Early postnatal l -Dopa treatment causes behavioral alterations in female vs. male young adult Swiss mice

Neuropharmacology 170 (2020) 108047

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Early postnatal L-Dopa treatment causes behavioral alterations in female vs. male young adult Swiss mice

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Lorena Oliveira de Matosa, Ana Luiza de Araujo Lima Reisa, Lorena Terene Lopes Guerraa, Leonardo de Oliveira Guarnieria, Muiara Aparecida Moraesa, Laila Blanc Arabea, Renan Pedra de Souzab, Grace Schenatto Pereiraa, Bruno Rezende Souzaa,∗ a b

Núcleo de Neurociências, Department of Physiology and Biophysics, Universidade Federal de Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil Department of Genetics, Universidade Federal de Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil

H I GH L IG H T S

-Dopa treatment increases females' exploratory behavior. • Perinatal -Dopa treatment increases females' anxiety-like and hedonic behavior. • Perinatal Perinatal -Dopa treatment decreases males' anxiety- and depressive-like behavior. • The behavioral consequences of perinatal -Dopa treatment are sexually dimorphic. • L L L

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A R T I C LE I N FO

A B S T R A C T

Keywords: Dopamine Neurodevelopment Behavior Sexual dimorphism Ontogeny Neonatal

Dopaminergic signaling and neurodevelopment alterations are associated with several neuropsychiatric disorders. Knockout mice for dopamine transporters (DAT) as well as site-specific knockout mice lacking dopaminergic D2 autoreceptors in dopaminergic neurons (DA-D2RKO) display behavioral alterations such as hyperlocomotion and abnormal prepulse inhibition. However, it is possible that dopaminergic imbalances may have different effects during varied neurodevelopmental windows. In our previous study, we observed that elevated levels of dopamine during the perinatal developmental window increased exploratory behavior of juvenile (4-week-old) Swiss female mice and impaired hedonic behavior in males. In this study, we investigated whether these behavioral alterations persist through young adulthood. In order to do so, we administered daily doses of L-Dopa to mice pups beginning from postnatal day 1 (PD1) to PD5. At the age of 8 weeks, we submitted the young adult males and females to the open field test, elevated plus maze, forced swimming test, and sucrose preference test. We observed that augmentation of dopamine levels during the perinatal developmental window increased locomotor behavior in females, but not males. We also observed an increase in anxiety-behavior in females and anxiolytic-like behavior in males. In addition, we observed stress-coping behavior in males and an increase of hedonic behavior in females. Our results show that dopamine signaling is important for behavioral development and that transient imbalances of dopamine levels can cause permanent behavioral alterations – alterations which are different in males than in females. These data may help in better understanding the spectrum of symptoms associated with different neuropsychiatric disorders.

1. Introduction Different studies support both dopaminergic and neurodevelopmental hypotheses for many neuropsychiatric disorders. However, only a handful of these studies have shown a convergence of this evidence (Bale et al., 2010; Robinson et al., 2001; Souza and Tropepe, 2011). One good example comes from studies of schizophrenic (SCZ) patients,

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who present alterations in volume and morphology of specific brain regions (Bähner and Meyer-Lindenberg, 2017; Hoftman et al., 2017; van Erp et al., 2015; Zhuo et al., 2017). It is possible to detect behavioral alterations and early symptoms of SCZ during adolescence but the clinical diagnosis is usually given at adulthood (Cornblatt and Keilp, 1994; Erlenmeyer-Kimling et al., 2000; Hart et al., 2013). The alteration of dopaminergic signaling in SCZ patients is by now a

Corresponding author. E-mail address: [email protected] (B.R. Souza).

https://doi.org/10.1016/j.neuropharm.2020.108047 Received 11 November 2019; Received in revised form 28 January 2020; Accepted 8 March 2020 Available online 12 March 2020 0028-3908/ © 2020 Published by Elsevier Ltd.

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in maternal behavior, it is possible that the lack of maternal care is also affecting the development of pups (Chocyk et al., 2013; Teicher et al., 2004). Our hypothesis is that an increase of dopamine during specific developmental windows causes different alterations in brain and behavior development. There is a significant increase in dopaminergic synaptic formation in the first few days after birth (Jung, 1996; Kalsbeek et al., 1988; Leroux-Nicollet et al., 1990; Schmidt et al., 1982; Verney et al., 1982). Thus, the first 5 PD of mice is an important developmental window, and it is therefore possible that an imbalance of dopaminergic signaling within this period would impair behavioral development (Ignacio et al., 1995; Rice and Barone, 2000). In our previous study, we observed that elevated levels of dopamine during the perinatal developmental window increased the exploratory behavior of juvenile (4-week-old) Swiss female mice and impaired hedonic behavior in males (de Matos et al., 2018). In this study, we investigated whether a transient increase of brain dopamine levels during the first 5 PD would cause behavioral abnormalities in young adult (8-week-old) female and male mice.

