Isabel Quadros | Universidade Federal de São Paulo (UNIFESP) (original) (raw)

Papers by Isabel Quadros

Behavioural Brain Research, Jan 1, 2009

Repeated administration of drugs may induce adaptations which affect the behavioral responses to ... more Repeated administration of drugs may induce adaptations which affect the behavioral responses to the drug itself or to other drugs. Whether individual characteristics to repeated drug administration predict sensitivity to the effects of another drug is not clear. We evaluated whether or not mice that present higher vs. lower locomotor response after repeated treatment with ethanol display increased or decreased locomotor responses when challenged with methamphetamine or morphine, and vice versa. Mice received daily i.p. 2.2 g/kg ethanol (21 days), 1.0 mg/kg methamphetamine or 10 mg/kg morphine (10 days). According to the response presented during repeated drug treatment, mice were classified as HIGH or LOW activity groups. Locomotor activity was monitored after mice were challenged with saline, and 48 h later with a drug. Ethanol-treated mice were challenged with methamphetamine or morphine, methamphetamine- and morphine-treated animals were challenged with ethanol. After repeated treatment with ethanol or methamphetamine, locomotor sensitization was observed only in HIGH mice, not LOW mice. Ethanol-treated mice with HIGH activity showed sensitized, increased locomotor responses to methamphetamine (p < 0.05), but not to morphine. Locomotor responses to ethanol were not affected by a previous history of methamphetamine treatment. Although repeated administration of morphine failed to induce sensitization, morphine-treated mice with HIGH activity presented sensitized locomotor responses after an ethanol challenge. The current experiments confirm important individual differences in response to repeated administration of ethanol, methamphetamine and morphine, which in some cases affected the locomotor response to a second drug challenge, in an asymmetrical pattern.

Behavioural Pharmacology, 2003

Behavioral sensitization to drugs of abuse seems to involve learning processes. In mice, ethanol-... more Behavioral sensitization to drugs of abuse seems to involve learning processes. In mice, ethanol-induced locomotor sensitization is potentiated by repeated pairing of ethanol (EtOH) injections and the testing chamber. The present study aimed to test: (1) the association between the performance in a contextual conditioning task and the development of behavioral sensitization to EtOH in mice;

Handbook of Behavioral Neuroscience, 2010

Traditional clinical research on the neurobiology of aggressive behavior focuses on individuals w... more Traditional clinical research on the neurobiology of aggressive behavior focuses on individuals who are characterized by their impulsive, hostile, antisocial and violent traits and who show some deficiency in brain serotonin (5-HT) activity relative to those who have a propensity to engage in premeditated, calculating and instrumental aggressive acts. Preclinical research has focused on territorial, dominant or maternal aggressive behavior

Psychopharmacology, 2011

Rationale Exposure to intermittent episodes of social defeat stress can increase drug seeking and... more Rationale Exposure to intermittent episodes of social defeat stress can increase drug seeking and leads to intense drug taking in rats. Objectives This study investigated the consequences of repeated, intermittent social defeat stress on patterns of drug self-administration in rats with access to heroin, cocaine, or a heroin-cocaine combination ("speedball"). Methods Male Long-Evans rats were either handled (controls) or subjected to 25-min social defeat stress episodes on days 1, 4, 7, and 10 during confrontations with an aggressive resident. Ten days following the last defeat, rats were assessed for locomotor cross-sensitization in response to heroin or cocaine. Animals were then prepared with intrajugular catheters for drug self-administration. Separate groups of controls and defeated rats were examined for selfadministration of heroin (experiment 1), a heroin-cocaine combination (experiment 2), or cocaine (experiment 3). Drug self-administration patterns were evaluated using fixed or progressive ratio schedules of reinforcement during limited access sessions or a 24-h unlimited access binge. Results Rats with a history of intermittent social defeat stress showed sensitized locomotor behavior when challenged with heroin or cocaine relative to controls. During the 24-h binge session, defeated rats escalated cocainetaking behavior (ca. 110 mg/kg vs. 66 mg/kg in controls), persisted in self-administering cocaine or the heroincocaine mixture for more hours, and showed a tendency for increased heroin-cocaine intake, but no effects on heroin taking. Conclusions A history of social defeat stress seems to preferentially promote escalated intake of cocaine but not heroin, unless a heroin-cocaine combination is available.

