Anticonvulsants lamotrigine and riluzole disrupt maternal behavior in postpartum female rats

Accepted Manuscript Anticonvulsants lamotrigine and riluzole disrupt maternal behavior in postpartum female rats

Meng Sun, Pan Huang, Yan Wang, Weihai Chen PII: DOI: Reference:

S0091-3057(18)30069-8 doi:10.1016/j.pbb.2018.03.008 PBB 72581

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Pharmacology, Biochemistry and Behavior

Received date: Revised date: Accepted date:

12 February 2018 18 March 2018 20 March 2018

Please cite this article as: Meng Sun, Pan Huang, Yan Wang, Weihai Chen , Anticonvulsants lamotrigine and riluzole disrupt maternal behavior in postpartum female rats. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Pbb(2017), doi:10.1016/j.pbb.2018.03.008

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ACCEPTED MANUSCRIPT Anticonvulsants lamotrigine and riluzole disrupt maternal behavior in postpartum female rats Meng Sun1,2, Pan Huang1,2, Yan Wang1,2, Weihai Chen1,2*

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1. Key Laboratory of Cognition and Personality (Southwest University), Ministry of Education, Chongqing, China 2. Faculty of Psychology, Southwest University, Chongqing, China

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Weihai Chen, PhD Faculty of Psychology, Southwest University Tianshen Road 2, Beibei District Chongqing, China Phone: 86-23-13594021891 E-mail: [email protected]

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* Corresponding authors:

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Abstract Maternal behavior is a highly motivated and well-organized social behavior. Previous studies have reported that anticonvulsants are frequently used in postpartum bipolar disorder. However, the maternal disruptive effect of the anticonvulsants has not been explored. The purpose of the present study was to examine the effect of anticonvulsants lamotrigine and riluzole on maternal behavior in postpartum female rats. On postpartum Day 3, Sprague-Dawley mother rats were given a single intraperitoneal injection of vehicle, lamotrigine (15, 25, 35 mg/kg), or riluzole (2, 4, 8 mg/kg). Maternal behavior was tested 30 min before and after injection. Animals treated with lamotrigine or riluzole had a longer pup retrieval latency, retrieved fewer pups into the nest, spent less time on nursing pups, as well as on building the disturbed nest, and animals treated with riluzole spent less time on pup licking. Whereas, the drugs in the tested doses did not shorten the total duration of behavior unrelated to maternal behavior. Overall, these data indicate that lamotrigine and riluzole disrupt major components of maternal behavior in postpartum female rats, but do not inhibit the behaviors unrelated to maternal behavior, which indicates that the maternal disruptive effect is not due to nonspecific sedative effect.

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Key words: anticonvulsant; glutamatergic transmission; maternal behavior; lamotrigine; riluzole

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Abbreviations: 5-HT, 5-hydroxytryptamine; PP, postpartum day; NMDA, N-methyl-d-aspartate; mGlu2/3Rs, Group II metabotropic glutamate receptors; GABA, γ-aminobutyric acid; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid

