Zebrafish anxiety-like behavior was assessed in the novel tank test after the formation of domina... more Zebrafish anxiety-like behavior was assessed in the novel tank test after the formation of dominant-subordinate hierarchies. Ten pairs of animals were subjected to dyadic interactions for 5 days, and compared with control animals. After this period, a clear dominance hierarchy was established across all dyads, irrespective of sex. Social status affected parameters of anxiety-like behavior in the novel tank test, with subordinate males and females displaying more bottom-dwelling, absolute turn angle, and freezing than dominant animals and controls. The results suggest that subordinate male and female zebrafish show higher anxiety-like behavior, which together with previous literature suggests that subordination stress is conserved across vertebrates.
Serotonin (5-HT) receptors have been implicated in responses to aversive stimuli in mammals and f... more 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-HT2Creceptor 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 (potentia...
Decynium-22 (D-22) is an inhibitor of the uptake2 system of monoamine clearance, resulting in inc... more Decynium-22 (D-22) is an inhibitor of the uptake2 system of monoamine clearance, resulting in increased levels of dopamine and norepinephrine (and in some cases serotonin) in the nervous system and elsewhere. Uptake2 is mediated by low-affinity, high-capacity transporters that are inhibited by glucocorticoids, suggesting a mechanism of fast glucocorticoid-monoamine interaction in the brain and a possible target for antidepressants. D-22 dose-dependently increased anxiety-like behavior in adult zebrafish exposed to the light/dark test, monotonically increasing scototaxis (dark preference), but affecting risk assessment with an inverted-U-shaped response. These results suggest that the uptake2 system has a role in defensive behavior in zebrafish, presenting a novel mechanism by which stress and glucocorticoids could produce fast neurobehavioral adjustments in vertebrates.
Nitric oxide has been implicated in symptoms of ethanol withdrawal in animal models. Zebrafish ha... more Nitric oxide has been implicated in symptoms of ethanol withdrawal in animal models. Zebrafish have been used as models to study neurobehavioral effects of ethanol (EtOH) withdrawal, but the mechanisms associated with these effects are not yet clear. Adult zebrafish were treated with 1% EtOH for 20 min per day for 8 days, injected with the nitric oxide synthase 2 (NOS-2) inhibitor aminoguanidine (50 mg/kg), and allowed to experience withdrawal (WD) in their hometanks for 7 days. EtOH WD increased anxiety-like behavior in the novel tank test, an effect that was blocked by aminoguanidine. EtOH WD also increased brain levels of nitrite, an effect that was partially blocked by aminoguanidine. These results underline a novel mechanism by which NOS-2 controls anxiety-like responses to ethanol withdrawal, with implications for the mechanistic study of symptoms associated with chronic ethanol abuse.
Fear can sometimes paralyze us, and it can sometimes be exciting; for some people, fear is so cri... more Fear can sometimes paralyze us, and it can sometimes be exciting; for some people, fear is so crippling it can significantly mix up their lifes! We understand a little bit about how the brain acts when we are afraid, mainly by studying the brains of animals. Recently, surprising findings were made using a humble animal, the zebrafish – a small aquarium fish that in the past has helped scientists figure out how our organs develop. Zebrafish are useful because they develop quickly, reproduce richly, and have brains which are similar to ours. They also produce what we call an “alarm substance” that alerts shoalmates when one of them has been injured; when they smell this substance in the water they act as if they are very scared. When this happens, they release serotonin in their brains, a neurotransmitter that acts as a light switch, making them less afraid but more cautious – as if trying to figure out if a predator is there or not. Hopefully, finding more abo...
Certain teleost fishes present a behavioral trait of scototaxis, the preference for dark environm... more Certain teleost fishes present a behavioral trait of scototaxis, the preference for dark environments and not bright ones. The present work tried to evaluate some parameters of the exploratory behavior of the zebrafish (Danio rerio Hamilton 1822) in the black/white tank, aiming to establish the reliability of measures in different contexts. White compartment avoidance presents a biphasic pattern, with an increase in avoidance preceding a decrease (Experiment 1). This same avoidance does not habituate to repeated exposure, independently of the intersession interval, on the contrary of total locomotion (Experiments 2 and 3); forced exposure to the white compartment does not alter the subsequent exploratory behavior (Experiment 4). These results suggest that novelty is not the controlling dimension of scototaxis; besides, these results also suggest that the preference for the Black compartment is not caused simply by avoidance of the white compartment, although this certainly has an im...
