Silvia Navarro - Academia.edu (original) (raw)

Papers by Silvia Navarro

Research paper thumbnail of Behavioral Biomarkers of Schizophrenia in High Drinker Rats: A Potential Endophenotype of Compulsive Neuropsychiatric Disorders

Schizophrenia Bulletin, 2016

Psychogenic polydipsia, which is compulsive, non-regulatory fluid consumption, is present in 6%-2... more Psychogenic polydipsia, which is compulsive, non-regulatory fluid consumption, is present in 6%-20% of chronic psychiatric patients and frequently associated with the schizophrenia diagnosis. In the present study, we investigated the relation between schizophrenia-like symptoms and biomarkers with a compulsive drinking behavior phenotype in rats. Rats that were selected for low drinking vs high drinking behavior following schedule-induced polydipsia (SIP) were assessed in a latent inhibition (LI) paradigm using tone and electrical foot shock and in a spatial reversal learning task to evaluate behavioral inflexibility. We also analyzed the myelin basic protein in different brain areas of high drinker (HD) and low drinker (LD) rats. The HD rats, which were characterized by a compulsive drinking behavior on SIP, had a reduced level of LI effect and increased behavioral inflexibility in the spatial reversal learning task in comparison to the LD group. Moreover, HD rats showed less myelination in the center of the corpus callosum, striatum, and amygdala in comparison to LD rats. These findings strengthen the validity of HD rats that were selected by SIP as a possible phenotype of compulsive neuropsychiatric disorders, as evidenced by the existence of behaviors and biological markers that are related to schizophrenia and obsessive-compulsive disorder, including a reduced LI effect, behavioral inflexibility and reduced brain myelination. Future studies could contribute to the elucidation of the mechanisms underlying the compulsive phenotype of HD rats and its relation to vulnerability to schizophrenia.

Research paper thumbnail of Activation of serotonin 5-HT2A receptors inhibits high compulsive drinking on schedule-induced polydipsia

Psychopharmacology, 2014

Rationale Schedule-induced polydipsia (SIP) is an established model for studying compulsive behav... more Rationale Schedule-induced polydipsia (SIP) is an established model for studying compulsive behaviour in rats. Serotoninergic drugs effectively reduce compulsive drinking on SIP, and high compulsive drinker rats selected by SIP have shown differences in serotoninergic brain activity. However, the specific serotoninergic receptors that modulate compulsive SIP remain unclear. Objective We investigated the functional role of serotonin 5hydroxytryptamine 2A or C (5-HT 2A/C) receptors in compulsive SIP behaviour. Methods Rats were selected for low (LD) versus high drinking (HD) behaviour on SIP. The effects of the systemic administration of the selective serotonin reuptake inhibitor citalopram, selective norepinephrine reuptake inhibitor atomoxetine, serotonin 5-HT 2A/C receptor agonist DOI hydrochloride ((±)-2,5-dimethoxy-4-iodoamphetamine), serotonin 5-HT 2C receptor antagonist SB242084, serotonin 5-HT 2A receptor antagonist ketanserin and M100907 were assessed on SIP. Subsequently, the effects of DOI were tested after the preadministration of SB242084, ketanserin and M100907 on SIP. Results Citalopram and DOI reduced compulsive drinking in HD compared with LD rats on SIP. In contrast, SB242084 increased compulsive drinking in HD compared with LD rats on SIP. Atomoxetine, ketanserin and M100907 had no effect on SIP. The reduction in water intake produced by DOI was blocked by ketanserin and M100907, but not by SB242084 administration, in HD rats. Conclusions These findings highlight the contribution of serotoninergic 5-HT 2A/C receptors compared with noradrenergic mechanisms on SIP and reveal the "therapeutic" activation of serotonin 5-HT 2A in the inhibition of the compulsive drinking behaviour in HD rats. Thus, it may represent a potentially new marker of vulnerability and provides additional insight for potential treatments on compulsive behaviours in neuropsychiatric populations.

Research paper thumbnail of B.9 - Prefrontal Cortex Serotoninergic Dysfunction in Compulsive Rats Selected by Schedule-Induced Polydipsia