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1. Introduction

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Maternal behavior is a highly motivated and well-organized social behavior (Olazabal et al. , 2013). The mother rats (dams) instinctively express maternal behavior for the first time with the birth of the first litter. Within hours of parturition, the dams begin to exhibit the full repertoire of maternal behavior including pup-licking, pup retrieval, nest-building, nursing as well as maternal aggression over 2-3 weeks period (Li, 2015). Maternal behavior is a valid and complex behavior system cross mammalian species and shares common features with human mothering behavior (Fleming and Corter, 1988, Rosenblatt, 1989). Thus, maternal behavior in postpartum female rats is a useful model to study human mothering behaviors and to investigate the neurobiological mechanisms underlying mother behaviors. Bipolar disorder is a severe mental disorder characterized by recurrent episodes of manic and depressive states with intervening epsiodes of euthymia (Phillips and Kupfer, 2013). The postpartum period is a time with heightened vulnerablility for bipolar disorder, especially in women who used to suffer from bipolar disorder. It was reported that 14% of postpartum women suffered from postpartum depression. In this population, 22.6% had bipolar disorders (Beyer and Freund, 2017). A meta-analysis has shown that the relapse rate of bipolar disorder in postpartum female was significantly higher among those who were medication free during pregnancy than those who under prophylactic medication (Wesseloo et al. , 2016). The emergence of bipolar disorder is associated with higher risk for self-harm, suicide as well as infanticide during the postpartum (Beyer and Freund, 2017, Brockington, 2004, Pope et al. , 2013, Tavares et al. , 2012). As such postpartum bipolar disorder requires immediate medical attention and treatment. However, the pharmacotherapeutic treatment of postpartum bipolar disorder is complicated, as the drugs that treat bipolar disorder always deteriorate maternal behavior. For example, atypical antipsychotics such as clozapine, quetiapine (Doucet et al. , 2011, Gentile, 2004, Gobbi, 2014), reported to treat postpartum bipolar disorder also show disruptive effects on the active components of maternal behavior such as pup approach, pup retrieval and nest building in postpartum female rats at clinically relevant doses (Li, 2015, Li et al. , 2004). Atypical antipsychotics exert disruptive effect primarily by blocking the 5-HT2A/2C receptors (Zhao and Li, 2009). In addition, mood stabilizers such as lithium, lamotrigine are used to treat bipolar postpartum depression (Bergink et al. , 2016, Sharma and Sommerdyk, 2016). However, there is no idea whether mood stabilizers disrupt maternal behavior. Anticonvulsants as mood stabilizers such as lamotrigine, are frequently used drugs for postpartum bipolar (Khan et al. , 2016, Sharma and Sommerdyk, 2016). Previous studies reported that lamotrigine stabilizes presynaptic neuronal membranes by blockade of voltage-dependent sodium channels, thus preventing the release of glutamate in several brain regions (Deng et al. , 2013, Goa et al. , 1993, Nakato et al. , 2011). In addition to lamotrigine, we also tested another glutamate release inhibitor riluzole. Although riluzole has not been approved for mania or dipolar disorder yet, it is similar with lamotrigine in pharmacological characteristics (Doble, 1996, Jehle et

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al. , 2000). Moreover, riluzole has been tested in a series of trials in schizophrenia (Farokhnia et al. , 2014), obsessive-compulsive disorder (Wu et al. , 2012), bipolar depression (Brennan et al. , 2010, Zarate et al. , 2004) with some promising initial results. As such, riluzole is a promising drug for bipolar disorder and mental disorder during postpartum period. Indeed, previous studies have shown that glutamatergic transmission is critical in other motivated behavior, such as exploratory activity (Raudkivi et al. , 2015), nicotine seeking (D'Souza and Markou, 2014), drug craving (Li et al. , 2015), as well as methamphetamine self-administration (Crawford et al. , 2013). Lamotrigine and riluzole are also reported to inhibit motivation behaviors. For example, lamotrigine disrupted the acquisition and expression of morphine-induced place preference in mice (Tehrani et al. , 2009). Riluzole decreased ethanol self-administration and reduced the severity of ethanol-induced convulsions 2 hours after ethanol withdrawal in mice (Besheer et al. , 2009). In addition, riluzole is also determined to impair cue- and cocaine-primed reinstatement to cocaine while rectifying several cellular adaptations in glutamatergic signaling within the brain's reward circuitry (Sepulveda-Orengo et al. , 2017). As maternal behavior is also a social motivated behavior, it is postulated that lamotrigine and riluzole could disrupt maternal behavior. Therefore, it is necessary to determine whether anticonvulsants exacerbate the deficit of maternal behavior in postpartum mothers. Thus in the present study, we used classical paradigm of maternal behavior to determine whether lamotrigine or riluzole might disrupt maternal behavior in postpartum female rats. 2. Material and methods

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2.1 Subjects and housing A total of 56 virgin female Sprague-Dawley rats (60–80 days, Experiment Animal Center, Daping Hospital & Research Institute of Surgery, Third Military Medical University, China) were used as subjects in the present study. Animals were initially housed in pairs in transparent cages (47 cm L × 32 cm W × 21 cm H) with corn-cob granule for bedding in a colony on a 12-hour light/dark cycle (lights on at 08:00), and allowed ad libitum access to food and water. We placed each female rat into the cage of a proven stud male for ten days to ensure pregnancy seven days after their arrival. After then, we housed pregnant females singly until parturition after which they were housed together with their litters for the remainder of the experiments. All experiments were conducted in strict accordance with the recommendations of “Regulations for the Administration of Affairs Concerning Experimental Animals”, the State Science and Technology Commission, China. All animal procedures were approved by the animal care and use committee at Southwest University, China. 2.2 Groups and choices of drug doses The tested drugs, lamotrigine and riluzole, were selected on the basis of our extensive literature research and our pilot experiments that suggested these drugs represented the available drugs to test our hypothesis. Lamotrigine and riluzole were purchased from Shanghai Haoyuan Chemexpress (Shanghai, China). Three doses of each drug were chosen based on our literature review and pilot experiments:

ACCEPTED MANUSCRIPT lamotrigine at 15, 25 and 35 mg/kg, and riluzole at 2, 4 and 8 mg/kg (Sepulveda-Orengo et al., 2017, Shourmasti et al. , 2014). Lamotrigine and riluzole were dissolved in DMSO because they are very hard to be dissolved in the other vehicle. All drugs were administered intraperitoneally in a volume of 1.0 ml/kg 30 min prior to the start of behavioral tests. This interval was chosen primarily based on the previous studies and our pilot experiments (Sepulveda-Orengo et al., 2017, Shourmasti et al., 2014, Tremblay and Winstanley, 2016). DMSO was used as the vehicle.

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2.3 Procedure We carried out the classical paradigm to test the effects of lamotrigine and riluzole on maternal behavior. The basic procedure was similar to what has been described in Chen et al (Chen et al. , 2014). Briefly, we observed animals every day for signs of parturition from two or three days before the first possible expected parturition date. The day that pups were found in cages at 10:00 a.m. was designated as Day 1 postpartum (PP1), and at 17:00 p.m. as Day 0 postpartum. Once the dam was found with pups, we provided dams with two shredded paper towels as nesting materials. On Day 2 postpartum (PP2), we culled each litter to eight pups (4 males and 4 females with the most visible milk bands) and moved all dams to clean transparent cages with their pups. On Day 3 (PP3), we conducted experiments about the effects of lamotrigine and riluzole on maternal behavior in postpartum mother rats. All experiments started at the same time of each experimental day (around 9:00 am each day). The protocols for maternal behavior on PP3 is illustrated in Figure 1(A), we measured maternal behavior at two timepoints, the first test was conducted before the drug injections (i.e., baseline). Thirty minutes after the first test, all drugs were administered intraperitoneally in a volume of 1.0 ml/kg. Thirty minutes after administration, the second test was carried out. Each test consisted of two phases. At the first phase, we continuously observed maternal behavior and other spontaneous behaviors for 10 min under the undisturbed condition. At the second phase which was immediately followed the first undisturbed phase, we firstly took the 8 pups away from the dams and destroyed the nest. One minute later, we placed the pups back to the corner of the cage diagonal to the nest site and then continuously observed maternal behavior and other spontaneous behaviors for 10 min. As such pup retrieval behavior could be observed in the second phase. At the end of the 10-min period, we returned the unretrieved pups to the nest site. Both phases were recorded by video cameras and analyzed manually using a laptop computer with an event recording program (JWatcher, http://www.jwatcher.ucla.edu/). Data in both phases at each test timepoint were combined. The analyzers were blind to each subject’s drug condition. The following behaviors were recorded and analyzed as maternal behavior: pup retrieval, which means a rat picked up a pup outside of the nest in her mouth and carried it back to the nest site; pup nursing, which means a rat positioned herself over the pups with legs splayed to accommodate the pups, including hover, high, and low crouching-over postures; pup licking, which means a female rat placed its tongue on

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the anogenital area and the rest of a pup’s body; nest building, which means a rat picked up nesting material in her mouth and transporting it back to the nest site or pushed the material with her forepaws toward the nest site. The number of animals in each group was eight. Besides, some behaviors unrelated to maternal behavior were also analyzed in the present study. These unrelated behaviors were used to determine whether test drugs destroyed all behaviors by the nonspecific sedative effect or more focused on maternal behavior. The following unrelated behaviors were also recorded and analyzed: combing (a dam cleaning its fur with mouth), roaming (a dam walking freely in the cage), rearing (a dam standing up), looking around (a dam looking around by turning its head left and right), as well as drinking/eating (a dam drinking water or eating food). 2.4 Statistical Analysis Maternal behavior data from the 1st 10 min undisturbed observation period and 2nd 10 min pup retrieval test period at 30 min before and 30 min after injection were combined and were presented as mean ± SEM. Duration (in second) data and the number of pup retrieval of group differences on PP3 were analyzed using one-way ANOVA followed by Bonferroni post hoc tests. Statistical significance was accepted at p < 0.05, two-tailed. SPSS statistics 21 was used to analyze all data. 3. Results