Current theories on the role of serotonin (5-HT) in vertebrate defensive behavior suggest that th... more 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 ...
The two-factor theory predicts that the acquisition of avoidance responses is dependent on fear r... more The two-factor theory predicts that the acquisition of avoidance responses is dependent on fear reduction; as such, drugs that reduce or increase fear or anxiety states should alter inhibitory avoidance (IA) acquisition. The present experiment used white spaces as aversive unconditioned stimuli in IA in zebrafish. Adult zebrafishes were tested in three experiments: validation of white compartment as aversive in IA; open field test; and effect of antidepressant (fluoxetine, imipramine) and anxiolytic (diazepam, clonazepam). The data show the effectiveness of the white compartment as an aversive stimulus in IA. Antidepressant fluoxetine did not alter and imipramine impairs avoidance acquisition in higher doses. Imipramine also produced a sedative effect in lower doses. Anxiolytic and stimulant drugs facilitated learning at doses which did not impair locomotion, suggesting that pharmacological manipulation of other factors in addition to fear/anxiety can impact aversive learning in zebrafish.
Chrysin (5,7-dihydroxyflavone), a flavonoid present in diverse plants, has a backbone structure s... more Chrysin (5,7-dihydroxyflavone), a flavonoid present in diverse plants, has a backbone structure shared with the basic structure of the flavones, with additional hydroxyl groups that confers its antioxidant properties. Moreover, chrysin is also an aromatase inhibitor, as well as a ligand at the benzodiazepine site; these properties suggest an anxiolytic potential, which has been shown in rodent biobehavioral assays. However, whether these effects are due to the hydroxyl groups is unknown. Here we report the effects of chrysin (1 mg/kg) and the flavone basic structure (1 mg/kg) on rat behavior in the elevated plus-maze and a locomotor activity test (arena), as well as in the zebrafish light/dark test. Chrysin, but not flavone, increased entries and time in the open arms of the elevated plus-maze, as well as time on white in the zebrafish light/dark test. These effects were comparable to diazepam, and were devoid of motor effects in both tests, as well as in the rat locomotor activity ...
In guppies (Poecilia reticulata), a small number of individuals break away from a shoal and appro... more In guppies (Poecilia reticulata), a small number of individuals break away from a shoal and approach a potential predator, a behavior termed "predator inspection". These animals employ a "conditional approach" strategy, in which an individual approaches the predator in the first move and subsequently approaches it only if a second individual swims even with it during inspection. This strategy is analogous to the "tit-for-tat" strategy of the Prisoner's Dilemma, suggesting that it could be used to study cooperation. Serotonin is thought to mediate cooperative behavior in other fish species. Exposure to the animated image of a predator in a tank that contained a parallel mirror - mimicking a equally cooperating conspecific - promoted inspection and decreased refuge use, but increased freezing, suggesting that conditional approach is also associated with fear. To understand whether serotonin participates in conditional approach in guppies, we treated a...
Defensive behavior is a function of specific survival circuits, the “aversive brain system&... more Defensive behavior is a function of specific survival circuits, the “aversive brain system”, that are thought to be conserved across vertebrates, and involve threat detection and the organization of defensive responses to reduce or eliminate threat. In mammals, these circuits involve amygdalar and hypothalamic subnuclei and midbrain circuits. The increased interest in teleost fishes as model organisms in neuroscience created a demand to understand which brain circuits are involved in defensive behavior. Telencephalic and habenular circuits represent a “high road” for threat processing and organization of responses, being important to mounting appropriate coping responses. Specific hypothalamic circuits organize neuroendocrine and neurovegetative outputs, but are the less well-studied in fish. A “low road” is represented by projections to interneurons in the optic tectum which mediate fast escape responses via projections to the central gray and/or...
Chemical communication of predation risk has evolved multiple times in fish species, with conspec... more Chemical communication of predation risk has evolved multiple times in fish species, with conspecific alarm substance (CAS) being the most well understood mechanism. CAS is released after epithelial damage, usually when prey fish are captured by a predator and elicits neurobehavioural adjustments in conspecifics which increase the probability of avoiding predation. As such, CAS is a partial predator stimulus, eliciting risk assessment-like and avoidance behaviours and disrupting the predation sequence. The present paper reviews the distribution and putative composition of CAS in fish and presents a model for the neural processing of these structures by the olfactory and the brain aversive systems. Applications of CAS in the behavioural neurosciences and neuropharmacology are also presented, exploiting the potential of model fish [e.g., zebrafish Danio rerio, guppies Poecilia reticulata, minnows Phoxinus phoxinus) in neurobehavioural research.