well-known phenomenon. Many studies have shown an increase of dopaminergic D2 receptors and alterations in levels of proteins related to dopaminergic intracellular pathways, such as Neuronal Calcium Sensor-1 (NCS-1) and Dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa (DARPP-32), which are independent of antipsychotic treatments (Albert et al., 2002; Feldcamp et al., 2008; Ishikawa et al., 2007; Kreczmanski et al., 2007; Kunii et al., 2011; Souza et al., 2010, 2008; Wong et al., 1986). In addition, there is an increase of presynaptic dopamine levels and dopamine release within the brain of SCZ patients (Abi-Dargham et al., 1998; Breier et al., 1997; Howes et al., 2009; Laruelle et al., 1996; Lindström et al., 1999; Reith et al., 1994). In addition, dopaminergic signaling can be temporarily affected by perinatal exposure to drugs, causing cognitive alterations and mental health issues later in life (reviewed by Ross et al., 2015). Viral, fungal or even parasitic infections can also harm dopaminergic signaling and may lead to behavioral anomalies (Abercrombie et al., 1989; Kumar et al., 2011; Prandovszky et al., 2011; Rasheed et al., 2010; Severance et al., 2016; Simanjuntak et al., 2017). Dopamine is not only involved in the cell cycle but also in many neurodevelopmental functions, including cell proliferation, cell differentiation, morphogenesis, and neuronal migration (Crandall et al., 2007; Hedlund et al., 2016; Popolo et al., 2004; Schmidt et al., 1996; Souza et al., 2011). Dopamine and dopaminergic receptors are expressed from the early stages of prenatal development. It is therefore possible that imbalances in dopaminergic signaling may be involved in some of the developmental alterations found in many neuropsychiatric disorders (Björklund et al., 1968; Coyle and Axelrod, 1972; Olson and Seiger, 1972b; Schambra et al., 1994; Specht et al., 1981; Unis et al., 1998). Several animal models were developed in order to understand the role of dopamine in neurodevelopment. For example, knockout (KO) mice for the dopaminergic enzyme tyrosine hydroxylase (TH) and dopaminergic receptors show several behavioral alterations with respect to motor behavior, feeding behavior, reward behavior, and cognition (Baik et al., 1995; El-Ghundi et al., 2003; Maldonado et al., 1997; Smith et al., 1998; Szczypka et al., 1999; Xu et al., 1994). To study the consequences of the increase in dopamine levels, several studies used KO mice for dopamine transporter (DAT), which showed hyperdopaminergia within the brain and locomotor hyperactivity, and alterations in exploratory and maternal behavior (Giros et al., 1996; Spielewoy et al., 2000). However, DAT KO mice do not express DAT throughout their entire lives, and it is therefore virtually impossible to know if the behavioral abnormalities presented by the KO mice are due to the dopaminergic imbalance during development or due instead to the alterations in the dynamic of dopaminergic signaling during the behavioral tests. Also problematic is the fact that neurodevelopment is of course a very dynamic process and occurs over multiple stages (Andersen, 2000). During prenatal development, phenomena like neurogenesis, neuronal migration, and cell differentiation are very pronounced (Bayer et al., 1993; McConnell, 1990; O'Rourke et al., 1992). On the other hand, during early postnatal development there is an increase in synaptogenesis and apoptosis (Aghajanian and Bloom, 1967; Blaschke et al., 1998). In the same vein, there are also ontogenetic sex differences during brain development (Tobet et al., 2009). For example, female rat pups have more dopaminergic projections to striatum than do their male counterparts, with higher levels of dopamine and tyrosine hydroxylase (TH). Instead, male pups show higher levels of testosterone and estradiol than females, which delays the perinatal development of the dopaminergic system (Ovtscharoff et al., 1992). Given the well-known historical bias toward male animals and cells in research, efforts must be made to include both sexes in current neurodevelopmental studies (Prendergast et al., 2014; Zucker and Beery, 2010). Taking all these data into consideration, it is important to understand exactly which phenomenon was affected by the increase of dopamine and when (i.e. during which developmental window) this alteration occurred. Furthermore, since DAT KO females show alterations

2. Materials 2.1. Animals Male and female Swiss mice (Tac:UFMG:SW/8–12 weeks of age) were purchased from the Animal Facility of the Universidade Federal de Minas Gerais (CEBIO, UFMG, Brazil) for mating. Mice were raised in polypropylene cages (27 cm × 17 cm × 12 cm), provided with wood shavings, housed three to five per cage, maintained in a climate-controlled room with 12 h–12 h light/dark cycle (lights on from 8am to 8pm) and temperature at 22 ± 2 °C and 40–70% relative humidity. Free access to food (Nuvilab CR1-Nuvital) and water was provided throughout the study. All protocols were performed during the light phase of the cycle. Behavioral protocols were performed in young adult (60- to 63-day-old) male and female Swiss mice offspring. The Animal Use Ethics Committee of the Universidade Federal de Minas Gerais (CEUA 39/ 2015) approved all procedures and the experiments were carried out in accordance with NIH guidelines for the use and care of animals. 2.2. Experimental design and drug administration Mating was stimulated by placing two females with one male. After 4 days, the male was removed from the cage and two females were housed per cage. On the 19th day of gestation, each female was housed individually. Cages were then inspected daily for the presence of pups. The day of birth was designated PD 0. All pups were randomly assigned to their treatment groups and, for identification, the distal phalanx (toe clipping) of PD 1 pups were removed. The pups were treated daily with L-Dopa (Sigma-Aldrich, D-1507) or saline as a control from PD 1 to PD 5 as performed in our previous study (de Matos et al., 2018). The pups were treated with L-Dopa at concentrations of 10 mg/kg, 25 mg/kg or 50 mg/kg body weight (de Matos et al., 2018; Kashihara et al., 2002; Kim et al., 2002). They were intraperitoneally injected with a final volume of 20 μL using a 30G needle coupled to a 25 μl Hamilton. A Naïve non-manipulated group was also included. Litter size ranged from 5 to 11 pups. For each litter there was at least one pup of each sex injected with saline, while the remaining pups were injected with the three different L-Dopa concentrations. Weaning took place at PD 22 and animals were housed according to sex (2–3 per cage) and treatment. The animals underwent all behavioral testing with the exception of the sucrose preference test (SPT), which was performed at a later stage, i.e. after the 60 to 63-day window (Fig. 1). During the first day of behavioral tests, animals were submitted to an open field test (OFT) and elevated plus maze test (EPM). On the following day, animals were submitted to a forced swimming test (FST). A set of animals was submitted to SPT after reaching 60–63 days of age. 2

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Fig. 1. Experimental design. Male and female Swiss mice with 6–8 weeks old were housed together for mating for four days. The pregnant females were housed in pair and on the 19th day of pregnancy they were separated for birth. From the first day of birth (PD0) until the 5th day of age (PD5), the pups were weighed and intraperitoneally injected once a day with Saline, L-Dopa 10 mg/kg, L-Dopa 25 mg/kg or L-Dopa 50 mg/kg, in a final volume of 20 μL. Each manipulation lasted an average of 1–2 min and the pups were returned to the cage with the mother immediately after the manipulation. The pups were left together with their mothers until PD22 when they were separated by sex and drug. Both PD60 female and male mice were subjected to the Open Field Test in the morning and to the Elevated Plus Maze Test in the afternoon. At the PD61, the mice were subjected to Forced Swimming Test. Another group of mice was subjected to Sucrose Preference Test from PD60 to PD63.

