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. Author manuscript; available in PMC: 2025 Nov 1.
Published in final edited form as: Dev Psychobiol. 2024 Nov;66(7):e22543. doi: 10.1002/dev.22543

Agomelatine is unable to attenuate kainic acid induced deficits in early life communicative behavior

Matthew S Binder 1, Zachary J Pranske 1, Samantha L Hodges 2, Paige D Womble 1, Eliesse M Kwok 1, Saul I Quintero 1, Andrew D Kim 1, David A Narvaiz 1, Joaquin N Lugo 1,2,3
PMCID: PMC11376987  NIHMSID: NIHMS2018496  PMID: 39205500

Abstract

Early life seizures (ELS) are associated with a variety of behavioral comorbidities. Among the most prevalent of these are deficits in communication. Auditory communicative behaviors in mice, known as ultrasonic vocalizations (USVs), can be used to assess potential treatments. Agomelatine is a melatonin agonist that effectively reduces behavioral comorbidities of seizures in adults, however, its ability to attenuate seizure-induced communicative deficits in neonates is unknown. To address this, we administered C57 mice either saline or kainic acid (KA) on postnatal day (PD) 10. The mice then received either agomelatine or saline 1-hour post status epilepticus. On PD 11, we assessed the quantity of USVs produced, the duration, peak frequency, fundamental frequency, and amplitude of the vocalizations, as well as the call type utilization. We found that KA increased vocal production and reduced USV variability relative to controls. KA also increased USV duration and amplitude, and significantly altered the types of calls produced. Agomelatine did not attenuate any of the deficits. Our study is the first to assess agomelatine’s efficacy to correct USVs and thus provides an important point of context to the literature, indicating that despite its high therapeutic efficacy to attenuate other behavioral comorbidities of seizures, agomelatine’s ability to correct neonatal communicative deficits is limited.

Introduction

Early life seizures (ELS) adversely impact the developing brain and predispose neonates to a variety of cognitive and behavioral comorbidities (Aaberg et al., 2016; Holmes & Ben-Ari, 2001). Comorbid conditions are a serious concern, as they have implications for medical costs, family care, treatment regimens, and the infants’ overall health (Aaberg et al., 2016; Jafarpour et al., 2018; Roy et al., 2011). While there are various comorbidities that can arise following ELS, one of the most prevalent is autism spectrum disorder (ASD) (Clarke et al., 2005) A defining feature of ASD are deficits in communication (DSM-5, 2013). Neonatal communicative deficits can impact the relationship between caregiver and infant and impede the neonate’s healthy social development, thereby having far reaching implications for the infant’s quality of life (DeMyer et al., 1973; Esposito & Venuti, 2008; Kasari & Sigman, 1997). Although less severe seizure induced comorbidities are associated with a better long term prognosis, there are few treatment options that address the communication deficits associated with ELS (Goodwin et al., 2015).

The efficacy of potential treatments to attenuate seizure-induced deficits in communication can be determined via the use of mouse models. Communication in mice refers to the production of ultrasonic vocalizations (USVs). USVs are whistle-like sounds between 30–90 kHz and are produced in neonates when they are isolated from their dam (Branchi et al., 2001). Neonatal vocalizations play a vital role in dam-pup communication as they elicit maternal retrieval and care, thereby helping to foster healthy developmental trajectories. Various ecologically relevant parameters of vocalizations can be assessed such as their total quantity, duration, pitch, and loudness. Furthermore, USVs can be sorted into 10 distinct categories of calls based off of internal pitch changes, length, and 2-dimensional shape, comprising a comprehensive assessment (Scattoni et al., 2009; Scattoni et al., 2008). Notably, neonatal communicative behaviors are highly conserved across species as too are communicative deficits. For instance, a previous study found that pilocarpine induced early life seizures decreased the latency and the duration of USVs (López-Meraz et al., 2014). Another study found that pups treated with the chemoconvulsant kainic acid produced fewer USVs, emitted calls of a shorter duration, and had several changes in call type utilization relative to control animals (Reynolds et al., 2017). Furthermore, Bigelow et al. (2022) found that a single kainic acid episode in neonatal rats altered their response to vocalizations as an adult, thereby highlighting both the chronic impact of ELS on long term auditory communication and the need for treatment (Bigelow et al., 2022). Altogether, these studies indicate that the autistic comorbidity that commonly accompanies ELS in humans is conserved in select seizure models, allowing for the screening of potential therapeutic treatments.