The International Journal of Neuropsychopharmacology, 2010

Repeated ethanol administration may induce behavioural sensitization, defined as a progressive po... more Repeated ethanol administration may induce behavioural sensitization, defined as a progressive potentiation of locomotor stimulant effects. This process is associated with neuroadaptations in the mesolimbic pathway and the nucleus accumbens. The aim of the present study was to analyse dopamine D 1 receptor (D 1 R) participation in locomotor response to an agonist and an antagonist of the D 1 R in mice with different levels of sensitization to ethanol. In three separate experiments, mice received administrations of 2.2 g/kg ethanol or saline every other day for 10 d. According to their locomotor response on the last day, ethanol-treated animals were classified into two groups : sensitized or non-sensitized. After the treatment, mice were challenged with 4 or 8 mg/kg SKF-38393 (i.p.), a D 1 R agonist (expt 1) ; or with 0.01 or 0.1 mg/kg SCH-23390 (i.p.), a D 1 R antagonist, followed by 2.2 g/kg ethanol (i.p.) administration (expt 2). In expt 3, mice were challenged with intra-accumbens (intra-NAc) SKF-38393 (1 mg/side, in 0.2 ml), and with intra-NAc SCH-23390 (3 mg/side, in 0.2 ml) followed by 2.2 g/kg ethanol (i.p.). Although the i.p. administration of SKF-38393 did not affect the locomotion of mice, the intra-NAc administration of SKF-38393 significantly increased the locomotor activity in sensitized mice, suggesting that sensitized mice present functionally hyperresponsive D 1 Rs in the NAc. Both i.p. and intra-NAc administration of SCH-23390 blocked the expression of ethanol sensitization, suggesting that the activation of NAc D 1 Rs seems to be essential for the expression of ethanol sensitization.

Current Topics in Behavioral Neurosciences, 2011

Serotonin (5-HT) has long been considered as a key transmitter in the neurocircuitry controlling ... more Serotonin (5-HT) has long been considered as a key transmitter in the neurocircuitry controlling aggression. Impaired regulation of each subtype of 5-HT receptor, 5-HT transporter, synthetic and metabolic enzymes has been linked particularly to impulsive aggression. The current summary focuses mostly on recent findings from pharmacological and genetic studies. The pharmacological treatments and genetic manipulations or polymorphisms of a specific target (e.g., 5-HT1A receptor) can often result in inconsistent results on aggression, due to "phasic" effects of pharmacological agents vs "trait"-like effects of genetic manipulations. Also, the local administration of a drug using the intracranial microinjection technique has shown that activation of specific subtypes of 5-HT receptors (5-HT1A and 5-HT1B) in mesocorticolimbic areas can reduce species-typical and other aggressive behaviors, but the same receptors in the medial prefrontal cortex or septal area promote escalated forms of aggression. Thus, there are receptor populations in specific brain regions that preferentially modulate specific types of aggression. Genetic studies have shown important gene × environment interactions; it is likely that the polymorphisms in the genes of 5-HT transporters (e.g., MAO A) or rate-limiting synthetic and metabolic enzymes of 5-HT determine the vulnerability to adverse environmental factors that escalate aggression. We also discuss the interaction between the 5-HT system and other systems. Modulation of 5-HT neurons in the dorsal raphe nucleus by GABA, glutamate, and CRF profoundly regulate aggressive behaviors. Also, interactions of the 5-HT system with other neuropeptides (arginine vasopressin, oxytocin, neuropeptide Y, opioid) have emerged as important neurobiological determinants of aggression. Studies of aggression in genetically modified mice identified several molecules that affect the 5-HT system directly (e.g., Tph2, 5-HT1B, 5-HT transporter, Pet1, MAOA) or indirectly (e.g. BDNF, nNOS, αCaMKII, Neuropeptide Y). The future agenda delineates specific receptor subpopulations for GABA, glutamate and neuropeptides as they modulate the canonical aminergic neurotransmitters in brainstem, limbic and cortical regions with the ultimate outcome of attenuating or escalating aggressive behavior.

Psychopharmacology, 2011

Rationale-Intermittent exposure to social defeat stress can induce long-term neural plasticity th... more Rationale-Intermittent exposure to social defeat stress can induce long-term neural plasticity that may influence escalated cocaine-taking behavior. Stressful encounters can lead to activation of dopamine neurons in the ventral tegmental area (VTA), which are modulated by corticotropin releasing factor (CRF) neurons.