2.3. Open field test (OFT)

and was quantified.

Spontaneous locomotor activity in a new environment was assessed using an automatic open field apparatus (LE 8811 IR Motor Activity Monitors PANLAB, Harvard Apparatus; Spain), along with an acrylic box measuring 23 × 23 × 35 cm. Animals explored the open field for 5 min. Total distance traveled was recorded (Walsh and Cummins, 1976) and the percentage of time spent in the center of box (10 × 10 cm) was used as an anxiety measure (Prut and Belzung, 2003). Increased locomotion and rearing was considered a stimulant effect (Prut and Belzung, 2003). The open field arena was cleaned with 70% ethanol between each trial.

2.6. Sucrose preference test (SPT) Sucrose preference was assessed using the two-bottle choice method. Animals were maintained alone in the home cage and were habituated for 8 h with two bottles containing water. Eighteen hours before the test, the animals were water-deprived. The test consisted of placing two bottles in the home cage: one containing water and the other containing a 3% sucrose solution. Both bottles were weighed immediately before the test, and then again 1 h and 36 h afterward. Sucrose preference was analyzed using the equation: [sucrose consumption/sucrose consumption + water consumption] (Imai et al., 2013).

2.4. Elevated plus maze test (EPM) EPM is a simple method that induces an approach-avoidance conflict for assessing anxiety responses of rodents (Walf and Frye, 2007). The apparatus consists of two open arms (30 cm × 6 cm) and two closed arms (30 cm × 6 cm x 16 cm) crossed in the middle perpendicularly to each other and elevated 30 cm above the floor. Mice were placed in the central area and allowed to move freely for 5 min (PáduaReis et al., 2017). The number of entries into the open arms and the time spent in the open arms were used as indices of anxiety.

2.7. Statistical analysis Parametric data were analyzed by One Way ANOVA followed by Tukey's posthoc test. Non-parametric data were analyzed by KruskalWallis One Way Analysis of Variance on Ranks followed by Dunn's Method posthoc test. Parametric data are presented as mean and standard deviation (SD). Non-parametric data are presented as median and interquartile (Weissgerber et al., 2015). Significance was set at p < 0.05 for all tests. To evaluate whether there was a difference in results between sexes, we normalized female and male data by their own control (Saline). We then performed Two-Way ANOVA followed by Tukey's posthoc test. Data are presented as mean and standard deviation (SD). Significance was set at p < 0.05 for all tests.

2.5. Forced swimming test (FST) The FST is a useful tool to assess depressive-like behavior in mice and was carried out as described by Porsolt et al. (1977), with minor modifications. Mice were individually transferred to a vertical glass cylinder (17 cm inner diameter × 27 cm height) filled with water. The water's temperature was monitored throughout the test and maintained between 25 and 27 °C. At the end of the test, the animal was removed and gently dried under a heated air jet. Merely floating, with no movement of the forelimbs or hind limbs, was considered immobility 3

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Fig. 2. Increased levels of dopamine in the first 5 PD increases the locomotor activity of young adult females but not males. Locomotor activity of young adult Swiss mice (PD60) daily treated with Saline, L-Dopa 10 mg/kg, L-Dopa 25 mg/kg or L-Dopa 50 mg/kg from PD0 to PD5 were tested by OFT. (A) Only L-Dopa 50 mg/kg treated females showed an increase in total distance. (B) LDopa treatment did not affect the time spent in the center on females or males. (C) L-Dopa 50 mg/kg treated females showed a slight increase in the number of rearings compared to Saline and L-Dopa 25 mg/kg treated females. (A–C) There were no differences between males. The number of animals is between parenthesis. Nonparametric data are represented as median with interquartile range. Parametric data are represented as mean ± SD. For parametric data, it was used One Way ANOVA test and Tukey Test. For nonparametric data, it was used Kruskal-Wallis One Way ANOVA on Ranks and Tukey Test. *p < 0.05. Dashed lines are the mean of Naïve groups.

3. Results

However, we did not detect any alterations in L-Dopa treated females in terms of percentage of entries on open arms (Fig. 3A), number of rearings (Fig. 3C), or number of dippings (Fig. 3D). On the other hand, we observed an increase of 150% in the number of dippings in the L-Dopa 25 mg/kg treated males (KW H = 12.001, 3 d.f., Dunn's Method, p < 0.05) and an increase of 110% in the L-Dopa 10 mg/kg treated group compared to the Saline group (p < 0.05) (Fig. 3D). Young adult males treated with L-Dopa 25 mg/kg also showed an increase of 67% in time spent in the center as compared to the Saline group (F (3,35) = 4.052, One Way Anova, Tukey, p = 0.008) (Fig. 3F). In addition, we observed a slight increased percentage of entries onto the open arm areas (F (3,35) = 2.891, One Way Anova, p = 0.051) (Fig. 3A) as well as a slightly longer time spent on the arms (F (3,35) = 2.629, One Way Anova, Tukey, p = 0.067) in males treated with L-Dopa (Fig. 3B). We did not observe any alteration in the number of rearings (Fig. 3C), the number of stretchings (Fig. 3E) or the time spent on the edge of open arms (Fig. 3G) in young adult males treated with L-Dopa. We tested whether the opposite sex-related effects were statistically different. Our results indicated that the difference between females and males in percentage of entries in open arms was statistically significant when treated with L-Dopa 10 mg/kg (F (3,67) = 3.182, Two Way Anova, Tukey, p = 0.017) and 50 mg/kg (p = 0.001) (Fig. 6A-A′). We also observed that the difference in percentage of time in open arms between sexes was statistically significant when treated with L-Dopa 10 mg/kg (F (3,67) = 2.917, Two Way Anova, Tukey, p = 0.01), with L-Dopa 25 mg/kg (p = 0.036) and L-Dopa 50 mg/kg (p = 0.009) (Fig. 6B-B’).