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3.1 Lamotrigine impaired nursing and nest building activities, reduced number of pups retrieved, as well as prolonged pup retrieval latency

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Figure 1 Effects of lamotrigine treatment on maternal behavior (n = 8). (A) A schematic illustration of the experimental procedure for experiment. (B) Lamotrigine 25 mg/kg and 35 mg/kg impaired nursing activity 30 min after injection on PP3. (C) There is no enough evidence to support the idea that lamotrigine can impair pup licking. (D) Lamotrigine 25 mg/kg and 35 mg/kg impaired nest building activity 30 min after injection on PP3. (E) Animals treated with 35 mg/kg lamotrigine retrieved fewer pups. (F, G) Lamotrigine prolonged the latencies of the first and last pup retrieval. The data of nursing, licking, nest building duration, number of retrieved, first and last retrieval latencies are expressed as mean ± SEM. *p < 0.05, ***p < 0.001 versus the vehicle group.

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Lamotrigine reduced nursing duration. Effects of Lamotrigine on nursing behavior at 30 min before injection and 30 min after injection on PP3 are shown in Figure 1(B), On PP3, no significant group difference was found at 30 min before injection, the duration of nursing behavior was significantly shortened in mother rats treated with Lamotrigine at 30 min after injection. One-way ANOVA revealed a main effect of group [F(3,28) = 14.214, p < 0.000]. Post hoc Bonferroni test shows that the Lamotrigine 25 mg/kg group and 35 mg/kg shorten nursing behavior compared with ones treated with vehicle (p = 0.018 and p < 0.000, respectively). Lamotrigine did not show the influence on licking duration. Figure 1(C) shows pup licking 30 min before injection and the influence of lamotrigine on pup licking 30 min after injection on PP3. Thirty min after lamotrigine administration, One-way ANOVA showed no overall drug treatment effect of licking behavior [F(3,28) = 2.693, p = 0.065], suggesting that there is no enough evidence to support the idea that lamotrigine can impair pup licking. Lamotrigine reduced nest building duration. Figure 1(D) demonstrates the effect of lamotrigine treatment on nest building at test points on PP3. In comparison to the vehicle group, nest building activity was severely impaired by lamotrigine 30 min after the injection. One-way ANOVA revealed a main effect of group [F(3,28) = 19.726, p < 0.000], and Bonferroni post hoc test indicated that lamotrigine 25 mg/kg and 35 mg/kg groups had significant lower building activity than the vehicle group (all ps < 0.000). Lamotrigine reduced number of pups retrieved. Figure 1(E) shows the number of retrieved pups at baseline and the effects of lamotrigine treatment on pup retrieval 30 min after injection on PP3. Each dam retrieved all pups 30 min before injection. The number of retrieved pups was significantly reduced in mother animals treated with lamotrigine on PP3. One-way ANOVA revealed a main effect of group [F(3,28) = 21.537, p < 0.000], and Bonferroni post hoc test demonstrated that animals treated with lamotrigine 35 mg/kg retrieved fewer pups than the vehicle group (p < 0.000). Lamotrigine prolonged the latency of pup retrieval. Figure 1(F, G) illustrate effects of the three doses of lamotrigine on first and last pup retrieval latencies 30 min after injection on PP3. The first and last pup retrieval latencies were defined as the time elapsed from the first pup approach to the retrieval of the first and eighth pup into the nest, respectively. We assigned 600 s to dams which did not approach or

ACCEPTED MANUSCRIPT retrieve the testing pups. Thirty minutes after lamotrigine administration, one-way ANOVA test revealed a significant overall drug treatment effect on the first and last pup retrieval latencies on PP3 (ps < 0.000). Bonferroni post hoc test showed that dams treated with lamotrigine 35 mg/kg took significantly longer to retrieve their first and last pups to the nest in comparison to the vehicle treatment (ps < 0.000).