One such promising treatment is agomelatine. Agomelatine is a MT1/MT2 melatonin receptor agonist and a 5HT2C serotonin receptor antagonist that boasts both a high tolerability and translatability (Guardiola-Lemaitre et al., 2014; Jiang et al., 2024). Relevant to seizure pathology, agomelatine decreases glutamate release, promotes neurogenesis, reduces cellular damage due to oxidation, and protects against excitotoxity while facilitating secondary lesion repair (Gressens et al., 2008; Guardiola-Lemaitre et al., 2014; Milanese et al., 2013; Tchekalarova et al., 2017). Behaviorally, these effects have been shown to counteract common comorbidities of seizures such as depression, memory loss, anxiety, increased locomotor activity, dysregulated sleep patterns, and deficits in social interaction (Kumar et al., 2015; Su et al., 2023; Tchekalarova et al., 2018). Furthermore, while agomelatine has predominately been assessed in adults, one study did find that a single administration of agomelatine reduced hippocampal excitotoxicity in neonates (Gressens et al., 2008). This suggests that agomelatine has beneficial effects regardless of the age it is administered and thus may be ideally suited to counteract early life behavioral deficits.

Despite agomelatine’s strong therapeutic potential, its ability to attenuate seizure induced communicative deficits has not been assessed. This is significant as communicative deficits are among the first behavioral comorbidities to emerge and may contribute to the onset and severity of subsequent comorbidities (Delehanty et al., 2018; Laister et al., 2021). Thus, early treatments are needed as they may have particularly large effects on an individual’s long-term quality of life. To address this need, the present study used the chemoconvulsant kainic acid to create ELS-induced communicative deficits. We then administered agomelatine and assessed its efficacy to attenuate quantitative and qualitative changes in ultrasonic vocalizations.

Materials and methods

Animals and housing

Male and female C57BL/6J mice were bred at Baylor University. A total of 83 pups from 14 litters were used in this study and were separated into 4 conditions, described below. To mitigate litter effects, all of the conditions were represented in each litter. All behavioral procedures took place during the light cycle between 12 and 4 p.m. Animals were housed in a facility kept at 22 °C on a 12-hr light/dark cycle. Mice had ad libitum access to food and water. All procedures performed were in accordance with Baylor University Institutional Animal Care and Use Committee, as well as the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals.

Seizure and pharmacological treatment

On postnatal day (PD) 10 the pups were randomly assigned into either a seizure condition that was administered a single intraperitoneal (i.p.) injection of kainic acid (1.5 mg/kg) or a control condition that was administered 0.9% physiological saline (Reynolds et al., 2017). After kainic acid injection, the pups were observed until they entered status epilepticus (SE) at which point the seizure was scored using the Racine scale (Racine, 1972). In line with previous studies, 1 hour after SE ended the mice were administered either agomelatine (25 mg/kg) or 0.9% physiological saline (Tchekalarova et al., 2018). The mice then had a 24 hour recovery period before behavioral assessment (Reynolds et al., 2017; Reynolds et al., 2016). Altogether, there were 4 experimental conditions: saline/saline, saline/agomelatine, kainic acid/saline, and kainic acid/agomelatine. Each of these conditions was comprised of an equal number of male and female mice for a total of 8 groups.

Ultrasonic vocalizations (USVs)

Ultrasonic vocalizations were elicited via the maternal isolation paradigm which has been shown to consistently elicit USVs in pups (Shair, 2007). Mice were tested on postnatal day (PD) 11 to determine the effect of agomelatine on early life communicative behaviors, similar to prior studies (Binder & Lugo, 2017; Reynolds et al., 2017; Reynolds et al., 2016). Before testing, pups were weighed and allowed to habituate in the testing room for 30 minutes. Next, they were removed from their dam and placed into a clean, preheated (22°C) cage. Each pup was then individually tested by removing the mouse from the warmed cage and placing it into the center of another room temperature cage contained within a 40 cm × 40 cm × 30 cm sound-attenuated chamber (Scattoni et al., 2008; Shair, 2007; Tsai et al., 2012). The vocalizations were recorded for 2 minutes using an ultrasonic microphone (CM16/CMPA, Avisoft Bioacoustics, Germany, part #40011) and an ultrasound recording program (UltraSoundGate 116Hb, Avisoft Bioacoustics, part # 41161/41162). The microphone was suspended in the center of the chamber, 6 ½ inches above the bottom of the cage. The pups were placed directly under the microphone at the start of recording. Therefore, the pups were always 6 ½ to 8 inches from the microphone depending on their position in the cage. Due to the sensitivity of the microphone, pup orientation was not thought to significantly affect amplitude detection. Following testing, the pups were placed back in the pre-warmed cage, returning to their dam once testing had concluded.