3.1. An increase of dopamine during the first 5 PD induces hyperactivity in young adult females, but not in males Hyperactivity of the dopaminergic system is correlated with alterations in locomotor activity. We recently demonstrated that an increase in the levels of dopamine during the first days of life affects the locomotor activity of juvenile female mice (de Matos et al., 2018). Here we investigate whether these alterations persist through adulthood. We administered daily injections of saline, L-Dopa 10 mg/kg, L-Dopa 25 mg/kg or L-Dopa 50 mg/kg, from PD0 to PD5, and we evaluated locomotor activity at PD60 by OFT (Fig. 1). We observed no alterations in the locomotor activity of young adult males (Fig. 2). We also did not see any changes in the time spent in the center by young adult females (Fig. 2B). However, we observed a significant increase in the total distance in L-Dopa 50 mg/kg treated females (Fig. 2A). The L-Dopa 50 mg/kg treated females moved around approximately 50% more than the saline (F (3,38) = 3.885, One Way Anova, Tukey, p = 0.023) and 25% more than L-Dopa 10 mg/kg (p = 0.043) groups (Fig. 2A). There was also a slight increase in the number of rearings in the L-Dopa 50 mg/kg treated group (F (3,28) = 2.405, One Way Anova, p = 0.084) (Fig. 2C). Interestingly, we observed locomotor hyperactivity only in young adult females that suffered an imbalance of dopaminergic signaling in the first 5 PD. However, we did not observe a statistical difference between female and male data (data not shown) . 3.2. Opposite sex-related effects of increased levels of dopamine in the first 5 PD in anxious-like behavior in young adult Swiss mice

3.3. Increased levels of dopamine in the first 5 PD impact depressive-like behavior only in young adult male mice

Female young adult mice treated with L-Dopa in the first 5 PD showed hyperactivity and an increase in the number of rearings (Fig. 2). Since dopaminergic signaling is also involved in anxiety-like behavior, and alterations in the number of rearings can indicate this behavior in mice, we tested this behavioral phenotype by EPM (Calhoon and Tye, 2015; Prut and Belzung, 2003). Young adult females treated with LDopa 50 mg/kg showed a significant increase (roughly 40%) in time spent in the center as compared to L-Dopa 10 mg/kg treated females (F (3,38) = 4.661, One Way Anova, Tukey, p = 0.009) as well as a slightly increase compared to the Saline group (p = 0.06) (Fig. 3F). The females from the L-Dopa 50 mg/kg treated group also showed an increase of 32% in the number of stretchings as compared to Saline treated group (F (3,38) = 4.340, One Way Anova, Tukey, p = 0.037) and an increase of 36% as compared to L-Dopa 10 mg/kg (p = 0.013) (Fig. 3E). In addition, females treated with L-Dopa 50 mg/kg showed a 57% decrease in time spent on the edge of open arms as compared to Saline treated females (KW H = 7.819, 3 d.f., Dunn's Method, p < 0.05) and the L-Dopa 25 mg/kg group showed a slight decrease compared to Saline as well (Fig. 3G). We also observed a slight decreased time spent on the open arms in L-Dopa 50 mg/kg treated females (F (3,38) = 2.408, One Way Anova, p = 0.084) (Fig. 3B).

Several studies have shown the role of dopamine in depressive behavior, and dopaminergic signaling is therefore one of the targets for antidepressants (Otte et al., 2016; Tye et al., 2012). With this in mind, we used FST to investigate whether L-Dopa treatment in the first 5 PD would lead to depressive-like behavior in young adult mice. We observed no alterations in FST in young adult females treated with L-Dopa (Fig. 4). On the other hand, we observed an increase of 80% in latency immobility in L-Dopa 50 mg/kg group (KW H = 9.100, 3 d.f., Dunn's Method, p < 0.05) and in increase of 90% in L-Dopa 25 mg/kg (p < 0.05) compared to the Saline group (Fig. 4D). We also observed a decrease of 51% in the time of immobility of males treated with L-Dopa 50 mg/kg (F (3,35) = 5.744, One Way Anova, Tukey, p = 0.002) and a slight decrease in the 25 mg/kg group (p = 0.054) compared to the Saline group (Fig. 4F). L-Dopa 50 mg/kg males also showed an increase of 60% in swimming time compared to Saline injected mice (F (3,35) = 4.375, One Way Anova, Tukey, p = 0.006) (Fig. 4C). In addition, we observed an increase of 137% in the number of climbings of the L-Dopa 50 mg/kg group (F (3,35) = 4.024, One Way Anova, Tukey, p = 0.036) and an increase of 163% in L-Dopa 25 mg/kg group 4