Behavioural Pharmacology, 2013

responsible for GABA synthesis, glutamate decarboxylase (GAD 65/67, P < 0.01), as well as the den... more responsible for GABA synthesis, glutamate decarboxylase (GAD 65/67, P < 0.01), as well as the dendritic marker microtubule associated protein (MAP2, P < 0.05), and the dendritic spine marker spinophilin (P < 0.05) in the left NAcb core of HI rats compared with LI rats. There were no significant differences in any of these markers in the other brain regions investigated. We also identified a strong inverse relationship between impulsivity and the lower levels of GAD 65/67 (P < 0.01; r =-0.71) and MAP2 (P < 0.05; r =-0.66) in the left NAcb core. Finally, we investigated the effects of bilateral microinfusions of GAD 65/67 antisense into the NAcb core on the level of impulsivity in LI rats. Infusions of GAD65/67antisense in this region resulted in a robust and selective increase in impulsive responding compared to a second group of LI rats infused with a scramble sequence. These findings indicate that while the number of neurons in the NAcb core may be unaltered by variation in impulsivity, the structural integrity and density of dendritic spines, together with GABA neurotransmission, may be deficient in HI rats. Collectively, these data suggest that decreased dopamine D2/3 receptor availability in the ventral striatum of HI rats may be secondary to a reduction in the density of spines on medium spiny GABA-ergic neurons in the NAcb core.

Research paper thumbnail of B.8 - Tryptophan Depletion Diet in Low Versus High Compulsive Drinker Rats Selected by Schedule-Induced Polydipsia

Behavioural Pharmacology, 2013

responsible for GABA synthesis, glutamate decarboxylase (GAD 65/67, P < 0.01), as well as the den... more responsible for GABA synthesis, glutamate decarboxylase (GAD 65/67, P < 0.01), as well as the dendritic marker microtubule associated protein (MAP2, P < 0.05), and the dendritic spine marker spinophilin (P < 0.05) in the left NAcb core of HI rats compared with LI rats. There were no significant differences in any of these markers in the other brain regions investigated. We also identified a strong inverse relationship between impulsivity and the lower levels of GAD 65/67 (P < 0.01; r =-0.71) and MAP2 (P < 0.05; r =-0.66) in the left NAcb core. Finally, we investigated the effects of bilateral microinfusions of GAD 65/67 antisense into the NAcb core on the level of impulsivity in LI rats. Infusions of GAD65/67antisense in this region resulted in a robust and selective increase in impulsive responding compared to a second group of LI rats infused with a scramble sequence. These findings indicate that while the number of neurons in the NAcb core may be unaltered by variation in impulsivity, the structural integrity and density of dendritic spines, together with GABA neurotransmission, may be deficient in HI rats. Collectively, these data suggest that decreased dopamine D2/3 receptor availability in the ventral striatum of HI rats may be secondary to a reduction in the density of spines on medium spiny GABA-ergic neurons in the NAcb core.

Research paper thumbnail of Behavioral Biomarkers of Schizophrenia in High Drinker Rats: A Potential Endophenotype of Compulsive Neuropsychiatric Disorders

Schizophrenia Bulletin, 2016

Psychogenic polydipsia, which is compulsive, non-regulatory fluid consumption, is present in 6%-2... more Psychogenic polydipsia, which is compulsive, non-regulatory fluid consumption, is present in 6%-20% of chronic psychiatric patients and frequently associated with the schizophrenia diagnosis. In the present study, we investigated the relation between schizophrenia-like symptoms and biomarkers with a compulsive drinking behavior phenotype in rats. Rats that were selected for low drinking vs high drinking behavior following schedule-induced polydipsia (SIP) were assessed in a latent inhibition (LI) paradigm using tone and electrical foot shock and in a spatial reversal learning task to evaluate behavioral inflexibility. We also analyzed the myelin basic protein in different brain areas of high drinker (HD) and low drinker (LD) rats. The HD rats, which were characterized by a compulsive drinking behavior on SIP, had a reduced level of LI effect and increased behavioral inflexibility in the spatial reversal learning task in comparison to the LD group. Moreover, HD rats showed less myelination in the center of the corpus callosum, striatum, and amygdala in comparison to LD rats. These findings strengthen the validity of HD rats that were selected by SIP as a possible phenotype of compulsive neuropsychiatric disorders, as evidenced by the existence of behaviors and biological markers that are related to schizophrenia and obsessive-compulsive disorder, including a reduced LI effect, behavioral inflexibility and reduced brain myelination. Future studies could contribute to the elucidation of the mechanisms underlying the compulsive phenotype of HD rats and its relation to vulnerability to schizophrenia.

