Exploration of sex differences in Rhes effects in dopamine mediated behaviors

Abstract

Studies have shown that Ras homolog enriched in striatum (Rhes) proteins are highly expressed in areas of the central nervous system that have high dopaminergic innervation. In this study, we used Rhes mutant mice (Wild type, Rhes KO, Rhes Heterozygous) of both sexes to explore differences in the effects of Rhes protein levels in basal levels of activity, anxiety, and stereotypy, in relation to sex. Adult male and female mice were evaluated in an open field test for measuring basal levels of activity and anxiety for 5 consecutive days, and they were tested in the apomorphine-induced stereotypy paradigm. Rhes protein levels affected basal levels of activity but it was not found to be related to sex differences. Moreover, a decrease in Rhes protein levels was linked to a nonsignificant anxiolytic effect, mainly in female mice. Finally, a decrease in Rhes protein levels does not affect dopamine D(1) and D(2) receptor (D(1)/D(2)) synergism in female or male mice. Together, these results suggest that Rhes protein levels affect locomotion activity, and have an influence in anxiety depending on sex; Rhes protein levels do not affect D(1)/D(2) synergism in both sexes.

Keywords: Rhes protein; behavior; dopamine receptor; mutant mice; sexes.

Figure 1

Profile of locomotor activity in female and male wild type (WT), knockout (KO), and heterozygous (Het) mice (day X sex X genotype) in the open field. Note: Each point of the graph represents the average distance traveled (cm) in the open field (±SE) per day. Abbreviations: WT, wild type; KO, knockout; Het, heterozygous; SE, standard error.

Figure 2

Profile of locomotor activity in WT, KO, and Het mice during the first 15 minutes of day 1 in the open field. Notes: Each point of the graph represents the average distance traveled (m) in the open field (±SE) per time interval. Data for males and females were pooled (n = 18 to 23 per genotype). Abbreviations: WT, wild type; KO, knockout; Het, heterozygous; SE, standard error.

Figure 3

Profile of anxiety behavior in female and male WT, KO, and Het mice in the open field. Notes: Every bar represents the mean time in seconds spent in the periphery of the open field (±SE). The total amount of time for screening the behavior per day was 30 minutes (1800 seconds). Abbreviations: WT, wild type; KO, knockout; Het, heterozygous; SE, standard error.

Figure 4

Profile of stereotypy behavior in female and male WT, KO, and Het mice. Notes: Every bar represents the average score of all the time points (±SE). The higher the score, the higher the level of stereotypy. There was significant treatment effect (P < 0.001), genotypic effect (P < 0.001), and sex effect (P < 0.05). Specifically, D2 + D1 Treatment differed significantly from the rest of the Treatments (P < 0.001). Moreover, D1 Treatment differed significantly from the rest of the Treatments (P < 0.001). **P < 0.001 WT groups differs from KO and HET; *P < 0.01 male WT groups differs from male KO and HET. Abbreviations: WT, wild type; KO, knockout; Het, heterozygous; SE, standard error.