Ultrasonic vocalization analysis

Ultrasonic vocalizations were analyzed with the Avisoft SASLab Pro software (Avisoft SASLabPro, RRID:SCR_014438). The following parameters were used: a fast Fourier transformation (FTT) length of 1024, a time window overlap of 75%, a 100% hamming window, a frequency resolution of 488 Hz, a time resolution of 1 ms, and a sampling frequency of 250 Hz (Binder & Lugo, 2017; Scattoni et al., 2008). Specifically, the total quantity of calls produced, their duration, fundamental frequency, peak frequency, and amplitude (determined via the power of the call) were assessed. Qualitative aspects of the vocalizations were determined by visually identifying each call using an established call type taxonomy in addition to grouping the calls based on the length, shape, and the internal changes in fundamental and peak frequency of a call (Scattoni et al., 2008). The predefined call type categories were complex, harmonic, two-component, upward, downward, flat, chevron, short, composite, and frequency steps call types (Scattoni et al., 2008; Scattoni et al., 2011). A total of 4 scorers were used for this project, each of which was extensively trained on practice files until there was 100% reliability across scorers at which point they were assigned a subset of USV files from each condition. The scorers were blind to the condition of the animal at the time of scoring.

Statistical analysis

All analyses were conducted using GraphPad Prism 7 software (La Jolla, CA) or SPSS 25.0 (IBM, USA). When assessing USV production, analysis of variances (ANOVAs) were conducted. The dependent variable was the number of USVs and the independent variables were seizure (saline, kainic acid), sex (male, female), and treatment (saline, agomelatine). Tukey’s HSD post hoc was used to assess any interactions and specific group differences. A similar analysis was run to analyze the differences in the average duration, peak frequency, fundamental frequency, and the mean amplitude (loudness) of the calls. These parameters were chosen since each has been shown to be of particular relevance to communicative behaviors (Esposito et al., 2017; Esposito & Venuti, 2008, 2009, 2010). All interactions were again clarified using the Tukey HSD post hoc analysis. To determine the relative variability of the groups, we calculated the coefficient of variability (CV). Lastly, the call type composition of each group was analyzed with a Pearson Chi-Square, along with individual z-tests, to compare significant call type proportions between groups. A value of p < .05 was considered significant for each statistical test, with figures depicting the mean ± standard error of the mean (SEM).

Results

USV production

When assessing vocalization production, we found that there was a main effect of seizure, with kainic acid treated mice producing significantly more vocalizations than saline treated mice (F(1,75) = 8.78, p = .004) (Figure 1A). We did not observe any main effects for sex, treatment, nor any significant interactions (sex: (F(1,75) = .56, p = .46, treatment: F(1,75) = 1.28, p = .26, seizure by sex interaction: F(1,75) = 1.05, p = .31, treatment by sex interaction: F(1,75) = .05, p = .82, seizure by treatment interaction: F(1,75) = .28, p = .60, seizure by sex by treatment interaction: F(1,75) = .01, p = .92) (Figure 1A). We then assessed the inherent variability of USV production per each group by calculating the coefficient of variation (CV). We found that both the male and female negative control groups had the highest variability (CV=71.2, 106.4 respectively). Conversely the variability between the kainic acid and agomelatine groups were lower (male kainic acid saline CV= 63.4, female kainic acid saline CV= 58.1, male saline agomelatine CV= 49.3, female, saline agomelatine CV= 53.7, male kainic acid agomelatine CV= 65.7, female kainic acid agomelatine CV=58.6) (Figure 1B).

Figure 1.

Figure 1.

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The effect of early life seizures on vocal production and USV variability. A. Kainic acid treated animals emitted significantly more USVs than control mice which was not normalized by administering agomelatine, no effects of sex were found. B. Saline saline treated animals produced the most variable vocalizations relative to kainic acid treated animals. Bars represent the mean and the error bars represent the standard error of the mean. ** = p < .01