Research paper thumbnail of Activation of serotonin 5-HT2A receptors inhibits high compulsive drinking on schedule-induced polydipsia

Psychopharmacology, 2014

Rationale Schedule-induced polydipsia (SIP) is an established model for studying compulsive behav... more Rationale Schedule-induced polydipsia (SIP) is an established model for studying compulsive behaviour in rats. Serotoninergic drugs effectively reduce compulsive drinking on SIP, and high compulsive drinker rats selected by SIP have shown differences in serotoninergic brain activity. However, the specific serotoninergic receptors that modulate compulsive SIP remain unclear. Objective We investigated the functional role of serotonin 5hydroxytryptamine 2A or C (5-HT 2A/C) receptors in compulsive SIP behaviour. Methods Rats were selected for low (LD) versus high drinking (HD) behaviour on SIP. The effects of the systemic administration of the selective serotonin reuptake inhibitor citalopram, selective norepinephrine reuptake inhibitor atomoxetine, serotonin 5-HT 2A/C receptor agonist DOI hydrochloride ((±)-2,5-dimethoxy-4-iodoamphetamine), serotonin 5-HT 2C receptor antagonist SB242084, serotonin 5-HT 2A receptor antagonist ketanserin and M100907 were assessed on SIP. Subsequently, the effects of DOI were tested after the preadministration of SB242084, ketanserin and M100907 on SIP. Results Citalopram and DOI reduced compulsive drinking in HD compared with LD rats on SIP. In contrast, SB242084 increased compulsive drinking in HD compared with LD rats on SIP. Atomoxetine, ketanserin and M100907 had no effect on SIP. The reduction in water intake produced by DOI was blocked by ketanserin and M100907, but not by SB242084 administration, in HD rats. Conclusions These findings highlight the contribution of serotoninergic 5-HT 2A/C receptors compared with noradrenergic mechanisms on SIP and reveal the "therapeutic" activation of serotonin 5-HT 2A in the inhibition of the compulsive drinking behaviour in HD rats. Thus, it may represent a potentially new marker of vulnerability and provides additional insight for potential treatments on compulsive behaviours in neuropsychiatric populations.

Research paper thumbnail of B.9 - Prefrontal Cortex Serotoninergic Dysfunction in Compulsive Rats Selected by Schedule-Induced Polydipsia

Behavioural Pharmacology, 2013

responsible for GABA synthesis, glutamate decarboxylase (GAD 65/67, P < 0.01), as well as the den... more responsible for GABA synthesis, glutamate decarboxylase (GAD 65/67, P < 0.01), as well as the dendritic marker microtubule associated protein (MAP2, P < 0.05), and the dendritic spine marker spinophilin (P < 0.05) in the left NAcb core of HI rats compared with LI rats. There were no significant differences in any of these markers in the other brain regions investigated. We also identified a strong inverse relationship between impulsivity and the lower levels of GAD 65/67 (P < 0.01; r =-0.71) and MAP2 (P < 0.05; r =-0.66) in the left NAcb core. Finally, we investigated the effects of bilateral microinfusions of GAD 65/67 antisense into the NAcb core on the level of impulsivity in LI rats. Infusions of GAD65/67antisense in this region resulted in a robust and selective increase in impulsive responding compared to a second group of LI rats infused with a scramble sequence. These findings indicate that while the number of neurons in the NAcb core may be unaltered by variation in impulsivity, the structural integrity and density of dendritic spines, together with GABA neurotransmission, may be deficient in HI rats. Collectively, these data suggest that decreased dopamine D2/3 receptor availability in the ventral striatum of HI rats may be secondary to a reduction in the density of spines on medium spiny GABA-ergic neurons in the NAcb core.

Research paper thumbnail of B.8 - Tryptophan Depletion Diet in Low Versus High Compulsive Drinker Rats Selected by Schedule-Induced Polydipsia

Behavioural Pharmacology, 2013

responsible for GABA synthesis, glutamate decarboxylase (GAD 65/67, P < 0.01), as well as the den... more responsible for GABA synthesis, glutamate decarboxylase (GAD 65/67, P < 0.01), as well as the dendritic marker microtubule associated protein (MAP2, P < 0.05), and the dendritic spine marker spinophilin (P < 0.05) in the left NAcb core of HI rats compared with LI rats. There were no significant differences in any of these markers in the other brain regions investigated. We also identified a strong inverse relationship between impulsivity and the lower levels of GAD 65/67 (P < 0.01; r =-0.71) and MAP2 (P < 0.05; r =-0.66) in the left NAcb core. Finally, we investigated the effects of bilateral microinfusions of GAD 65/67 antisense into the NAcb core on the level of impulsivity in LI rats. Infusions of GAD65/67antisense in this region resulted in a robust and selective increase in impulsive responding compared to a second group of LI rats infused with a scramble sequence. These findings indicate that while the number of neurons in the NAcb core may be unaltered by variation in impulsivity, the structural integrity and density of dendritic spines, together with GABA neurotransmission, may be deficient in HI rats. Collectively, these data suggest that decreased dopamine D2/3 receptor availability in the ventral striatum of HI rats may be secondary to a reduction in the density of spines on medium spiny GABA-ergic neurons in the NAcb core.