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3.2 Riluzole impaired nursing, licking and nest building activities, reduced number of pups retrieved, as well as prolonged pup retrieval latency

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Figure 2 Effects of riluzole treatment on maternal behavior (n = 8). (A) Riluzole 8 mg/kg impaired nursing activity 30 min after injection on PP3. (B) Riluzole 8 mg/kg disrupted pup licking activity 30 min after injection. (C) Riluzole 4 mg/kg and 8 mg/kg impaired nest building activity 30 min after injection on PP3. (D) Animals treated with 8 mg/kg riluzole retrieved fewer pups. (E, F) Riluzole 8 mg/kg prolonged the latencies of the first and last pup retrieval. The data of nursing, licking, nest building duration, number of retrieved, first and last retrieval latencies are expressed as mean ± SEM. **p < 0.01, ***p < 0.001 versus the vehicle group. Riluzole reduced nursing duration. Nursing behavior before the injection and the effects of riluzole on nursing behavior 30 min after injection on PP3 are shown in Figure 2(A). The duration of nursing behavior was significantly shortened by riluzole in mother rats 30 min after injection. One-way ANOVA revealed a main effect of

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group [F(3,28) = 19.444, p < 0.000], and Bonferroni post hoc test illustrated that animals treated with riluzole 8 mg/kg had significant lower nursing activity than vehicle animals (p < 0.000). Riluzole suppressed licking duration. Figure 2(B) shows the effects of riluzole on pup licking on PP3. The duration of licking behavior was significantly shortened by riluzole in mother rats 30 min after injection. One-way ANOVA revealed a main effect of group [F(3,28) = 6.211, p = 0.002], and Bonferroni post hoc test illustrated that riluzole 8 mg/kg significantly impaired licking activity than vehicle (p = 0.009). Riluzole decreased nest building duration. Figure 2(C) shows the effects of riluzole on nest building on PP3. The duration of nest building behavior was significantly shortened by riluzole in mother rats 30 min after injection. One-way ANOVA revealed a main effect of group [F(3,28) = 16.034, p < 0.000], and Bonferroni post hoc test illustrated that riluzole 4 mg/kg and 8 mg/kg significantly impaired nesting activity than vehicle (ps < 0.000). Riluzole reduced number of pups retrieved. Figure 2(D) shows the number of retrieved pups at baseline and effects of riluzole on pup retrieval 30 min after injection on PP3. Each dam retrieved all pups 30 min before injection. The number of retrieved pups was significantly reduced in animals treated with riluzole on PP3. One-way ANOVA indicated a main effect of group [F(3,28) = 17.838, p < 0.000] , and Bonferroni post hoc test illustrated that riluzole 8 mg/kg retrieved fewer pups than the vehicle group (p < 0.000). Riluzole prolonged the latency of pup retrieval. Figure 2(E, F) show effects of the three doses of riluzole on first and last pup retrieval latencies 30 min after injection on PP3. Thirty min after riluzole injection, one-way ANOVA test suggested a significant overall drug treatment effect on the first and last pup retrieval latencies on PP3 (ps < 0.000). Bonferroni post hoc test showed that mother rats treated with riluzole 8 mg/kg took significantly longer to retrieve their first and last pups to the nest in comparison to ones treated with vehicle (ps < 0.000).

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3.3 Lamotrigine or riluzole did not shorten the total duration of behaviors unrelated to maternal behavior In order to determine whether lamotrigine or riluzole disrupted maternal behavior by nonspecific sedative effect, we also analyzed some behaviors which are unrelated to maternal behavior, such as combining, roaming, rearing, looking around, as well as drinking/eating. As Figure 3 shown, one-way ANOVA and Bonferroni post hoc test showed that lamotrigine significantly inhibited combing and rearing behavior (ps < 0.001), but significantly prolonged eating/drinking and looking around behaviors (ps < 0.031). Totally, as the duration of each unrelated behavior was short and variant, we put the lasting time of all unrelated behaviors together into a total duration for all unrelated behaviors, lamotrigine did not inhibit behaviors unrelated with maternal behavior (Figure 3F), which indicates that lamotrigine did not disrupt maternal behavior by nonspecific sedative effect in the test doses.