Journal of Neuroscience, 2014

Slow and persistent synaptic inhibition is mediated by metabotropic GABA B receptors (GABA B Rs).... more Slow and persistent synaptic inhibition is mediated by metabotropic GABA B receptors (GABA B Rs). GABA B Rs are responsible for the modulation of neurotransmitter release from presynaptic terminals and for hyperpolarization at postsynaptic sites. Postsynaptic GABA B Rs are predominantly found on dendritic spines, adjacent to excitatory synapses, but the control of their plasma membrane availability is still controversial. Here, we explore the role of glutamate receptor activation in regulating the function and surface availability of GABA B Rs in central neurons. We demonstrate that prolonged activation of NMDA receptors (NMDA-Rs) leads to endocytosis, a diversion from a recycling route, and subsequent lysosomal degradation of GABA B Rs. These sorting events are paralleled by a reduction in GABA B R-dependent activation of inwardly rectifying K + channel currents. Postendocytic sorting is critically dependent on phosphorylation of serine 783 (S783) within the GABA B R2 subunit, an established substrate of AMP-dependent protein kinase (AMPK). NMDA-R activation leads to a rapid increase in phosphorylation of S783, followed by a slower dephosphorylation, which results from the activity of AMPK and protein phosphatase 2A, respectively. Agonist activation of GABA B Rs counters the effects of NMDA. Thus, NMDA-R activation alters the phosphorylation state of S783 and acts as a molecular switch to decrease the abundance of GABA B Rs at the neuronal plasma membrane. Such a mechanism may be of significance during synaptic plasticity or pathological conditions, such as ischemia or epilepsy, which lead to prolonged activation of glutamate receptors. endocytic | recycling | excitation-inhibition | glutamate T he availability of neurotransmitter receptors, a major determinant of synaptic efficacy, is regulated by coordinated mechanisms of intracellular trafficking that deliver newly synthesized receptors to the plasma membrane and remove them for storage, recycling, or degradation (1). The molecular mechanisms controlling the availability of GABA B receptors (GABA B Rs), which are central players in the modulation of excitatory and inhibitory synaptic activity, are unclear.

Behavioural Brain Research, Jan 1, 2009

Repeated administration of drugs may induce adaptations which affect the behavioral responses to ... more Repeated administration of drugs may induce adaptations which affect the behavioral responses to the drug itself or to other drugs. Whether individual characteristics to repeated drug administration predict sensitivity to the effects of another drug is not clear. We evaluated whether or not mice that present higher vs. lower locomotor response after repeated treatment with ethanol display increased or decreased locomotor responses when challenged with methamphetamine or morphine, and vice versa. Mice received daily i.p. 2.2 g/kg ethanol (21 days), 1.0 mg/kg methamphetamine or 10 mg/kg morphine (10 days). According to the response presented during repeated drug treatment, mice were classified as HIGH or LOW activity groups. Locomotor activity was monitored after mice were challenged with saline, and 48 h later with a drug. Ethanol-treated mice were challenged with methamphetamine or morphine, methamphetamine- and morphine-treated animals were challenged with ethanol. After repeated treatment with ethanol or methamphetamine, locomotor sensitization was observed only in HIGH mice, not LOW mice. Ethanol-treated mice with HIGH activity showed sensitized, increased locomotor responses to methamphetamine (p < 0.05), but not to morphine. Locomotor responses to ethanol were not affected by a previous history of methamphetamine treatment. Although repeated administration of morphine failed to induce sensitization, morphine-treated mice with HIGH activity presented sensitized locomotor responses after an ethanol challenge. The current experiments confirm important individual differences in response to repeated administration of ethanol, methamphetamine and morphine, which in some cases affected the locomotor response to a second drug challenge, in an asymmetrical pattern.