USV spectral and temporal characteristics

We next examined the spectral and temporal characteristics of the USVs. For duration, we found a main effect of seizure, with kainic acid treated mice emitting a significantly longer average duration of calls than controls (seizure: F(1,75) = 4.81, p = .03) (Figure 2A). No main effect of treatment, sex, nor any significant interactions for duration were found (treatment: F(1,75) = .05, p = .82, sex: F(1,75) = .04, p = .84, seizure by sex interaction: F(1,75) = .01, p = .98, treatment by sex interaction: F(1,75) = .25, p = .62, seizure by treatment interaction: F(1,75) = .11, p = .75, seizure by sex by treatment interaction: F(1,75) = .51, p = .48) (Figure 2A). We then assessed USV peak frequency and did not detect any significant differences between groups, although there was a trend for kainic acid treated animals to produce USVs of a lower peak frequency relative to controls (seizure: F(1,75) = 3.43, p = .06, treatment: F(1,75) = .55, p = .46, sex: F(1,75) = 1.81, p = .18, seizure by sex interaction: F(1,75) = .002, p = .97, treatment by sex interaction: F(1,75) = .27, p = .11, seizure by treatment interaction: F(1,75) = .11, p = .75, seizure by sex by treatment interaction: F(1,75) = .46, p = .83) (Figure 2B). For fundamental frequency, females emitted calls of a lower frequency than males (sex: F(1,75) = 4.30, p = .04) (Figure 2C). No other significant differences were found between groups (seizure: F(1,75) = .22, p = .64, treatment: F(1,75) = .17, p = .68, seizure by sex interaction: F(1,75) = .41, p = .52, treatment by sex interaction: F(1,75) = .06, p = .81, seizure by treatment interaction: F(1,75) = .14, p = .71, seizure by sex by treatment interaction: F(1,75) = .27, p = .61) (Figure 2C). Lastly, we assessed amplitude and found a main effect of seizure, with kainic acid treated animals producing significantly louder calls than controls (seizure: F(1,75) = 7.79, p = .007) (Figure 2D). We also found an interaction between sex and treatment (treatment by sex interaction: F(1,75) = 4.36, p = .04). However, Tukey’s post hoc test detected no significant differences between groups (p > .05). No other significant differences for amplitude were detected (sex: F(1,75) = .74, p = .39 treatment: F(1,75) = .01, p = .93, seizure by sex interaction: F(1,75) = 3.53, p = .06, seizure by treatment interaction: F(1,75) = 1.66, p = .20, seizure by sex by treatment interaction: F(1,75) = 2.40, p = .13) (Figure 2D).

Figure 2.

Figure 2.

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Spectral and temporal characteristics of ultrasonic vocalizations. A. Kainic acid treated mice produced USVs of a longer average duration than saline treated mice, no other differences between groups were found. B. There were no significant differences in peak frequency between groups. C. Females produced USVs of a lower average fundamental frequency than males, no other differences were present. D. Kainic acid treated mice produced significantly louder USVs than control groups. Bars represent the mean and the error bars represent the standard error of the mean. * = p < .05, ** = p < .01

Call type utilization

Lastly, we assessed the qualitative aspects of the vocalizations per each condition (saline saline, kainic acid saline, saline agomelatine, and kainic acid agomelatine). Significant population differences for call type utilization per condition were found (X2 27, 301.33, p <.001). Accompanying z tests for proportional differences were conducted per each call type. We found that the saline agomelatine group produced a significantly higher proportion of complex calls than the other conditions (p < .05). The saline saline and kainic acid agomelatine conditions produced a similar number of complex calls and the kainic acid saline condition produced the fewest calls (Figure 3A). For two component-vocalizations, the saline saline group produced significantly more calls than all of the other groups (p < .05), with no other differences present (p > .05) (Figure 3B). For upward vocalizations, the saline saline group produced significantly more calls than the kainic acid and saline agomelatine conditions (p < .05). The kainic acid agomelatine and saline agomelatine conditions had a similar proportion of upward calls whereas the kainic acid saline condition produced the fewest calls (Figure 3C). For downward vocalizations, kainic acid saline treated mice produced the highest proportion of calls followed by the kainic acid agomelatine, saline saline, and saline agomelatine conditions (p < .05) (Figure 3D). For chevron vocalizations, kainic acid saline treated animals produced fewer calls than the other conditions, with no other differences present (Figure 3E). When assessing the short call type, the saline saline mice produced significantly more vocalizations than all other conditions (p < .05). There were no other significant differences between groups (p > .05) (Figure 3F). For composite vocalizations, kainic acid saline mice produced significantly more calls than the other groups (p < .05). The kainic acid agomelatine and saline agomelatine conditions produced a similar number of calls as did the saline agomelatine and saline saline groups (p > .05) (Figure 3G). When assessing the frequency step vocalization, we found that the kainic acid saline condition produced a similar number of calls as the saline agomelatine mice but significantly more calls than the saline saline and kainic acid agomelatine conditions. No differences between the saline agomelatine and kainic acid agomelatine groups were found (p > .05) (Figure 3H).