Chronic alcohol use induces adaptations and toxicity that can induce symptoms of anxiety, autonom... more Chronic alcohol use induces adaptations and toxicity that can induce symptoms of anxiety, autonomic hyperarousal, and epileptic seizures when alcohol is removed (withdrawal syndrome). Zebrafish has recently gained wide attention as a behavioral model to study the neurobehavioral effects of acute and chronic alcohol use, including withdrawal. The literature, however, is very contradictory on findings regarding withdrawal effects, with some studies reporting increased anxiety, while others report no effect. A meta-analytic approach was taken to find the sources of this heterogeneity, and ethanol concentration during exposure and exposure duration were found to be the main sources of variation. A conceptual replication was also made using continuous exposure for 16 days in waterborne ethanol (0.5%) and assessing anxiety-like behavior in the light/dark test after 60 min withdrawal. Withdrawal was shown to reduce preference for darkness, consistent with decreased anxiety, but to increase...
Zebrafish anxiety-like behavior was assessed in the novel tank test after the formation of domina... more Zebrafish anxiety-like behavior was assessed in the novel tank test after the formation of dominant-subordinate hierarchies. Ten pairs of animals were subjected to dyadic interactions for 5 days, and compared with control animals. After this period, a clear dominance hierarchy was established across all dyads, irrespective of sex. Social status affected parameters of anxiety-like behavior in the novel tank test, with subordinate males and females displaying more bottom-dwelling, absolute turn angle, and freezing than dominant animals and controls. The results suggest that subordinate male and female zebrafish show higher anxiety-like behavior, which together with previous literature suggests that subordination stress is conserved across vertebrates.
Serotonin (5-HT) receptors have been implicated in responses to aversive stimuli in mammals and f... more 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-HT2Creceptor 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 (potentia...
Decynium-22 (D-22) is an inhibitor of the uptake2 system of monoamine clearance, resulting in inc... more Decynium-22 (D-22) is an inhibitor of the uptake2 system of monoamine clearance, resulting in increased levels of dopamine and norepinephrine (and in some cases serotonin) in the nervous system and elsewhere. Uptake2 is mediated by low-affinity, high-capacity transporters that are inhibited by glucocorticoids, suggesting a mechanism of fast glucocorticoid-monoamine interaction in the brain and a possible target for antidepressants. D-22 dose-dependently increased anxiety-like behavior in adult zebrafish exposed to the light/dark test, monotonically increasing scototaxis (dark preference), but affecting risk assessment with an inverted-U-shaped response. These results suggest that the uptake2 system has a role in defensive behavior in zebrafish, presenting a novel mechanism by which stress and glucocorticoids could produce fast neurobehavioral adjustments in vertebrates.
Nitric oxide has been implicated in symptoms of ethanol withdrawal in animal models. Zebrafish ha... more Nitric oxide has been implicated in symptoms of ethanol withdrawal in animal models. Zebrafish have been used as models to study neurobehavioral effects of ethanol (EtOH) withdrawal, but the mechanisms associated with these effects are not yet clear. Adult zebrafish were treated with 1% EtOH for 20 min per day for 8 days, injected with the nitric oxide synthase 2 (NOS-2) inhibitor aminoguanidine (50 mg/kg), and allowed to experience withdrawal (WD) in their hometanks for 7 days. EtOH WD increased anxiety-like behavior in the novel tank test, an effect that was blocked by aminoguanidine. EtOH WD also increased brain levels of nitrite, an effect that was partially blocked by aminoguanidine. These results underline a novel mechanism by which NOS-2 controls anxiety-like responses to ethanol withdrawal, with implications for the mechanistic study of symptoms associated with chronic ethanol abuse.
Fear can sometimes paralyze us, and it can sometimes be exciting; for some people, fear is so cri... more Fear can sometimes paralyze us, and it can sometimes be exciting; for some people, fear is so crippling it can significantly mix up their lifes! We understand a little bit about how the brain acts when we are afraid, mainly by studying the brains of animals. Recently, surprising findings were made using a humble animal, the zebrafish – a small aquarium fish that in the past has helped scientists figure out how our organs develop. Zebrafish are useful because they develop quickly, reproduce richly, and have brains which are similar to ours. They also produce what we call an “alarm substance” that alerts shoalmates when one of them has been injured; when they smell this substance in the water they act as if they are very scared. When this happens, they release serotonin in their brains, a neurotransmitter that acts as a light switch, making them less afraid but more cautious – as if trying to figure out if a predator is there or not. Hopefully, finding more abo...