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Figure 3 Lamotrigine did not significantly shorten the total duration of behaviors unrelated to maternal behavior. Duration of unrelated behaviors is expressed as mean ± SEM, *p < 0.05, **p < 0.01, and ***p < 0.01.

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As Figure 4 shown, one-way ANOVA and Bonferroni post hoc test showed that riluzole significantly inhibited combing, roaming and rearing behavior (ps < 0.018), but significantly prolonged eating/drinking and looking around behaviors (ps < 0.030). Totally, we put the lasting time of all unrelated behaviors together into a total duration for all unrelated behaviors, riluzole did not significantly inhibit behaviors unrelated with maternal behavior (p = 0.384, Figure 4F), which indicates that riluzole did not disrupt maternal behavior by nonspecific sedative effect in the test doses.

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Figure 4 Riluzole did not significantly shorten the total duration of behaviors unrelated to maternal behavior. Duration of unrelated behaviors is expressed as mean ± SEM, *p < 0.05, **p < 0.01, and ***p < 0.01.

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4. Discussion

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The present study shows that rats treated with lamotrigine or riluzole had a longer pup retrieval latency, retrieved fewer pups into the nest, spent less time on licking and nursing pups, as well as on building the disturbed nest. In addition, the doses of lamotrigine or riluzole disrupted maternal behavior did not shorten the total duration of behaviors unrelated to maternal behavior. These data indicate that lamotrigine and riluzole disrupt major components of maternal behavior in postpartum female rats and not due to nonspecific sedative effect. Although the present study shows that lamotrigine and riluzole disrupt maternal behavior in postpartum female rats, the psychological and behavioral mechanisms underlying the disruptive effect remain unclear. Furthermore, as maternal behavior has motivational as well as motor components, and given that riluzole also gives rise to sedation due to the inhibition of re-uptake of γ-aminobutyric acid (GABA) (Kretschmer et al. , 1998), the question is raised of whether the disruptive effect on maternal behavior is motivational or nonspecific sedative. In order to confirm the idea that lamotrigine and riluzole disrupted maternal behavior not by nonspecific sedative effect, we also analyzed the behaviors unrelated to maternal behavior. Indeed, the drugs at the doses which disrupted maternal behavior did not significantly inhibit the total duration of unrelated behaviors. Taken together, these data indicate that the maternal disruptive effect of lamotrigine or riluzole is not due to the nonspecific sedative effect. In the further, we should pay more attention to explore the precise

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behavioral mechanisms underlying it. Anticonvulsants lamotrigine and riluzole stabilize presynaptic neuronal membranes and prevent the release of glutamate (Deng et al., 2013, Doble, 1996, Goa et al., 1993, Jehle et al., 2000, Nakato et al., 2011). Glutamate is an important excitatory neurotransmitter in the central nervous system and substantial evidence shows that glutamatergic transmission facilitates motivated behaviors. It is reported that systemic or intra-ventral tegmental area injection of the highly selective N-methyl-d-aspartate (NMDA) receptor antagonist LY235959 decreased nicotine reinforcement (Mansvelder and McGehee, 2000). Consistent with the role of glutamate transmission in the nicotine-reinforcement, nicotine increased excitatory glutamate-mediated input to the ventral tegmental area, and such facilitated midbrain dopamine transmission, which in turn activated NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors located on neurons in the ventral tegmental area (Fu et al. , 2000, Grillner and Svensson, 2000, Mansvelder and McGehee, 2000). Furthermore, Group II metabotropic glutamate receptors (mGlu2/3Rs) agonist LY379268, which has been demonstrated to attenuate glutamate release in cortex (Zhai et al. , 2003), reduced the motivation to self-administer psychostimulant methamphetamine (Crawford et al., 2013). Also, in vivo microdialysis procedures, increased extracellular glutamate in the nucleus accumbens enhanced excessive ethanol drinking in ethanol dependent mice, whereas decreased glutamatergic transmission in the nucleus accumbens via bilateral injections of the mGlu2/3Rs agonist LY379268 reduced drinking in dependent mice (Griffin et al. , 2014). As such, it is postulated that glutamatergic transmission may be involved in maternal behavior in postpartum female rats and lamotrigine and riluzole may disrupt maternal motivation via inhibiting glutamate release. In combination with the main finding of the present study that lamotrigine and riluzole disrupted maternal behavior in postpartum female rats, it seems like that lamotrigine and riluzole disrupted maternal behavior due to inhibiting the release of glutamate. Nevertheless, lamotrigine or riluzole does not solely affect glutamergic transmission. For example, lamotrigine also concentration-dependently inhibits serotonin re-uptake in both human platelets and rat brain synaptosomes (Southam et al. , 1998). Riluzole inhibits re-uptake of γ-aminobutyric acid (GABA) (Kretschmer et al., 1998). Lamotrigine reduced marble-burying behavior, which may be also reduced by GABA receptor agonist muscimol (1.0 mg/kg) (Egashira et al. , 2013). Thus, lamotrigine and riluzole do inhibit the release of the glutamate, but they also influence other circuits. Therefore, we cannot confirm that lamotrigine or riluzole disrupts maternal behavior by preventing glutamatergic transmission. As such, the role of glutamergic transmission in the expression of normal maternal behavior needs more investigation. Most of studies focused on the efficacy of anticonvulsants on clinical manifestations of bipolar disorder. Lamotrigine is recommended to be the first line monotherapy for postpartum bipolar disorder (Sharma et al. , 2017). However, the effect of anticonvulsants on social behaviors, especially maternal behavior has been largely ignored. Previous article suggests that maternal side effects of medication