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Fig. 3. Opposite sex-related effects of increased levels of dopamine in the first 5 PD in anxious-like behavior in young adult Swiss mice. Anxiety-like behavior of young adult Swiss mice (PD60) daily treated with Saline, L-Dopa 10 mg/kg, L-Dopa 25 mg/kg or L-Dopa 50 mg/kg from PD0 to PD5 were tested by EPM. (A) We did not observe any alterations in the percentage of entries in the open arms of young females. (B) Females treated with L-Dopa 50 mg/kg showed a slight decreased in time spent on the open arms. There were no alterations in (C) the number of rearings and (D) in the number of dippings in young adult females. Females treated with L-Dopa 50 mg/kg showed an increase in the number of stretchings (E) and of time spent on the center (F) compared to Saline and L-Dopa 10 mg/kg. (G) Females treated with L-Dopa 50 mg/kg showed a decrease in time on the edge of open arms compared to Saline and females treated with L-Dopa 25 mg/kg showed a slight decrease in time on edge of open arms. On the other hand, we observed a slightly increased of percentage of (A) entries into the open arms as well as (B) a slightly longer time spent in the open arms in males treated with L-Dopa. (C) We did not observe any alterations in the number of rearings. (D) There is an increase in the number of dippings in the L-Dopa 10 mg/kg and L-Dopa 25 mg/kg treated groups compared to the Saline group. (E) However, there were no alterations in the number of stretchings. (F) Young adult males treated with L-Dopa 25 mg/kg showed an increase in time spent in the center. (G) We did not observe any alterations in the time spent on the edge of open arms in young adult males treated with L-Dopa. The number of animals is between parenthesis. Nonparametric data are represented as median with interquartile range. Parametric data are represented as mean ± SD. For parametric data it was used One Way ANOVA test and Tukey Test. For nonparametric data it was used Kruskal-Wallis One Way ANOVA on Ranks and Tukey Test. *p < 0.05. Dashed lines are the mean of Naïve groups.

Dopa treatment were statistically different between sexes. We observed that the difference between females' and males' climbing time was statistically significant when individuals were treated with L-Dopa 25 mg/kg (F (3,67) = 2.514, Two Way Anova, Tukey, p = 0.029) (Fig. 7A-A’).

(p = 0.023) (Fig. 4A). L-Dopa treated mice also showed a slight increase climbing times (p = 0.065) (Fig. 4B). However, we did not observe alterations in the number of immobility episodes in L-Dopa treated young adult males (Fig. 4E). We tested whether the depressive-like behavioral consequences of L5

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Fig. 4. Increased levels of dopamine in the first 5 PD impact depressive-like behavior only in young adult male mice. Depressive-like behavior of young adult Swiss mice (PD60) daily treated with Saline, L-Dopa 10 mg/kg, L-Dopa 25 mg/kg or L-Dopa 50 mg/kg from PD0 to PD5 were tested by FST. (A–G) We did not observe any alterations between young adult females. On the other hand, we observed an increase in the number of (A) climbings in the L-Dopa 50 mg/kg and 25 mg/kg groups compared to Saline group. (B) L-Dopa treated males showed a slight increase in climbing time. (C) L-Dopa 50 mg/kg treated males showed an increase in swimming time compared to the Saline injected group. (D) We observed an increase in the latency immobility in the L-Dopa 50 mg/kg and 25 mg/kg groups compared to Saline. (E) However, there were no alterations in the number of immobility episodes in L-Dopa treated young adult males. (F) We observed a decrease in the time of immobility of males treated with L-Dopa 50 mg/kg and a slight decrease in the 25 mg/kg group. (G) In addition, the L-Dopa 50 mg/kg males treated showed a decrease in the total time of immobility compared to the Saline group. The number of animals is between parenthesis. Nonparametric data are represented as median with interquartile range and parametric data are represented as mean ± SD. For parametric data it was used One Way ANOVA test and Tukey Test. For nonparametric data it was used Kruskal-Wallis One Way ANOVA on Ranks and Tukey Test. *p < 0.05. Dashed lines are the mean of Naïve groups.

3.4. Increased levels of dopamine in the first 5 PD affect the hedonic behavior of female young adult mice only

Finally, we investigated whether the disparity between sexes as concerned sucrose preference was statistically different. We observed that the difference between females and males in sucrose preference was statistically significant at 2 h (F (3,51) = 1.834, Two Way Anova, Tukey, p = 0.035), 3 h (F (3,51) = 2.279, Two Way Anova, Tukey, p = 0.011) and 12 h (F (3,51) = 2.764, Two Way Anova, Tukey, p = 0.001) when treated with L-Dopa 10 mg/kg, and at 3 h when treated with L-Dopa 50 mg/kg (F (3,51) = 2.279, Two Way Anova, Tukey, p = 0.042) (Fig. 7B-D’).

Dopamine plays a key role in the reward system, and it is well known that pups exposed to cocaine show alterations in reward behavior. Here we tested whether an increase of dopamine levels in the first 5 PD would impact the hedonic behavior of young adult mice. Firstly, we evaluated the total liquid consumption of young adult females over time, and we detected no alterations in liquid consumption in L-Dopa treated females (Fig. 5A). Subsequently, we investigated sucrose preference over 48 h and we observed a difference in sucrose preference between the groups (Fig. 5B). L-Dopa 10 mg/kg treated females showed an increase of sucrose preference compared to the Saline group over all measured time periods (F (25,125) = 20.20, Two Way Anova, p < 0.001). The L-Dopa 50 mg/kg and 25 mg/kg treated females showed an increase of sucrose preference only within the first 3 h (p < 0.05) (Fig. 5B). We did not observe alterations in sucrose preference in young adult males treated with L-Dopa (Fig. 5D). We did however observe an increase in liquid consumption in the L-Dopa 25 mg/kg treated group as compared to Saline after 24 and 48 h of test time (F (26,130) = 18.34, Two Way Anova, Tukey, p < 0.001) (Fig. 5C).