Certain teleost fishes present a behavioral trait of scototaxis, the preference for dark environm... more Certain teleost fishes present a behavioral trait of scototaxis, the preference for dark environments and not bright ones. The present work tried to evaluate some parameters of the exploratory behavior of the zebrafish (Danio rerio Hamilton 1822) in the black/white tank, aiming to establish the reliability of measures in different contexts. White compartment avoidance presents a biphasic pattern, with an increase in avoidance preceding a decrease (Experiment 1). This same avoidance does not habituate to repeated exposure, independently of the intersession interval, on the contrary of total locomotion (Experiments 2 and 3); forced exposure to the white compartment does not alter the subsequent exploratory behavior (Experiment 4). These results suggest that novelty is not the controlling dimension of scototaxis; besides, these results also suggest that the preference for the Black compartment is not caused simply by avoidance of the white compartment, although this certainly has an im...
Current theories on the role of serotonin (5-HT) in vertebrate defensive behavior suggest that th... more 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 ...
The two-factor theory predicts that the acquisition of avoidance responses is dependent on fear r... more The two-factor theory predicts that the acquisition of avoidance responses is dependent on fear reduction; as such, drugs that reduce or increase fear or anxiety states should alter inhibitory avoidance (IA) acquisition. The present experiment used white spaces as aversive unconditioned stimuli in IA in zebrafish. Adult zebrafishes were tested in three experiments: validation of white compartment as aversive in IA; open field test; and effect of antidepressant (fluoxetine, imipramine) and anxiolytic (diazepam, clonazepam). The data show the effectiveness of the white compartment as an aversive stimulus in IA. Antidepressant fluoxetine did not alter and imipramine impairs avoidance acquisition in higher doses. Imipramine also produced a sedative effect in lower doses. Anxiolytic and stimulant drugs facilitated learning at doses which did not impair locomotion, suggesting that pharmacological manipulation of other factors in addition to fear/anxiety can impact aversive learning in zebrafish.
Chrysin (5,7-dihydroxyflavone), a flavonoid present in diverse plants, has a backbone structure s... more Chrysin (5,7-dihydroxyflavone), a flavonoid present in diverse plants, has a backbone structure shared with the basic structure of the flavones, with additional hydroxyl groups that confers its antioxidant properties. Moreover, chrysin is also an aromatase inhibitor, as well as a ligand at the benzodiazepine site; these properties suggest an anxiolytic potential, which has been shown in rodent biobehavioral assays. However, whether these effects are due to the hydroxyl groups is unknown. Here we report the effects of chrysin (1 mg/kg) and the flavone basic structure (1 mg/kg) on rat behavior in the elevated plus-maze and a locomotor activity test (arena), as well as in the zebrafish light/dark test. Chrysin, but not flavone, increased entries and time in the open arms of the elevated plus-maze, as well as time on white in the zebrafish light/dark test. These effects were comparable to diazepam, and were devoid of motor effects in both tests, as well as in the rat locomotor activity ...
In guppies (Poecilia reticulata), a small number of individuals break away from a shoal and appro... more In guppies (Poecilia reticulata), a small number of individuals break away from a shoal and approach a potential predator, a behavior termed "predator inspection". These animals employ a "conditional approach" strategy, in which an individual approaches the predator in the first move and subsequently approaches it only if a second individual swims even with it during inspection. This strategy is analogous to the "tit-for-tat" strategy of the Prisoner's Dilemma, suggesting that it could be used to study cooperation. Serotonin is thought to mediate cooperative behavior in other fish species. Exposure to the animated image of a predator in a tank that contained a parallel mirror - mimicking a equally cooperating conspecific - promoted inspection and decreased refuge use, but increased freezing, suggesting that conditional approach is also associated with fear. To understand whether serotonin participates in conditional approach in guppies, we treated a...
Defensive behavior is a function of specific survival circuits, the “aversive brain system&... more Defensive behavior is a function of specific survival circuits, the “aversive brain system”, that are thought to be conserved across vertebrates, and involve threat detection and the organization of defensive responses to reduce or eliminate threat. In mammals, these circuits involve amygdalar and hypothalamic subnuclei and midbrain circuits. The increased interest in teleost fishes as model organisms in neuroscience created a demand to understand which brain circuits are involved in defensive behavior. Telencephalic and habenular circuits represent a “high road” for threat processing and organization of responses, being important to mounting appropriate coping responses. Specific hypothalamic circuits organize neuroendocrine and neurovegetative outputs, but are the less well-studied in fish. A “low road” is represented by projections to interneurons in the optic tectum which mediate fast escape responses via projections to the central gray and/or...
