Light-at-night and chronic light exposure, whether dim or bright, is an increasingly pervasive environmental factor due to urbanization and artificial lighting. Studies using rodent models have demonstrated that dim light-at-night, bright light-at-night, and constant light (LL) can induce anxiety-like and depressive-like behaviors, as well as impair learning and memory (Copenhaver et al., 2022). Similarly, human studies have identified links between light-at-night and mood disorders, suggesting a translational relevance for investigating the neurobiological mechanisms underlying these effects (Guindon et al., 2024). The increasing use of electronic devices, including TVs, smartphones, and tablets at night has also been linked to poorer mood in humans (Figueiro and Overington, 2016). These findings emphasize the importance of understanding the specific pathways through which chronic and evening light exposure influences behavioral outcomes.

Dopamine (DA), a key neurotransmitter involved in mood regulation and reward processing, has emerged as a potential modulator of light-induced behavioral changes. DA signaling plays a crucial role in regulating circadian rhythms, with evidence showing that activation of D1-like dopamine receptors (D1R) can influence the expression of “core clock” genes in brain regions which govern mood and reward responses (Imbesi et al., 2009). Additionally, D1Rs are present in the mammalian suprachiasmatic nucleus, the brain area that regulates circadian rhythmicity (Rivkees and Lachowicz, 1997) and are necessary for circadian entrainment (Grippo et al., 2017). Dopamine concentration and release fluctuates with circadian periodicity in both the striatum and nucleus accumbens, areas that control behavioral responses and the reward pathway (Castaneda et al., 2004). Depletion of DA and DRs disrupt both the amplitude and rhythmicity of sleep–wake cycles, indicating dopamine’s participation in the bodies oscillating rhythms (Fifel et al., 2014). Furthermore, the presence of extracellular dopamine has been seen to play a role in regulating clock genes, including period1 and period2, in tissues peripheral to the suprachiasmatic nucleus (the central oscillator) (Hood et al., 2010). There remains a connection between altered dopaminergic signaling and circadian disruptions contributing to adverse behavioral consequences. Additionally, D1Rs are implicated in the regulation of anxiety-like behaviors (Tong et al., 2023) and activation can potentiate the effects of antidepressants (Shuto et al., 2020). The capacity of DA to modulate mood and circadian rhythmicity further supports its potential as a target for modulating the behavioral outcomes of aberrant light exposure. This study investigates the modulatory effects of oral SKF-38393, a selective D1R agonist, on anxiety-like, depressive-like, and cognitive behaviors in response to LL in mice.

This study uncovered several differences in the way consumption of a D1R agonist, SKF-38393 (DA), modulated behavior in mice under LL as well as sex differences in fluid consumption patterns. First, female mice consumed more DA compared to males, wherein males decreased their DA consumption, while females increased or had no change in their consumption over the course of the experiment. While we cannot definitely state that female mice exhibit increased DA preference compared to males because water consumption was also increased, other studies investigating drugs of abuse, including alcohol (Gelineau et al., 2017; Sneddon et al., 2019), cocaine (Russo et al., 2003; Roth and Carroll, 2004), and opiates (Hammerslag et al., 2021), illustrate an overall trend of increased drug intake in both binge-like and chronic consumption patterns in female rodents compared to males. There is also evidence to support that women also exhibit increased drug intake and addiction phenotypes compared to men (as reviewed by Becker and Hu, 2008; Little and Kosten, 2023). The estrous cycle is a potential influence on the behavioral difference seen between the males and females in this study, although it is worth noting that estrous phases were not measured in this study. Previous studies have illustrated connections among dopamine levels and altering phases on the mouse estrous cycle (Dazzi et al., 2007; Vandegrift et al., 2017). Differences in reward-seeking behavior exists in rodents in different phases of the estrous cycle and that progesterone attenuates, while estradiol can promote, drug-seeking behaviors (Giacometti et al., 2022; Hilz and Lee, 2023). While concentrations of DA and changes in inhibition might vary across studies, it is suggested that the change in ovarian hormones may play a role in the dopamine release and uptake in rodent models. Despite their reduced intake of DA compared to females, male mice still exhibited similar behavioral responses as females when consuming DA, indicating that the lower dosing of DA in males was still effective in attenuating some of the behavioral changes typically seen under LL.