Figure 3.

Figure 3.

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Call type utilization per condition. A. Saline agomelatine treated animals produced a significantly higher proportion of complex calls than all other conditions, additional differences are denoted by letters. B. Saline saline mice produced more two syllable calls than the kainic acid saline, saline agomelatine, and kainic acid agomelatine conditions. C,D, Mice receiving saline saline produced significantly more upward calls than the other groups whereas the kainic acid saline condition produced fewer downward calls. E. Kainic acid saline treated animals produced significantly fewer chevron calls than the other conditions. F. The saline saline groups produced the most short call types of all conditions. G. The kainic acid saline condition produced the most composite call types. H. The saline saline condition produced the lowest proportion of frequency steps call type relative to the other conditions. Letters are used to denote the conditions that are significantly different from one another. The same letter indicates that two conditions are not significantly different whereas different letters denote a significant difference (p <.05).

Discussion

Agomelatine was originally developed to treat depression however, its diverse therapeutic effects, tolerability, and high translatability has led to its use in various other conditions. It has shown particularly significant promise in epilepsy, where agomelatine’s anti-oxidant, anti-inflammatory, and anti-excitatory properties counteract many of the cellular changes incurred by seizures (Chumboatong et al., 2022; Dagyte et al., 2010; Gressens et al., 2008; Guardiola-Lemaitre et al., 2014; Tchekalarova et al., 2017). Consequently, agomelatine has also been shown to improve prominent behavioral comorbidities of seizures such as social deficits, depression, and anxiety (Kumar et al., 2015; Tchekalarova et al., 2018). Due to agomelatine’s strong efficacy, our current study assessed its therapeutic effects on communicative deficits using a kainic acid early life seizure (ELS) model. While we did find a seizure effect on USVs, surprisingly, agomelatine treated animals were statistically identical to ELS animals across the assessed parameters. Altogether our study provides evidence suggesting that a single dose of agomelatine is insufficient to counteract early life expressive auditory communication deficits.

Agomelatine’s lack of therapeutic efficacy may be in part attributed to the acute administration paradigm used. Due to the short recording window for early life communicative behaviors (which only occur during the first 14 days of life), the fragility of newborn pups (limiting repeat injections), and a prior study that found agomelatine reduced hippocampal excitotoxicity in pups following one injection, we limited our administration of agomelatine to a single dose (Gressens et al., 2008). However, nearly all prior studies examining agomelatine’s effects on seizure pathology and related behavioral comorbidities used a prolonged drug administration paradigm. For instance, one study administered agomelatine for 10 weeks and found that it effectively prevented comorbid depressive behaviors in a post status epilepticus model (Tchekalarova et al., 2018). Another study administered agomelatine for 30 days and reported an attenuation of social deficits and anxiety in a valproic acid model (Kumar et al., 2015). Several other studies that found therapeutic effects of agomelatine used a dosing paradigm ranging from 10–20 weeks (Demir Özkay et al., 2015; Tchekalarova et al., 2017). Altogether, the data suggests that agomelatine’s therapeutic effects, particularly its behavioral effects, are highest when it is administered chronically rather than acutely. Future studies exploring the minimum dosing paradigm required for agomelatine’s efficacious effects would help to clarify its potential.

Agomelatine’s lack of therapeutic efficacy may also be explained by the timepoint that it was administered. Nearly all previous studies have established agomelatine’s efficacy in adult models. While there are many neurological distinctions between neonatal and adult mice, one particularly relevant difference is in the levels and function of melatonin. In adults, melatonin release predominately occurs in tandem with the circadian rhythm and is associated with sleep, as there are low endogenous levels of melatonin throughout the day followed by a gradual increase in melatonin once the sun sets (Kennaway & Wright, 2002; Lewy, 1999; Tosini et al., 2014). Conversely, in neonates, melatonin has a dual role, as it contributes to both sleep wake cycles and to neurodevelopment (de Faria Poloni et al., 2011; Tosini et al., 2014). Specifically, melatonin has been shown to regulate various intracellular processes and second messenger signaling systems in order to modulate neural gene responses and promote neuronal differentiation (de Faria Poloni et al., 2011). The result of this dual role is consistently high melatonin levels throughout the neonatal period (Munoz-Hoyos et al., 2007). Furthermore, studies have shown that upon insult, such as a seizure, melatonin levels dramatically increase to help reduce inflammation and counteract oxidative stress (Esposito & Cuzzocrea, 2010; Reiter et al., 2016). Therefore, one likely explanation for our results is that adding a melatonin agonist into a neonatal system that already has high endogenous levels of melatonin, which are further increased due to a seizure, may have diminishing returns, as competition for binding sites and the rate of melatonin metabolism would increase. This problem would not be as pronounced in adults due to the comparatively low levels of endogenous melatonin. Future studies examining the effect of melatonin agonists on neonatal melatonin levels, metabolism, and bioavailability would help to address this hypothesis.

