Biology subjects

Lima-Maximino, M.

Publications and source records attributed to Lima-Maximino, M..

9 recordsLinked to original sources

bioRxiv2026

The anxiolytic-like effect of the aqueous extract of Punica granatum depends on the stress level of fish and mice: Evidence of a homeostatic re-establishing effect

Pomegranate (Punica granatum) has shown potential anxiolytic and antidepressant effects in preclinical research, but its mechanisms remain unclear. Importantly, some evidence suggests that the effects of P. granatum depend on previous stress, suggesting an adaptogenic effect. This study aimed to evaluate the anxiolytic-like effects of an aqueous extract of P. granatum (AE-PG) on lambaris and zebrafish exposed to acute restraint stress (ARS) and female BALB/c mice exposed to unpredictable chronic mild stress (CUMS). In addition, we evaluated antidepressant-like effects in female BALB/c mice. Acute administration of AE-PG (1 mg/kg, i.p.) was tested in the novel tank test (NTT) in lambaris and zebrafish and in the light/dark test (LDT) in zebrafish, while chronic (7 days) administration of AE-PG (1 mg/kg, i.p.) was tested in the elevated plus-maze (EPM), open-field test (OFT), splash test (ST), and forced swim test (FST) in mice. ARS increased geotaxis and erratic swimming in the NTT, as well as scototaxis, risk assessment, and erratic swimming in the LDT. Acute pre-treatment with AE-PG blocked the effects of ARS on these anxiety-like endpoints in both lambaris and zebrafish. CUMS increased open arm avoidance in the EPM, thigmotaxis and horizontal and vertical exploration in the OFT, and immobility in the FST, and decreased grooming in the ST. Chronic treatment with AE-PG blocked the effects of CUMS on anxiety-like endpoints, and depression-like endpoints, in mice. An in silico analysis of the main compounds in AE-PG suggested a possible mechanism of action on a wide network of targets that converge on PI3K/Akt and show differential expression in brain regions associated with fear- and anxiety-like behavior. Molecular docking suggests that a compound from AE-PG, ellagic acid, is likely to act through estrogen receptors, which could help reestablish homeostatic balance in response to stress.

pharmacology and toxicology↗

bioRxiv2026

Unpredictable chronic stress produces a mixed depression/anxiety behavioral profile in zebrafish

Stress is a physiological, adaptive, and preliminary response of the organism to situations of threats and instability caused by environmental and psychological stressors. The chronicity and predictability of stressors are important variables in determining neurobehavioral outcomes. While unpredictable chronic stress (UCS) protocols typically induce depressive-like phenotypes in rodents, in zebrafish the effects of these protocols are assessed using anxiety-like outcomes. This study aimed to analyze the effects of an unpredictable UCS on depressive-type behavioral parameters and brain lipid peroxidation in zebrafish. A 14-day UCS protocol was used, with 10 different types of stressors administered twice daily in a random manner, using draws, for greater unpredictability. Animals underwent the Novel Tank Test (anxiety-like outcome) and the Social Preference Test (depressive-like outcome) 24 hours after the end of the UCS protocol. Biochemical data were collected using a thiobarbituric acid reactive substances (TBARS) assay to quantify malondialdehyde (MDA), an indicator of lipid peroxidation. The findings suggest that prolonged exposure to stressors causes damage to the organism, with increased anxiety and decreased social preference, highlighting zebrafish as an efficient model in the investigation of the neurobiological and neuropathological mechanisms of stress.

neuroscience↗

bioRxiv2025

Role of the 5HT2C receptor in anxiety-like behavior in zebrafish (Danio rerio)

The present study aims to describe the acute effects of 5-HT2C receptor agonists and antagonists in behavioral tests related to anxiety in adult zebrafish (Danio rerio). For this, three groups of fish (n = 12/group) were used: a group treated with the drug MK-212 (2 mg/kg), a 5-HT2C receptor agonist; another group treated with the drug RS-102221 (2 mg/kg), a 5-HT2C receptor antagonist; and a third group, the control group, using a vehicle solution. The three groups were exposed to two behavioral tests: novel tank test (NTT) and light-dark preference (LDT). MK-212 produced no effects on the NTT, while RS-102221 decreased geotaxis (d = 0.99, 95%CI[0.3, 1.7]) and erratic swimming (d = 0.87, 95%CI[0.18, 1.56]) in this test; these effects are consistent with a tonic facilitation of defensive behavior in the NTT. Conversely, in the LDT, MK-212 increased scototaxis (d = 0.96, 95%CI[0.25, 1.65]), risk assessment (d = -1.31, 95%CI[-2.02, -0.59]), and thigmotaxis (d = -1.48, 95%CI[-2.21, -0.75]), consistent with an anxiogenic-like effect of this drug. Thus, tonic and phasic effects of the activation of this receptor are observed depending on the type of behavioral test used.

neuroscience↗

bioRxiv2024

Flavonoids as anxiolytics in animal tests: Bibliometry and meta-analysis of the effects of flavonoids on anxiety-like behavior in animal tests