4. Discussion Disturbances in dopaminergic signaling within the perinatal developmental window are associated with permanent alterations in juvenile and adult behavior (Brown et al., 2002; Brus et al., 2003; de Matos et al., 2018; Kostrzewa et al., 2016). In this study, we showed that a transient increase of dopamine levels during the perinatal developmental window can cause permanent behavioral alterations in young adult (60-day-old) Swiss mice, and, additionally, that these changes will be different in male than in and female individuals. Dopaminergic enzymes are expressed in the perinatal brain and dopamine levels are stable in the first 5 days of postnatal development 6

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Fig. 5. Increased levels of dopamine in the first 5 PD affect the hedonic behavior of female young adult mice only. Anhedonia behavior of juvenile Swiss mice (PD60-63) daily treated with Saline, L-Dopa 10 mg/kg, L-Dopa 25 mg/kg or L-Dopa 50 mg/kg from PD0 to PD5 were tested by Sucrose Preference test. (A) We did not detect any difference in total consumption between young adult female groups. (B) The L-Dopa treated females showed an increase of sucrose preference compared to the Saline group. (C) We observed an increase in liquid consumption in the L-Dopa 25 mg/kg treated young adult males. (D) There were no alterations in sucrose preference in young adult males treated with L-Dopa. The number of animals is between parenthesis. The data are parametric and is represented as mean ± SD. To analyze the differences between the groups throughout time, we used Two Way ANOVA and Tukey Test. *p < 0.05.

from E11 until birth display alterations in cocaine-induced behavior (Ren et al., 2011). In addition, treatment with the bupropion (dopamine transporter inhibitor) from E6 to PD20 affects male and female adult rats’ (PD60) behavior in different ways (Sprowles et al., 2017). In this study, we observed an increase in the total distance traveled (Fig. 2) of only female young adult Swiss mice administrated with LDopa from PD1 to PD5, which can be interpreted as an increase of exploratory behavior. Interestingly, we observed the same behavioral alterations only in female juvenile mice submitted to the same protocol (de Matos et al., 2018), suggesting that upregulation of dopaminergic signaling within the first 5 PD can stimulate exploratory behavior in prepubertal females, an effect which persists through adulthood. Similar to the juvenile female mice in our former study, we did not observe any changes in depressive-like behavior in young adult females on FST (Fig. 4) (de Matos et al., 2018). However, in contrast to juvenile female mice, the young adult females presented an increase in the number of stretchings and in time spent in the center, as well as a decrease in time spent on the edge and a slight decrease in percentage of time spent on open arms on EPM (Fig. 3). All these alterations suggest anxiety-like behavior in young adult females that underwent an increase of dopaminergic signaling tonus within the first 5 days of life (Grewal et al., 1997; Pellow et al., 1985; Walf and Frye, 2007).

in rats (Agrawal et al., 1966; Karki et al., 1962; Kellogg and Lundborg, 1973; Nachmias, 1960). Our previous study showed that L-Dopa i.p. administration increases the levels of dopamine and its metabolites within mice pups' striatum (de Matos et al., 2018). Still other studies have shown that acute L-Dopa administration in rat pups (PD1 and PD4) significantly increases dopamine levels 30 min post-injection (accompanied by an increase in motor activity), but that there is only a very slight increase in noradrenaline levels after L-Dopa administration (Kellogg and Lundborg, 1972a, 1972b; Van Hartesveldt et al., 1991). Since dopamine levels are very stable in the first 5 days of postnatal development, we wondered whether an increase of dopamine levels within this stable developmental window could permanently affect young adult mice (PD60) behavior. In our recent study we showed that juvenile Swiss mice treated with L-Dopa from PD1 to PD5 present certain behavioral alterations: namely, an increase of exploratory behavior in females and hedonic alterations in males (de Matos et al., 2018). Several studies have shown that dopaminergic imbalances during prenatal and postnatal development can cause behavioral alterations in adult rodents. For example, adult rats (PD60) treated postnatally with D2 agonist (Quinpirole) from PD1 until PD11 show higher active avoidance and deficits in spatial memory (Brown et al., 2002; Brus et al., 2003, 1997). Adult CD1 male mice (PD60) exposed to L-Dopa 7