Chemical communication of predation risk has evolved multiple times in fish species, with conspec... more Chemical communication of predation risk has evolved multiple times in fish species, with conspecific alarm substance (CAS) being the most well understood mechanism. CAS is released after epithelial damage, usually when prey fish are captured by a predator and elicits neurobehavioural adjustments in conspecifics which increase the probability of avoiding predation. As such, CAS is a partial predator stimulus, eliciting risk assessment-like and avoidance behaviours and disrupting the predation sequence. The present paper reviews the distribution and putative composition of CAS in fish and presents a model for the neural processing of these structures by the olfactory and the brain aversive systems. Applications of CAS in the behavioural neurosciences and neuropharmacology are also presented, exploiting the potential of model fish [e.g., zebrafish Danio rerio, guppies Poecilia reticulata, minnows Phoxinus phoxinus) in neurobehavioural research.
Chronic alcohol use induces adaptations and toxicity that can induce symptoms of anxiety, autonom... more Chronic alcohol use induces adaptations and toxicity that can induce symptoms of anxiety, autonomic hyperarousal, and epileptic seizures when alcohol is removed (withdrawal syndrome). Zebrafish has recently gained wide attention as a behavioral model to study the neurobehavioral effects of acute and chronic alcohol use, including withdrawal. The literature, however, is very contradictory on findings regarding withdrawal effects, with some studies reporting increased anxiety, while others report no effect. A meta-analytic approach was taken to find the sources of this heterogeneity, and ethanol concentration during exposure and exposure duration were found to be the main sources of variation. A conceptual replication was also made using continuous exposure for 16 days in waterborne ethanol (0.5%) and assessing anxiety-like behavior in the light/dark test after 60 min withdrawal. Withdrawal was shown to reduce preference for darkness, consistent with decreased anxiety, but to increase...
"Drogas", "fármacos", e "medicamentos" são objetos sócio-técnicos cuja definição, separação em re... more "Drogas", "fármacos", e "medicamentos" são objetos sócio-técnicos cuja definição, separação em relação a outras categorias, e efeitos dependem fundamentalmente de aspectos relacionais. No contexto contemporâneo ocidental atual, a transformação de uma molécula em um fármaco depende de um processo de farmacogênese, no qual as pesquisas pré-clínica e clínica fixam um conceito fluido ao mesmo tempo em que agregam informações farmacológicas e farmacêuticas. A partir desse processo, a identidade e as propriedades dos fármacos são transformadas através de suas associações em constante mudança. Apesar de se definir em oposição ao efeito placebo, a eficácia clínica também envolve processos bioculturais em que aspectos culturais, micropolíticos, e relacionais se emaranham com processos neurobiológicos, produzindo uma materialidade descontínua e contrastada subsumida em uma sensibilidade corporificada. Entender o fármaco como conceito fluido, fixado como "material informado", pode ter consequências para a terapêutica.
“Drogas”, “fármacos”, e “medicamentos” são objetos sócio-técnicos cuja definição, separação em re... more “Drogas”, “fármacos”, e “medicamentos” são objetos sócio-técnicos cuja definição, separação em relação a outras categorias, e efeitos dependem fundamentalmente de aspectos relacionais. No contexto contemporâneo ocidental atual, a transformação de uma molécula em um fármaco depende de um processo de farmacogênese, no qual a pesquisa pré-clínica e a pesquisa clínica representam dispositivos que fixam um conceito fluido ao mesmo tempo em que agregam informações de eficácia, potência, metabolismo, toxicidade, e mecanismos de ação, bem como informações sobre propriedade intelectual e marketing. A partir desse processo, a identidade e as propriedades dos fármacos são transformadas através de suas associações em constante mudança. Apesar de se definir em oposição ao efeito placebo, a eficácia clínica também envolve processos bioculturais em que aspectos culturais, micropolíticos, e relacionais se emaranham com processos neurobiológicos, produzindo uma materialidade descontínua e contrastada subsumida em uma sensibilidade corporificada. Entender o fármaco como conceito fluido, fixado como “material informado”, pode ter consequências para a terapêutica.
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