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/596117v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@177bd39org.highwire.dtl.DTLVardef@27f63forg.highwire.dtl.DTLVardef@197a43aorg.highwire.dtl.DTLVardef@9f0ad0_HPS_FORMAT_FIGEXP M_FIG C_FIG Flavonoids are natural secondary compounds of plants with a basic composition derived from polyphenols that can produce a plethora of different neurochemical effects, some of which are relevant to anxiety disorders. As such, many flavonoids have been evaluated in behavioral screens in preclinical research on anxiolytics. Given the many different molecular subclasses of flavonoids, the many different molecular targets that have been proposed for these compounds, and the different research priorities that arise in preclinical research, we sought to map the potential of flavonoids as anxiolytics by bibliometric analysis and a meta-analysis of animal tests using these compounds. Bibliometric analysis suggest that the field is highly concentrated on few research groups that are mostly located in the Global South, suggesting the need to improve international collaborations. The themes which emerged in the bibliometric analysis are driven by the exploratory steps of pharmacological research, including finding anxioselective effects and looking for dose-response patterns; this suggests that the field, as a whole, could benefit from more mechanistic and confirmatory research. The meta-analysis showed strong evidence for an anxiolytic-like effect of flavonoids on animal tests, including assays made in rats, mice, and zebrafish (SMD = -1.4398, 95%CI[-1.7319, - 1.1477]). Subgroup analysis suggested that this effect is present in acute treatment (SMD = -1.14, 95%CI[-1.36, -0.93]), but not after chronic treatment (SMD = -1.96, 95%CI[-4.93; 1.01]). For all molecule subclasses included in the study, only isoflavones, glycoside derivatives, and flavanolignans did not show evidence of an anxiolytic-like effect, although the low number of studies including these subclasses is low. We finish with a set of recommendations for preclinical research on the anxiolytic potential of flavonoids.

pharmacology and toxicology↗

bioRxiv2024

Roles of the 5-HT1A receptor in zebrafish responses to potential threat and in sociality

Anxiety is a normal emotion representing a reaction to potential danger, whereas fear can be defined as a reaction to real, explicit danger. Anxiety-like behavior in animal models has been associated with differences in the serotonergic system. Treatment of zebrafish cohorts with 8-OH-DPAT, a full agonist at the 5-HT1A receptor, decreased anxiety-like behavior in the novel tank test, but increased it in the phototaxis (light-dark preference) assay, both considered assays for anxiety-like behavior for this species. The same treatment decreased social approach in both the social investigation and social novelty phases of the social preference test. Blocking the 5-HT1A receptor with WAY 100,635 shifted the dose-response curve for the novel tank test rightward. These effects suggest a participation of the 5-HT 1A heteroreceptors in zebrafish anxiety and social preference, increasing anxiety and decreasing sociality. Thus, the study of this receptor is important for a better understanding of anxiety-like behavior in zebrafish and its relationship with similar phenomena in vertebrates. Preprint: https://www.biorxiv.org/content/10.1101/2024.04.17.588464v1 Data: https://github.com/lanec-unifesspa/5HT/tree/main/5HT1A Lay summaryThis study looked at how a certain type of protein, the 5-HT1A receptor, affected anxiety in zebrafish. Its important to understand that anxiety is a normal feeling we all get when were worried or scared about something, while fear is a reaction to an immediate danger. The researchers wanted to see how a specific drug that activates the 5-HT1A receptor, 8-OH-DPAT, affected the behavior of the fish. They used different tests to see how the fish reacted in different situations. When the fish were given the drug, their anxiety-like behavior decreased in one test where they were put in a new tank. But in another test where they had to choose between light and dark areas, their anxiety-like behavior actually increased. It also made the fish less interested in being social with other fish. When a drug that blocks the 5-HT1A receptor, WAY 100,635, was give together with 8-OH-DPAT, evidence was found for a receptor reserve. The researchers found that this drug affected the way the fish behaved in these situations. It seemed to make them more anxious in some cases and less interested in being social. This tells us that the receptor has an impact on how the fish are feeling, which can help us learn more about anxiety in zebrafish and, potentially, in other animals too, including humans. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/588464v3_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@14b3f13org.highwire.dtl.DTLVardef@11a2217org.highwire.dtl.DTLVardef@b42602org.highwire.dtl.DTLVardef@12b51c4_HPS_FORMAT_FIGEXP M_FIG C_FIG Significance statementThis research indicates that 5-HT1A heteroreceptors play a key role in increasing anxiety and decreasing sociality across vertebrates, shedding light on neural mechanisms that could inform treatments for anxiety-related disorders.

neuroscience↗

bioRxiv2024

Role of the NOS-cGMP pathways in time-dependent sensitization of behavioral responses in zebrafish

