Sex chromosome complement influences vulnerability to cocaine in mice - PubMed (original) (raw)

Sex chromosome complement influences vulnerability to cocaine in mice

Mariangela Martini et al. Horm Behav. 2020 Sep.

Abstract

Women acquire cocaine habits faster and are more motivated to obtain drug than men. In general, female rodents acquire intravenous cocaine self-administration (SA) faster and show greater locomotor responses to cocaine than males. Sex differences are attributed to differences in circulating estradiol. We used the four core genotype (FCG) mouse to ask whether sex chromosome complement influences vulnerability to cocaine's reinforcing and/or locomotor-activating effects. The FCG cross produces ovary-bearing mice with XX or XY genotypes (XXF, XYF) and testes-bearing mice with XX or XY genotypes (XXM, XYM). A greater percentage of gonadal females acquired cocaine SA via infusions into jugular catheters as compared with XYM mice, but XXM mice were not significantly different than any other group. Discrimination of the active versus inactive nose poke holes and cocaine intake were in general greater in gonadal females than in gonadal males. Progressive ratio tests for motivation revealed an interaction between sex chromosomes and gonads: XYM mice were more motivated to self-administer cocaine taking more infusions than mice in any other group. Locomotor responses to cocaine exposure revealed effects of sex chromosomes. After acute exposure, activity was greater in XX than in XY mice and the reverse was true for behavioral sensitization. Mice with XY genotypes displayed more activity than XX mice when given cocaine after a 10-day drug-free period. Our data demonstrate that sex chromosome complement alone and/or interacting with gonadal status can modify cocaine's reinforcing and locomotor-activating effects. These data should inform current studies of sex differences in drug use.

Keywords: Addiction; Cocaine; Locomotor activity; Mice; Self-administration; Sex chromosomes; Sex differences.

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Conflict of interest statement

Declaration of competing interest None.

Figures

Fig. 1.. Acquisition of cocaine self-administration.

Percent of each group reaching cocaine self-administration acquisition criteria. Mice were trained using a Fixed Ratio of 1 with escalating doses of cocaine (0.3, 0.6 and 1 mg/kg/infusion). Symbols in grey represent gonadal females and black are gonadal males. Data from XX genotypes are shown in circles and XY are in squares. *Significant difference between the XYM group as compared with both groups of gonadal females (p < 0.05). N's per group XXF = 15, XYF = 14, XXM = 15, XYM = 19.

Fig. 2.. Discrimination ratio between active and inactive nose poke holes.

Difference between active and inactive nose pokes (Mean + SEM) during acquisition training. Grey symbols represent gonadal females and black symbols show data from gonadal males. The XY genotype groups are in squares with dashed lines, and the XX are in circles with solid lines. * Significant difference between gonadal females and gonadal males (p < 0.05). ** Significant difference between the XYM group and both the XXM and XYF groups (p < 0.02 at least). N's per group XXF = 15, XYF = 14, XXM = 15, XYM = 19.

Fig. 3.. Cocaine intake over self-administration.

Mean (+SEM) cocaine intake (mg/kg). Grey symbols represent gonadal females and black symbols show data from gonadal males. The XY genotype groups are in squares and the XX are in circles. A. All mice in the SA study are included. #Significant difference based on gonadal sex, intake of cocaine in gonadal females is greater than in gonadal males (p < 0.05). *XYF intake significantly more than XYM mice on days 8 and 12. N's per group XXF = 15, XYF = 14, XXM = 15, XYM = 19. B. No significant effects were found for sex chromosomes or gonadal sex in mice that acquired SA. N's per group XXF = 10, XYF = 11, XXM = 7, XYM = 6.

Fig. 4.. Progressive ratio data for mice that acquired self-administration.

Individual scores for each mouse in the progressive ratio test. Average number of infusions recorded and ratio reached (breakpoints) after 3 daily consecutive PR cocaine self-administration sessions. Grey symbols represent gonadal females and black symbols show data from gonadal males. The XY genotype mice are in squares and the XX are in circles. *XYM group is significantly different from all other groups (p < 0.01). N's per group XXF = 10, XYF = 11, XXM = 7, XYM = 6.

Fig. 5.. Activity after the initial exposure to cocaine.

Mean (+SEM) horizontal distance traveled (in meters, m) after an initial acute injection of saline or cocaine. # Significant effect of sex chromosome complement, XX mice move a greater distance than XY mice (p < 0.001). *Significantly different from XYM given the same cocaine dose (p < 0.05). +Significant difference between XXF mice and XY mice (of both gonadal sexes) given the same dose (p < 0.05). N's per group: saline n = 14 for each group; cocaine dose of 5 mg/kg; n = 8 for XXF and XYF groups and n = 6 for XXM and XYM groups; for cocaine doses of 10 and 20 mg/kg; n = 8 for each group.

Fig. 6.. Behavioral sensitivity: Activity differences between the first and final injections.

Mean (+SEM) difference in horizontal distance traveled (in meters, m) between the final and first acute injection. One group of mice received saline for 5 days and after 10 days without disturbance an injection of cocaine (Saline+Cocaine 20 mg/kg, white histograms). A second group received 20mg/kg cocaine for 5 days and a cocaine challenge after 10-days without injections (Cocaine 20mg/kg, black histograms). * In Cocaine 20mg/kg mice XY individuals had more activity as compared with XX mice, on the final day as compared to the first day of treatment (p < 0.05). N's per group = 8/each treatment and genotype.

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Sex chromosome complement influences vulnerability to cocaine in mice - PubMed (original) (raw)