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well known. Dopamine release and uptake are greater in the striatum of adult female rats than in those of their male counterparts, and basal dopamine tone is chronically higher in the striatum of adult males than in females (Becker, 2009; Walker et al., 1999). There are also differences between adult male and female rats in the number of dopaminergic cells and projections in the mesocortical pathway, with females showing a higher number than males (Kritzer and Creutz, 2008). At the age of PD60, female rats have less D1 receptors than do males, but with pronounced lateralization of D1 receptors (Andersen et al., 1997; Andersen and Teicher, 2000). Thus, the behavioral differences observed between females and males can also be due to alterations in the dopaminergic synaptic and circuit plasticity. For example, it is possible that the distinct behavioral consequences in young adult female and male mice are due to the supersensitization of dopaminergic receptors, also known as receptor-priming, described in previous studies (Kostrzewa et al., 2016, 1993). Interestingly, we observed diverse behavioral alterations in females and males at distinct ages. In our previous study, prepubertal females showed an increase in exploratory behavior only, but young adult females showed an increase in exploratory behavior, anxiety-like behavior and hedonic behavior. On the other hand, prepubertal males showed abnormalities in hedonic behavior while young adult males showed resilience to stress (de Matos et al., 2018). It is well known that there is an increase of synapses from infancy to puberty, and subsequent pruning from adolescence to young adulthood (Peter R., 1979). The same dynamic is observed in the number of dopaminergic receptors, which decreases during adolescence (Gelbard et al., 1989; Giorgi et al., 1987; Pardo et al., 1977; Seeman et al., 1987; Teicher et al., 1995). There is also evidence that the male brain shows a higher increase and higher pruning of dopaminergic receptors than does the female brain (Andersen et al., 1997). These mechanisms likely play a part in the behavioral alterations described above, with consequent age-related but also sex-related disparities. One of the limitations identified in our study is the stress effect of the saline intraperitoneal injection. The saline injection can be used as a mild stress procedure, and a recent study has shown that a single intraperitoneal injection of saline solution is enough to change levels of corticosterone and proinflammatory cytokines in the blood and brains of adult male rats (Advani et al., 2009; Freiman et al., 2016). This stress response might be caused by novel-situation exposure, as suggested by Ryabinin et al. (1999), who compared the effects of two weeks of handling, sham and saline injection stress in adolescent male DBA/2J and C57BL/6J inbred mice. The results of their study showed that a single injection increased the expression of c-Fos and Fos-related antigens in the brain, but repeated saline injections led to experimental habituation in C57BL/6J adolescent mice (Ryabinin et al., 1999). In our own study, we observed that dopamine levels and the DOPAC/dopamine ratio in saline-injected pups were different than in naïve pups, a difference which might be caused by the stress of injection. Interestingly, this difference was mainly observed in female pups. On the other hand, after these neonatal treatments, all mice remained in their home cages and received minimal handling (only during bedding changes) until PD60. At the age of PD60, all animals were submitted to behavioral tests. Since exposure to a novel experimental situation induces stress and repeated saline injection stress can lead to habituation, the behavioral differences between naïve and saline-treated juvenile mice might be caused by the stress of naïve animals being intensely handled for the first time in their lives (Ryabinin et al., 1999). So, it is possible that L-Dopa treatment had a protective or an additional effect on the stress of saline injection. Because of this, we chose to show naïve data, but not to include them in the statistical analyses. However, as far as we know, none of the developmental studies using pharmacological tools included naïve animals as a control (Blažević and Hranilović, 2013; Brown et al., 2004, 2002; Hranilovic et al., 2011; Levav et al., 2004; Sprowles et al., 2017). Therefore, our study emphasizes the importance of naïve group inclusion in experimental designs and the need to

Fig. 6. Distinct anxiety-like behavioral consequences of perinatal dopamine increases between male and female mice. Anxiety-like behavioral differences between young adult females and males (PD60-63) treated daily with Saline, L-Dopa 10 mg/kg, L-Dopa 25 mg/kg or LDopa 50 mg/kg from PD0 to PD5. (A) The percentage of the entries by males treated with L-Dopa 10 mg/kg or with L-Dopa 50 mg/kg was higher than that of the female groups in the EPM test. The differences are highlighted in A’. (B) The time spent in open arms by males treated with L-Dopa 10 mg/kg, L-Dopa 25 mg/ kg or with L-Dopa 50 mg/kg was higher than that of female groups during the EPM test. The differences were highlighted in B’. The data are parametric and are represented as mean ± SD. To analyze the differences between the groups over time, we used the Two Way ANOVA and Tukey Test. *p < 0.05.

Furthermore, L-Dopa treated female young adult mice also showed an increase of sucrose preference, suggesting hedonic alterations as well, alterations which were not observed in juvenile females (de Matos et al., 2018; Der-Avakian and Markou, 2012) (Fig. 5). On the other hand, male young adult Swiss mice treated with L-Dopa from PD1 to PD5 showed an increase of head dippings and time spent in the center, as well as a slight increase in number of entries onto open arms and percentage of time spent on open arms during EPM (Fig. 3). These alterations suggest anxiolytic-like behavior in young adult males, which was not observed in juvenile males in our previous study (de Matos et al., 2018; Grewal et al., 1997; Pellow et al., 1985; Walf and Frye, 2007). In addition, male young adult Swiss mice treated with LDopa from PD1 to PD5 showed an increase in the number of climbings, in swimming time, in immobility latency, as well as a slight increase in climbing time. They showed a decrease in time of immobility (Fig. 4). These data suggest that young adult males having undergone an increase of dopaminergic tonus within the first 5 days of life are also resilient to stress (Castagné et al., 2009; Detke et al., 1995; Overstreet, 2012). In the present study, we observed distinct behavioral consequences of perinatal dopamine increases between male and female mice. Dopaminergic signaling, which is involved in many aspects of cell cycle and function, is different in the brains of perinatal male and female rodents (Crandall et al., 2007; Hedlund et al., 2016; Ovtscharoff et al., 1992; Popolo et al., 2004; Schmidt et al., 1996; Souza et al., 2011; Stewart et al., 1991; Stewart and Rajabi, 1994). It is therefore possible that the behavioral differences between females and males are the consequence of distinct morphological alterations. Furthermore, the sexual dimorphism of the dopaminergic system in adult rodents is also 8

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Fig. 7. Distinct depressive-like and hedonic behavioral consequences of perinatal dopamine increases between male and female mice. Depressive-like and hedonic behavioral differences between young adult females and males (PD60-63) treated daily with Saline, L-Dopa 10 mg/kg, L-Dopa 25 mg/kg or L-Dopa 50 mg/kg from PD0 to PD5. (A) The time of climbing by males treated with L-Dopa 25 mg/kg was higher compared to that of the female group in the FST. The differences were highlighted in A’. In addition, sucrose preference was higher in females treated with L-Dopa 10 mg/kg at (B) 2 h, (C) 3 h and (D) 12 h, and in females treated with L-Dopa 50 mg/kg at (C) 3 h when compared to their respective male groups. The differences were highlighted in B′, C′ and D’. FST, Forced Swimming Test. The data are parametric and are represented as mean ± SD. To analyze the differences between the groups over time, we used the Two Way ANOVA and Tukey Test. *p < 0.05.