In this study, LL induced anhedonia (reduced sucrose preference) in male mice but not female mice, and SKF-38393 consumption attenuated the depressive-like effects of LL in males. Other studies reported reduced sucrose and saccharine preference in male rodents housed under LL (Fonken et al., 2009; Tapia-Osorio et al., 2013; Tchekalarova et al., 2018; Capri et al., 2019; Yang et al., 2021), bright light-at-night (Li et al., 2024b), or dim light-at-night (Fonken et al., 2012; Bedrosian et al., 2013; Gutiérrez-Pérez et al., 2023). Additionally, a human study also showed increased depression and anxiety in humans who are exposed to light-at-night (Burns et al., 2023). Historically, SKF-38393 administration has been shown to alleviate depressive-like behaviors in rodents (Horita et al., 1991; D’Aquila et al., 1994), which has been corroborated by other D1R agonists (Desormeaux et al., 2020). Additionally, consumption of DA alleviated the LL-induced anxiety-like behaviors in both male and female mice, manifesting in reduced dark zone time and longer latency to first dark zone entry in the light–dark box. Other studies using housed under LL (Capri et al., 2019; Zhou et al., 2018; Yang et al., 2021) and other forms of bright light-at-night (Li et al., 2024a), reported increased anxiety, similar to what is found in humans (as reviewed by Tancredi et al., 2022). Alterations in D1R and DA signaling can induce anxiety within humans and animal models (Zweifel et al., 2011; Berry et al., 2019; Beyer et al., 2021) and treatment with D1R agonists, including SKF-38393, can reduce anxiety-like behaviors in rodents (Chan et al., 2017). In summary, these findings highlight the effects of LL on anxiety-like and depressive-like behaviors, the anxiolytic and antidepressant potential of SKF-38393 consumption, and the broader relevance of DA signaling and treatments in mitigating behavioral changes.

This study corroborates the previous results of novelty-induced hyperactivity in LL (Marin et al., 2015; Capri et al., 2019; Medeiros Contini and Seggio, 2023; Schröder et al., 2023), manifesting in increased locomotor activity within the open field. An open question that remains is: what behavior is this open field hyperactivity modeling? One possibility may be due to the animals being tested during their inactive period (ZT/CT 6), measuring increased arousal behavior. If the animals were tested during another part of the circadian cycle, such as during the night or in the dark, when arousal levels are generally higher in nocturnal animals, different open field results may have been found, as another study found (Richetto et al., 2019). Another potential model may be Attention-Deficit/Hyperactivity Disorder (ADHD), which manifests in lack of attention, increased impulsivity, and hyperactivity, and can be treated with dopamine agonists. Light-at-night is known to reduce inhibition and increase impulsivity in both humans and animal models (Byun et al., 2018; Cavalli et al., 2021; Meijdam et al., 2023). Other circadian disruptions, including shortened-day-cycles and simulated shift-work, can produce hyperactivity within the open field in rodents (McGowan and Coogan, 2013; Maroni et al., 2020). Connections exist between proper circadian signaling and ADHD—deficiencies in “core clock genes” including period1 and rev-erbα lead to both hyperactivity and alterations to dopaminergic signaling in animal models (Huang et al., 2015; Otsuka et al., 2022). Humans with ADHD are also known to have mutations within the period genes and altered temporal regulation of period genes transcription (Wang et al., 2020; Faltraco et al., 2021). Both mouse and rat models of ADHD exhibit increased novelty-induced locomotor activity and impulsivity, which can be ameliorated by dopamine agonists (Kamimura et al., 2001; Majdak et al., 2016; Bouchatta et al., 2018). As such, the amelioration of the open field hyperactivity seen in the DA-consuming mice in this study may be an emerging model of ADHD-like behaviors.