Behavioural Pharmacology, 2003

Behavioral sensitization to drugs of abuse seems to involve learning processes. In mice, ethanol-... more Behavioral sensitization to drugs of abuse seems to involve learning processes. In mice, ethanol-induced locomotor sensitization is potentiated by repeated pairing of ethanol (EtOH) injections and the testing chamber. The present study aimed to test: (1) the association between the performance in a contextual conditioning task and the development of behavioral sensitization to EtOH in mice;

Handbook of Behavioral Neuroscience, 2010

Traditional clinical research on the neurobiology of aggressive behavior focuses on individuals w... more Traditional clinical research on the neurobiology of aggressive behavior focuses on individuals who are characterized by their impulsive, hostile, antisocial and violent traits and who show some deficiency in brain serotonin (5-HT) activity relative to those who have a propensity to engage in premeditated, calculating and instrumental aggressive acts. Preclinical research has focused on territorial, dominant or maternal aggressive behavior

Psychopharmacology, 2011

Rationale Exposure to intermittent episodes of social defeat stress can increase drug seeking and... more Rationale Exposure to intermittent episodes of social defeat stress can increase drug seeking and leads to intense drug taking in rats. Objectives This study investigated the consequences of repeated, intermittent social defeat stress on patterns of drug self-administration in rats with access to heroin, cocaine, or a heroin-cocaine combination ("speedball"). Methods Male Long-Evans rats were either handled (controls) or subjected to 25-min social defeat stress episodes on days 1, 4, 7, and 10 during confrontations with an aggressive resident. Ten days following the last defeat, rats were assessed for locomotor cross-sensitization in response to heroin or cocaine. Animals were then prepared with intrajugular catheters for drug self-administration. Separate groups of controls and defeated rats were examined for selfadministration of heroin (experiment 1), a heroin-cocaine combination (experiment 2), or cocaine (experiment 3). Drug self-administration patterns were evaluated using fixed or progressive ratio schedules of reinforcement during limited access sessions or a 24-h unlimited access binge. Results Rats with a history of intermittent social defeat stress showed sensitized locomotor behavior when challenged with heroin or cocaine relative to controls. During the 24-h binge session, defeated rats escalated cocainetaking behavior (ca. 110 mg/kg vs. 66 mg/kg in controls), persisted in self-administering cocaine or the heroincocaine mixture for more hours, and showed a tendency for increased heroin-cocaine intake, but no effects on heroin taking. Conclusions A history of social defeat stress seems to preferentially promote escalated intake of cocaine but not heroin, unless a heroin-cocaine combination is available.

The International Journal of Neuropsychopharmacology, 2010

Repeated ethanol administration may induce behavioural sensitization, defined as a progressive po... more Repeated ethanol administration may induce behavioural sensitization, defined as a progressive potentiation of locomotor stimulant effects. This process is associated with neuroadaptations in the mesolimbic pathway and the nucleus accumbens. The aim of the present study was to analyse dopamine D 1 receptor (D 1 R) participation in locomotor response to an agonist and an antagonist of the D 1 R in mice with different levels of sensitization to ethanol. In three separate experiments, mice received administrations of 2.2 g/kg ethanol or saline every other day for 10 d. According to their locomotor response on the last day, ethanol-treated animals were classified into two groups : sensitized or non-sensitized. After the treatment, mice were challenged with 4 or 8 mg/kg SKF-38393 (i.p.), a D 1 R agonist (expt 1) ; or with 0.01 or 0.1 mg/kg SCH-23390 (i.p.), a D 1 R antagonist, followed by 2.2 g/kg ethanol (i.p.) administration (expt 2). In expt 3, mice were challenged with intra-accumbens (intra-NAc) SKF-38393 (1 mg/side, in 0.2 ml), and with intra-NAc SCH-23390 (3 mg/side, in 0.2 ml) followed by 2.2 g/kg ethanol (i.p.). Although the i.p. administration of SKF-38393 did not affect the locomotion of mice, the intra-NAc administration of SKF-38393 significantly increased the locomotor activity in sensitized mice, suggesting that sensitized mice present functionally hyperresponsive D 1 Rs in the NAc. Both i.p. and intra-NAc administration of SCH-23390 blocked the expression of ethanol sensitization, suggesting that the activation of NAc D 1 Rs seems to be essential for the expression of ethanol sensitization.