Although no effects of agomelatine on communicative behaviors were found, we did observe numerous seizure-induced changes in vocalizations. Specifically, kainic acid increased the quantity of USVs produced, decreased the amplitude of the calls, and increased call duration, in addition to affecting the type of calls emitted. Our results compare favorably to a prior study, Reynolds et al. 2017, which also reported significant kainic acid induced alterations in the total quantity and duration of USVs emitted, as well as select changes in the amplitude of the calls and an atypical call type utilization(Reynolds et al., 2017). While there is broad agreement between the two studies, there are some differences. For instance, we found an increase in call number and duration however, Reynolds et al. (2017) found a decrease in both parameters. This discrepancy is most likely due to the differences in the timing of USV assessment, as we evaluated USVs on PD 11 whereas Reynolds et al. (2017) evaluated USVs on PD 12. Importantly, while there may be select differences (increases vs decreases) in the communicative behaviors of kainic acid treated mice between studies, these differences occurred in the exact same parameters. Therefore, our finding that kainic acid leads to alterations in USV quantity, duration, amplitude, and call type utilization reproduces the same pattern of impairments previously observed, suggesting that kainic acid’s effects on USVs are consistent both across studies and throughout development.

In addition to recapitulating Reynolds et al. (2017) findings, our study also expanded upon them. Specifically, one limitation of past work is that kainic acid’s effects on broad spectrum vocalizations have only been assessed in males (Reynolds et al., 2017). This is notable as sex dependent differences have been reported in epilepsy yet females are significantly understudied (Beery, 2018; Scharfman & MacLusky, 2014). We then are the first to show that kainic acid affects both male and female communicative behaviors similarly. We also examined an understudied dimension of USVs, their variability. While not commonly assessed, examining variability provides another measure of behavior and may provide additional insights into an animal’s phenotype that are not reflected in the broad data. In our study, we found that the negative control groups produced the most variable vocalizations, a trend that was particularly pronounced in females. Conversely, animals that were treated with kainic acid emitted less variable USVs relative to controls, as did agomelatine treated animals. This indicates that USVs are innately highly variable and that select treatments may reduce the typical range USVs fall in. However, more studies assessing variability in USVs are needed to provide context to our results and interpretations. Future studies could also continue to expand the seizure-USV literature by examining the effects of kainic acid on adult USVs to determine if seizures produce consistent communicative deficits throughout the lifespan.

Conclusion

Our study is the first to assess the therapeutic potential of agomelatine to attenuate kainic acid induced deficits in early life communicative behaviors. Contrary to expectations, we found that agomelatine was unable to counteract seizure-induced alterations in USVs, thereby displaying minimal efficacy. Factors such as the acute dosing paradigm used and its administration in neonates may have contributed to its negligible effects. Over the last decade agomelatine has received much attention with the overwhelming majority of studies extolling its benefits across a wide range of neurological conditions. Our study then provides an important point of context in the literature, indicating that while agomelatine has clear therapeutic value, its beneficial effects are not universal, as its efficacy to counteract early life behavioral deficits is limited.

Agomelatine Paper Highlights.

  • Kainic acid increases ultrasonic vocalization production in C57 male and female neonates

  • Kainic acid increases vocalization duration and amplitude and alters call type utilization

  • Agomelatine displays minimal therapeutic efficacy to treat neonatal vocalization deficits

Acknowledgements

This work was supported by the National Institutes of Health grant R15S088776. The authors do not have any conflicts of interest to declare.

Footnotes

Conflict of interest disclosure: The authors do not have any conflicts of interest to declare.

Ethics Approval Statement: All procedures performed were in accordance with Baylor University Institutional Animal Care and Use Committee, as well as the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals.

Permission to Reproduce Material from Other Sources: We are not requesting permission to reproduce materials from other sources.

Data Availability Statement:

The data for this study are available upon request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data for this study are available upon request.

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