Nitric oxide (NO) is a molecule involved in plasticity across levels and systems. The role of NOergic pathways in time-dependent sensitization, a behavioral model of translational relevance to trauma and stress-related disorders, was assessed in adult zebrafish. In this model, adult zebrafish acutely exposed to a fear-inducing conspecific alarm substance (CAS) and left undisturbed for an incubation period show increased anxiety-like behavior 24 h after exposure. CAS increased forebrain glutamate immediately after stress and 30 min after stress, an effect that was accompanied by increased nitrite levels immediately after stress, 30 min after stress, 90 min after stress, and 24 h after stress. CAS also increased nitrite levels in the head kidney, where cortisol is produced in zebrafish. CAS-elicited nitrite responses in the forebrain 90 min (but not 30 min) after stress were prevented by a NOS-2 blocker. Blocking NOS-1 30 min after stress prevents TDS; blocking NOS-2 90 min after stress also prevents TDS, as does blocking calcium-activated potassium channels in this latter time window. TDS is also prevented by blocking guanylate cyclase activation in both time windows, and cGMP-dependent channel activation in the second time window. These results suggest that different NO-related pathways converge at different time windows of the incubation period to induce TDS.

neuroscience↗

bioRxiv2022

Roles of the 5-HT2C receptor on zebrafish sociality

Serotonin (5-HT) receptors have been implicated in social behavior in vertebrates. Zebrafish (Danio rerio) have been increasingly being used behavioral neuroscience to study the neurobiological correlates of behavior, including sociality. Nonetheless, the role of 5-HT2C receptors in different social functions were not yet studied in this species. Zebrafish were treated with the agonist MK-212 (2 mg/kg) or the antagonist RS-102221 (2 mg/kg) and tested in the social interaction and social novelty tests, conditional approach test, or mirror-induced aggressive displays. MK-212 increased preference for an unknown conspecific in the social investigation test, but also increased preference for the known conspecific in the social novelty test; RS-102221, on the other hand, decreased preference in the social investigation test but increased preference for the novel conspecific in the social novelty test. MK-212 also decreased predator inspection in the conditional approach test. While RS-102221 decreased time in the display zone in the mirror-induced aggressive display test, it increased display duration. Overall, these results demonstrate the complex role of 5-HT2C receptors in different social contexts in zebrafish, revealing a participation in social plasticity in vertebrates.

neuroscience↗

bioRxiv2020

Role of 5-HT2C receptors in zebrafish alarm reactions and post-exposure behavior

Serotonin (5-HT) receptors have been implicated in responses to aversive stimuli in mammals and fish, but its precise role is still unknown. Moreover, since at least seven families of 5-HT receptors exist in vertebrates, the role of specific receptors is still debated. Aversive stimuli can be classified as indicators of proximal, distal, or potential threat, initiating responses that are appropriate for each of these threat levels. Responses to potential threat usually involve cautious exploration and increased alertness, while responses to distal and proximal threat involve a fight-flight-freeze reaction. We exposed adult zebrafish to a conspecific alarm substance (CAS) and observed behavior during (distal threat) and after (potential threat) exposure, and treated with the 5-HT2C receptor agonists MK-212 or WAY-161503 or with the antagonist RS-102221. The agonists blocked CAS-elicited defensive behavior (distal threat), but not post-exposure increases in defensive behavior (potential threat), suggesting inhibition of responses to distal threat. MK-212 blocked changes in freezing elicited by acute restraint stress, a model of proximal threat, while RS-102221 blocked changes in geotaxis elicited this stressor. We also found that RS-102221, a 5-HT2C receptor antagonist, produced small effect on behavior during and after exposure to CAS. Preprint: https://www.biorxiv.org/content/10.1101/2020.10.04.324202; Data and scripts: https://github.com/lanec-unifesspa/5-HT-CAS/tree/master/data/5HT2C

neuroscience↗

bioRxiv2019

Phasic and tonic serotonin modulate alarm reactions and post-exposure behavior in zebrafish

Current theories on the role of serotonin (5-HT) in vertebrate defensive behavior suggest that this monoamine increases anxiety but decreases fear, by acting at different levels of the neuroaxis. This paradoxical, dual role of 5-HT suggests that a serotonergic tone inhibits fear responses, while an acute increase in 5-HT would produce anxiety-like behavior. However, so far no evidence for a serotonergic tone has been found. Using zebrafish alarm responses, we investigate the participation of phasic and tonic 5-HT levels in fear-like behavior, as well as in behavior after stimulation. Conspecific alarm substance (CAS) increased bottom-dwelling and erratic swimming, and animals transferred to a novel environment after CAS exposure (post-exposure behavior) showed increased bottom-dwelling and freezing. Clonazepam blocked CAS effects during and after exposure. Acute fluoxetine dose-dependently decreased fear-like behavior, but increased post-exposure freezing. Metergoline had no effect on fear-like behavior, but blocked the effects of CAS on post-exposure behavior; similar effects were observed with pCPA. Finally, CAS was shown to decrease the activity of monoamine oxidase in the zebrafish brain after exposure. These results suggest that phasic and tonic serotonin encode an aversive expectation value, switching behavior towards cautious exploration/risk assessment/anxiety when the aversive stimulus is no longer present.

neuroscience↗