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Acknowledgments

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should be taken into account because sedation of medication could affect mother’s ability to care for child, particularly at night (Jones et al. , 2014). However, our study indicates that both lamotrigine and riluzole may also disrupt maternal behavior via inhibiting maternal motivation. Therefore, it is a side effect of anticonvulsants that disrupt maternal behavior. Moreover, it is previously reported that mothers with postpartum psychosis exhibit decreased maternal and infant social contact and more negative emotional responses to the infant’s needs (McNeil et al. , 1985, Naslund et al. , 1985). As such, children may be at risk for various ways, including mental illness impairing mother-infant interaction (Stein et al. , 2014), or maternal disruptive effect of medications. Clinicians should remind the woman’s partner or her wider family that the patient may ignore infant care or abuse infant after administration of anticonvulsants. If the risk of harm to infant increased, including poor infant care and lack of bonding, the threshold for admission to hospital should be lowered. Besides, clinical trials should be carried out to investigate the effect of antipsychotics and anticonvulsants on maternal behavior in postpartum women. Taken together, the present study demonstrates that anticonvulsants lamotrigine and riluzole disrupt major components of maternal behavior, but hardly affect behaviors unrelated to maternal behavior, which indicates that the maternal disruptive effect is not due to nonspecific sedative effect. However, there is a limitation in the present study that lamotrigine and riluzole do not solely affect glutamatergic transmission. Thus, we cannot confirm that lamotrigine and riluzole disrupt maternal behavior must be caused by preventing glutamatergic transmission. As such, further work will determine the precious neural mechanisms underlying the maternal disruptive effect induced by lamotrigine and riluzole.

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This research was supported by the National Natural Science Foundation of China (81302757) and the Fundamental Research Funds for the Central Universities (SWU1709247).

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Conflict of interest statement The authors have no conflict of interest. References Bergink V, Rasgon N, Wisner KL. Postpartum Psychosis: Madness, Mania, and Melancholia in Motherhood. Am J Psychiatry. 2016;173:1179-88. Besheer J, Lepoutre V, Hodge CW. Preclinical evaluation of riluzole: assessments of ethanol self-administration and ethanol withdrawal symptoms. Alcohol Clin Exp Res. 2009;33:1460-8. Beyer DKE, Freund N. Animal models for bipolar disorder: from bedside to the cage. Int J Bipolar Disord. 2017;5:35. Brennan BP, Hudson JI, Jensen JE, McCarthy J, Roberts JL, Prescot AP, et al. Rapid enhancement of glutamatergic neurotransmission in bipolar depression following treatment with riluzole. Neuropsychopharmacology. 2010;35:834-46.

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ACCEPTED MANUSCRIPT Highlights

 Mood stabilizers lamotrigine and riluzole disrupt maternal behavior in postpartum female rats  Lamotrigine and riluzole at tested doses did not disrupt behaviors unrelated

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to maternal behavior, indicating the maternal disruptive effect is not due to

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nonspecific sedative effect.