are more responsive to cocaine 10 mg/kg ip and cocaine 15 mg/kg ip than males. The significant differences after post hoc analysis are shown on the graph. The p-values * show the differences when comparing saline + cocaine effects and saline + saline (controls) between groups. The p-values # show the difference when comparing CART + cocaine and saline + cocaine to each other within a cocaine dose group. The p-values ¶ show a comparison between males and females within each cocaine-dose and CART treatment group.

Fig. 2
Fig. 2. The effect of different doses of CART peptide on cocaine-10 mg/kg-mediated LMA in male and female rats (CART peptide dose-response)

CART 55-102 (0.0, 1.0 and 2.5 μg) was administered directly into the NAc of male and female rats immediately before an ip injection of saline or cocaine-10 mg/kg and LMA was measured. The y-axis represents the total distance covered in 90 mins. For males and females, the CART 0 + cocaine group is the same as in Fig 1, with other animals re-used for the other groups. 2- way ANOVA determined a significant difference in sex (F1, 25 = 20.633, ***P < 0.0001), a significant difference in the effect of CART (F2, 25 = 12.034, ***P < 0.0001) and no CART dose x sex interaction (F2, 25 = 0.777, P = 0.470). Bonferroni post hoc tests showed that, for both sexes, CART2.5 blunted cocaine-mediated LMA. Bonferroni post hoc tests showed that females are more responsive to cocaine 10 mg/kg ip than males. The significant differences after post hoc analysis are shown on the graph. The p-values * show difference when comparing CART doses control (CART0 + cocaine) within sex and p-values ¶ show a comparison between males and females within CART dose treatment groups.

Fig. 3
Fig. 3. The effect of CART peptide on DA-mediated LMA in males and females

CART55-102 (2.5 ug), CART 1-27 (2.5 μg) or saline was co-administered alone or with dopamine (DA)-15 μg (DA15) directly into the NAc of male and female rats and LMA was measured. The groups and number of animals/group are shown in Table 1. The y-axis represents total distance covered in 60 mins after infusion. The statistical analysis procedure was done as described in the Methods section. 3-way ANOVA showed a difference in sex (F1, 30 = 44.363, ***P < 0.0001), CART (F2, 30 = 13.307, ***P<0.0001), DA (F1, 30 = 51.251, ***P < 0.0001), CART x DA (F2, 30 = 7.043, ***P = 0.003) but no differences in sex x CART (F2, 30 = 0.000429, P = 1.000), sex x DA (F1, 30 = 1.871, P = 0.182) and sex x CART x DA (F2, 30 = 0.409, P = 0.668). Bonferroni post hoc tests showed that in both sexes (a) DA15 increased LMA compared to DA0, (b) CART 1-27 did not blunt DA15-mediated LMA (c) CART 55-102 suppressed DA mediated LMA. Bonferroni post hoc tests showed that (a) basal and DA15-mediated LMA was higher in females than in males. The significant differences after post hoc analysis are shown on the graph. The p-values * show the differences when comparing DA0 to DA15 (controls) between CART treatment groups, and the p-values # show the difference when comparing saline, CART 1-27 and CART 55-102 within each DA-dose group. The p-values ¶ show a comparison between males and females within each DA-dose and CART treatment group.

Fig. 4
Fig. 4. Histological analysis of injector tip placements in the NAc

The numbers in the left and right columns of the histological diagram show the distances from Bregma as described in Methods. Males: filled circles. Females: open circles.

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