expressed in the developing brain, it is possible that dopamine plays a role (or roles) during development (Olson et al., 1973; Olson and Seiger, 1972a; Schambra et al., 1994; Unis et al., 1998). Recent studies have shown that dopaminergic receptors can regulate cell cycle, neuronal proliferation, neuronal differentiation and neuronal migration (Crandall et al., 2007; Hedlund et al., 2016; Ohtani et al., 2003; Popolo et al., 2004; Schmidt et al., 1996; Souza et al., 2011). Because of this, it is probable that dopaminergic imbalances during specific windows of brain development may lead to particular behavioral abnormalities in later life, which could be involved in various symptoms of mental disorders in women and men (Souza and Tropepe, 2011). It is therefore crucial to understand the various roles of dopamine during different developmental stages in order to identify specific timepoints for better interventions, and thereby to prevent the onset of neuropsychiatric symptoms. Future studies are necessary in order to more fully understand the ontogenetic molecular mechanisms related to dopaminergic signaling and the morphophysiological consequences of perinatal increases of dopamine.

investigate the variables commonly used in developmental studies. A limitation of the present study is the possibility of oral drug transfer between animals following injection. Although we tried our best to avoid this problem by injecting the solution in small volumes only (in order to prevent a significant increase of intraperitoneal pressure and, consequently, liquid seepage), it is virtually impossible to avoid or detect solution seepage with 100% certainty. It therefore does remain possible that, to some limited extent, drug transfer amongst littermates and/or the dam may have occurred. In addition, sex hormones and the estrous cycle can influence dopaminergic signaling in adult rats, and we did not control for estrous cycles in females (Becker et al., 1982; Becker and Cha, 1989; Castner et al., 1993; Di Paolo et al., 1985; Jori et al., 1976; Joyce and Van Hartesveldt, 1984; Parvizi and Wuttke, 1983). However, the behavioral data distribution for females were not different from that of males. Finally, many neuropsychiatric disorders, such as SCZ, autism, and ADHD, share both dopaminergic and neurodevelopmental hypotheses (Bale et al., 2010; Pavăl, 2017; Robinson et al., 2001; Souza and Tropepe, 2011). Since dopaminergic neurons and receptors are 9

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5. Conclusion

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Perinatal L-Dopa treatment showed ontogenetically different dopaminergic signaling in male than in female Swiss mice, consequently leading to gender-specific behavioral alterations at the young adult stage. Author contributions LOM, ALALR, LTLG, LOG, MAM and LBA designed the research, performed the experiments and data collection, and analyzed the data; RPS, GSP and BRS designed the research, supervised the study, and drafted, revised and edited the manuscript. All authors have approved the final article. Funding This work was supported by CNPq [grant number 480,260/2012–5, and MAM and LOG scholarship]; FAPEMIG [grant numbers APQ01896-13, APQ-03109-16, and LTLG scholarship); CAPES (LOM, ALALR and LBA scholarships); Recém Contratado Grant from PRPqUFMG; International Society for Neurochemistry (ISN) Return Home Grant. CRediT authorship contribution statement Lorena Oliveira de Matos: Conceptualization, Methodology, Formal analysis, Investigation, Visualization. Ana Luiza de Araujo Lima Reis: Formal analysis, Investigation. Lorena Terene Lopes Guerra: Formal analysis, Investigation. Leonardo de Oliveira Guarnieri: Methodology, Validation, Formal analysis. Muiara Aparecida Moraes: Formal analysis, Investigation. Laila Blanc Arabe: Methodology, Formal analysis. Renan Pedra de Souza: Methodology, Validation. Grace Schenatto Pereira: Methodology, Validation, Supervision. Bruno Rezende Souza: Conceptualization, Methodology, Validation, Resources, Writing - original draft, Visualization, Supervision, Project administration, Funding acquisition. Declaration of competing interest The authors declare no conflicting financial interests. Acknowledgements To Dr. Roxanne Covelo (Ph.D.) for proofreading the article. References Abercrombie, E.D., Keefe, K. a, DiFrischia, D.S., Zigmond, M.J., 1989. Differential effect of stress on in vivo dopamine release in striatum, nucleus accumbens, and medial frontal cortex. J. Neurochem. 52, 1655–1658. https://doi.org/10.1111/j.1471-4159. 1989.tb09224.x. Abi-Dargham, A., Gil, R., Krystal, J., Baldwin, R.M., Seibyl, J.P., Bowers, M., van Dyck, C.H., Charney, D.S., Innis, R.B., Laruelle, M., 1998. Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am. J. Psychiatr. 155, 761–767. https://doi.org/10.1176/ajp.155.6.761. Advani, T., Koek, W., Hensler, J.G., 2009. Gender differences in the enhanced vulnerability of BDNF+/− mice to mild stress. Int. J. Neuropsychopharmacol. 12, 583. https://doi.org/10.1017/S1461145709000248. Aghajanian, G.K., Bloom, F.E., 1967. The formation of synaptic junctions in developing rat brain: a quantitative electron microscopic study. Brain Res. 6, 716–727. https:// doi.org/10.1016/0006-8993(67)90128-X. Agrawal, H.C., Glisson, S.N., Himwich, W.A., 1966. Changes in monoamines of rat brain during postnatal ontogeny. Biochim. Biophys. Acta Gen. Subj. 130, 511–513. https:// doi.org/10.1016/0304-4165(66)90247-9. Albert, K. a, Hemmings, H.C., Adamo, A.I.B., Potkin, S.G., Akbarian, S., Sandman, C. a, Cotman, C.W., Bunney, W.E., Greengard, P., 2002. Evidence for decreased DARPP-32 in the prefrontal cortex of patients with schizophrenia. Arch. Gen. Psychiatr. 59, 705–712. https://doi.org/10.1001/archpsyc.59.8.705. Andersen, S.L., Rutstein, M., Benzo, J.M., Hostetter, J.C., Teicher, M.H., 1997. Sex differences in dopamine receptor overproduction and elimination. Neuroreport 8,

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