We found several sex differences in the behavioral response of DA-consumption in both LD and LL, notably the ineffectiveness of DA to ameliorate the anhedonia of LL in female mice. It is somewhat surprising that female mice seemed to be resistant to the depressive effects of LL, given that females tend to be more sensitive to depressive effects of stressors and have higher rates of depression compared to males (Hasbi et al., 2020; Kropp and Hodes, 2023). The first possibility to this discrepancy may be due to the method of light-at-night used in the aforementioned studies, which used dim light-at-night and found anhedonia, and the current study which used chronic bright light and found no anhedonia; as such, the brightness of the light may lead to differences in behavioral responses. Female mice exhibit reduced depressive-like behaviors when tested under bright light compared to males as well as compared to females tested in the dark phase (Huynh et al., 2011). Sex differences also exist in the behavioral responses to anxiety and depression assays regarding the time-of-day when the tests are administered, wherein female mice exhibit increased anxiety-and depressive-like behaviors when tested in the dark phase compared to males (Verma et al., 2010); if we assayed the behavior during a different circadian or estrus cycle time, differing results may have been found. Female mice also show increased dopaminergic release following exposure to tests of depression and stressors compared to males (Dalla et al., 2010; Kokras et al., 2018). The bright light and the increased dopamine release may provide a countermeasure for the observance of anhedonia in females, although it is worth noting that DA levels, DA receptors, nor DA release were not measured in this study. Second, the removal of the DA for the sucrose preference test may have led to a mild form of withdrawal, which could alter the behavioral response in female mice. Generally, female rodents and women tend to be more susceptible to withdrawal symptoms and abstinence from a drug compared to males (Becker and Koob, 2016; Nicolas et al., 2022). These differences may explain the lack of depressive-like effects in water consuming female mice, as well as the reduced sucrose preference compared to males when consuming DA, under bright LL. Research also suggests that, in adult rodents, females tend to show an increase in locomotor activity when given injections of D1R agonists, including SKF-38393, compared to males (Díaz-Véliz et al., 1999; Heijtz et al., 2002; Schindler and Carmona, 2002). This increase in activity is modulated by the estrous cycle as well, wherein high-dose SKF-38393 injections produce increased locomotor activity within female rodents in diestrus compared to estrus (Díaz-Véliz et al., 1999). This result may partially explain why LD/F/DA animals exhibited increased distance traveled compared to the water controls and males. These findings highlight the importance of considering sex differences in behavioral responses to D1R agonists, but future work is needed to further elucidate the underlying mechanisms of how D1Rs influence anxiety, depression, and locomotion between males and females.

Although SKF-38393 is known to activate D1Rs, SKF-38393 also binds to D5Rs, so the question remains whether the behavioral effects of SKF-38393 on LL are at least partially mediated by D5Rs, rather than predominately D1Rs. While numerous behavioral abnormalities exist in rodent models with reduced D1Rs including hyperactivity, fewer exist in D5R knockouts, which may imply that the behavioral effects of DA-consumption in this study may be mostly due to D1R-specific pathways (Karlsson et al., 2008; Beyer et al., 2021; Sasamori et al., 2022). Interestingly, the effects of DR1 agonist injections (including SKF-38393) vs. oral consumption in this study on behavioral responses is somewhat contradictory and may depend upon dosing, the specific agonist/antagonist, and the injection site. For example, higher doses of SKF-38393 (> 2.5 mg/kg) produce increases to locomotion, impulsivity, and memory (Loos et al., 2010; Lejeune et al., 2013; Zhu et al., 2017), while low doses (including this study) have been shown to reduce impulsivity and hyperactivity, improve attention and vigilance, and have smaller effects on memory (Granon et al., 2000; Barnes et al., 2012; Abdulkader and Gigg, 2024). These smaller effects on memory due to low dosing may be why dopamine had little effects on memory within the object recognition test. Indeed, oral consumption of SKF-38393 has no effect on long-term potentiation by itself, although it can increase long-term potentiation if paired with nicotine and cocaine (Huang et al., 2014). Additionally, higher doses with injections tend to produce anxiogenic effects and in the case of antagonists can produce either anxiogenic or anxiolytic effects; different results on behavior also exist if the D1R is co-administered with other drugs, such as cocaine or nicotine (summarized by Zarrindast and Khakpai, 2015). By drinking the SKF-38393, it opens up the agonist to “first-pass metabolism,” which occurs in D1R agonists (Wu et al., 2005), potentially leading to dose-dependent biphasic responses. To our knowledge, the vast majority of studies have investigated the effects of injections of D1R agonists on behavior, rather than using oral consumption. Additional research is needed to determine how gut and liver metabolism can alter how D1R agonist oral consumption manifest behaviorally.

In conclusion, this study highlights the complex interplay among LL, dopamine agonism, and sex differences in modulating behavioral outcomes in mice. LL induced anxiety-like, hyperactive, and depressive-like behaviors, many of which were mitigated by the consumption of DA. Importantly, while DA attenuated anxiety and hyperactivity in both sexes, its effects on anhedonia was sex-specific, with males showing greater benefit. Moreover, this study supports prior findings on the anxiogenic and hyperactivity-inducing effects of LL, while providing new insights into how DA consumption modulates these behaviors, potentially offering a model for conditions such as ADHD. Future research should explore the mechanistic roles of D1R and D5R pathways, dose-dependent effects of DA, and the influence of circadian timing on behavioral outcomes to deepen our understanding of these interactions and their implications for translational research in mood disorders.