Current Topics in Behavioral Neurosciences, 2011

Serotonin (5-HT) has long been considered as a key transmitter in the neurocircuitry controlling ... more Serotonin (5-HT) has long been considered as a key transmitter in the neurocircuitry controlling aggression. Impaired regulation of each subtype of 5-HT receptor, 5-HT transporter, synthetic and metabolic enzymes has been linked particularly to impulsive aggression. The current summary focuses mostly on recent findings from pharmacological and genetic studies. The pharmacological treatments and genetic manipulations or polymorphisms of a specific target (e.g., 5-HT1A receptor) can often result in inconsistent results on aggression, due to "phasic" effects of pharmacological agents vs "trait"-like effects of genetic manipulations. Also, the local administration of a drug using the intracranial microinjection technique has shown that activation of specific subtypes of 5-HT receptors (5-HT1A and 5-HT1B) in mesocorticolimbic areas can reduce species-typical and other aggressive behaviors, but the same receptors in the medial prefrontal cortex or septal area promote escalated forms of aggression. Thus, there are receptor populations in specific brain regions that preferentially modulate specific types of aggression. Genetic studies have shown important gene × environment interactions; it is likely that the polymorphisms in the genes of 5-HT transporters (e.g., MAO A) or rate-limiting synthetic and metabolic enzymes of 5-HT determine the vulnerability to adverse environmental factors that escalate aggression. We also discuss the interaction between the 5-HT system and other systems. Modulation of 5-HT neurons in the dorsal raphe nucleus by GABA, glutamate, and CRF profoundly regulate aggressive behaviors. Also, interactions of the 5-HT system with other neuropeptides (arginine vasopressin, oxytocin, neuropeptide Y, opioid) have emerged as important neurobiological determinants of aggression. Studies of aggression in genetically modified mice identified several molecules that affect the 5-HT system directly (e.g., Tph2, 5-HT1B, 5-HT transporter, Pet1, MAOA) or indirectly (e.g. BDNF, nNOS, αCaMKII, Neuropeptide Y). The future agenda delineates specific receptor subpopulations for GABA, glutamate and neuropeptides as they modulate the canonical aminergic neurotransmitters in brainstem, limbic and cortical regions with the ultimate outcome of attenuating or escalating aggressive behavior.

Psychopharmacology, 2011

Rationale-Intermittent exposure to social defeat stress can induce long-term neural plasticity th... more Rationale-Intermittent exposure to social defeat stress can induce long-term neural plasticity that may influence escalated cocaine-taking behavior. Stressful encounters can lead to activation of dopamine neurons in the ventral tegmental area (VTA), which are modulated by corticotropin releasing factor (CRF) neurons.

Journal of Neuroscience, 2014

Slow and persistent synaptic inhibition is mediated by metabotropic GABA B receptors (GABA B Rs).... more Slow and persistent synaptic inhibition is mediated by metabotropic GABA B receptors (GABA B Rs). GABA B Rs are responsible for the modulation of neurotransmitter release from presynaptic terminals and for hyperpolarization at postsynaptic sites. Postsynaptic GABA B Rs are predominantly found on dendritic spines, adjacent to excitatory synapses, but the control of their plasma membrane availability is still controversial. Here, we explore the role of glutamate receptor activation in regulating the function and surface availability of GABA B Rs in central neurons. We demonstrate that prolonged activation of NMDA receptors (NMDA-Rs) leads to endocytosis, a diversion from a recycling route, and subsequent lysosomal degradation of GABA B Rs. These sorting events are paralleled by a reduction in GABA B R-dependent activation of inwardly rectifying K + channel currents. Postendocytic sorting is critically dependent on phosphorylation of serine 783 (S783) within the GABA B R2 subunit, an established substrate of AMP-dependent protein kinase (AMPK). NMDA-R activation leads to a rapid increase in phosphorylation of S783, followed by a slower dephosphorylation, which results from the activity of AMPK and protein phosphatase 2A, respectively. Agonist activation of GABA B Rs counters the effects of NMDA. Thus, NMDA-R activation alters the phosphorylation state of S783 and acts as a molecular switch to decrease the abundance of GABA B Rs at the neuronal plasma membrane. Such a mechanism may be of significance during synaptic plasticity or pathological conditions, such as ischemia or epilepsy, which lead to prolonged activation of glutamate receptors. endocytic | recycling | excitation-inhibition | glutamate T he availability of neurotransmitter receptors, a major determinant of synaptic efficacy, is regulated by coordinated mechanisms of intracellular trafficking that deliver newly synthesized receptors to the plasma membrane and remove them for storage, recycling, or degradation (1). The molecular mechanisms controlling the availability of GABA B receptors (GABA B Rs), which are central players in the modulation of excitatory and inhibitory synaptic activity, are unclear.