Proceedings of the National Academy of Sciences, 2016
A growing body of evidence indicates that treatments that typically impair memory consolidation b... more A growing body of evidence indicates that treatments that typically impair memory consolidation become ineffective when animals are given intense training. This effect has been obtained by treatments interfering with the neural activity of several brain structures, including the dorsal striatum. The mechanisms that mediate this phenomenon are unknown. One possibility is that intense training promotes the transfer of information derived from the enhanced training to a wider neuronal network. We now report that inhibitory avoidance (IA) induces mushroom spinogenesis in the medium spiny neurons (MSNs) of the dorsal striatum in rats, which is dependent upon the intensity of the foot-shock used for training; that is, the effect is seen only when high-intensity foot-shock is used in training. We also found that the relative density of thin spines was reduced. These changes were evident at 6 h after training and persisted for at least 24 h afterward. Importantly, foot-shock alone did not increase spinogenesis. Spine density in MSNs in the accumbens was also increased, but the increase did not correlate with the associative process involved in IA; rather, it resulted from the administration of the aversive stimulation alone. These findings suggest that mushroom spines of MSNs of the dorsal striatum receive afferent information that is involved in the integrative activity necessary for memory consolidation, and that intense training facilitates transfer of information from the dorsal striatum to other brain regions through augmented spinogenesis.
The synthesis of (E)-6,8-dioxo-7-propyl-9-styrylcarboxa- mido-1,3,4,6,7,8-hexahydro-2H-pyrimido(1... more The synthesis of (E)-6,8-dioxo-7-propyl-9-styrylcarboxa- mido-1,3,4,6,7,8-hexahydro-2H-pyrimido(1,6-a)pyrimidine (9) from 6-aminouracil (4) using a chemo- and regioselective pathway is des- cribed herein. Additionally we report the pharmaco-biological evalua- tion of the compound 9 using the anxiolitic test plus maze elevator and the effect of 9 over the locomotor activity in the Wistar rats. The results suggest that compound 9 exhibit a significant anxiolitic
Schizophrenia, a severe and debilitating disorder with a high social burden, affects 1% of the ad... more Schizophrenia, a severe and debilitating disorder with a high social burden, affects 1% of the adult world population. Available therapies are unable to treat all the symptoms, and result in strong side effects. For this reason, numerous animal models have been generated to elucidate the pathophysiology of this disorder. All these models present neuronal remodeling and abnormalities in spine stability. It is well known that the complexity in dendritic arborization determines the number of receptive synaptic contacts. Also the loss of dendritic spines and arbor stability are strongly associated with schizophrenia. This review evaluates changes in spine density and dendritic arborization in animal models of schizophrenia. By understanding these changes, pharmacological treatments can be designed to target specific neural systems to attenuate neuronal remodeling and associated behavioral deficits.
Accumulated evidence suggests that neuropeptide Y (NPY) is involved in emotional disorders by act... more Accumulated evidence suggests that neuropeptide Y (NPY) is involved in emotional disorders by acting on Y1 and Y2 receptors. This hypothesis is based on animal studies carried out in naïve normal animals but not in animal models of depression, including the olfactory bulbectomized (OBX) rat. The OBX rat produces a wide array of symptoms that mimic several aspects of human depression and anxiety disorders. In the present study, we aimed to investigate the effects of sustained (2 weeks) intracerebroventricular administration of NPY Y1 and Y2 agonists and antagonists in a battery of behavioral tests including the open field, forced swim test (FST) and social interaction (SI) tests in OBX rats. The levels of Y1 and Y2 receptors in the hippocampus and basolateral amygdala (BLA) were also evaluated. Treatment with the Y1-like receptor agonist, [Leu31Pro34]PYY, decreased both depressive- and anxiogenic-like behaviors. The Y2 receptor antagonist, BIIE0246, decreased the immobility time in the FST in OBX animals and increased active contacts in the SI test in sham rats. The Y2 agonist, PYY3-36, increased the immobility time in the FST in OBX rats. Additionally, increased levels of Y2 receptor binding were quantified in the dorsal hippocampus and BLA in OBX rats. Taken together, the autoradiographic results add further evidence that the NPYergic system is altered in disturbed emotional states. Moreover, we demonstrate a differential role for NPY Y1 and Y2 receptors in emotional processes under control and challenged conditions.This article is part of a Special Issue entitled ‘Anxiety and Depression’.► The neuropeptide Y mediates emotional behaviors by modulating Y1 and Y2 receptors. ► Emotional behaviors were evaluated in the OBX model of depression. ► Y1 agonist decreases depression and anxiogenic behaviors in the OBX rat. ► Y2 antagonist acts as antidepressant in OBX and as anxiolytic in control animals. ► The Y1 and Y2 receptors have a differential role in emotional processes.
The animal model of streptozotocin-induced diabetes mellitus type 1 (DM1) is used to study neuron... more The animal model of streptozotocin-induced diabetes mellitus type 1 (DM1) is used to study neuronal and behavioral changes produced by an increase in blood-glucose levels. Our previous report showed that chronic streptozotocin administration induced atrophy of dendritic morphology of pyramidal neurons of the CA1 dorsal hippocampus. In addition, we showed that Cerebrolysin (Cbl), a neurotrophic peptide mixture, reduces the dendritic atrophy in animal models of aging. This study aimed to determine whether Cbl was capable of reducing behavioral and neuronal alterations, after 6 weeks of hyperglycemia in mice (streptozotocin-induced DM1). The levels of glucose in the blood were evaluated before and after streptozotocin administration and only animals with more than 240 mg/dL of blood-levels of glucose were used. After streptozotocin treatment, the mice received 6 weeks of Cbl, locomotor activity was measured and dendritic morphological changes were evaluated using Golgi-Cox stain proced...
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 15, 1996
Functional and structural abnormalities in the medial prefrontal cortex (MPFC) and overactive dop... more Functional and structural abnormalities in the medial prefrontal cortex (MPFC) and overactive dopamine (DA) neurotransmission are thought to be the key pathologies in schizophrenia. To understand the role of MPFC in the pre- and postpubertal development of the subcortical DA system, the effects of neonatal [postnatal day 7 (PD7)] MPFC excitotoxic lesions on locomotor behaviors and the expression of DA receptor subtypes and DA transporter were investigated in Sprague Dawley rats at PD35 and PD56, respectively. No significant differences in the novelty of d-amphetamine-induced locomotion were observed between sham-operated and ibotenic acid-lesioned rats at PD35. Postpubertally (at PD56), however, the locomotor activity of lesioned rats in the novel environment and after d-amphetamine administration was enhanced significantly compared with controls. The expressions of DA D1, D2, D3, and D4 receptors and DA transporter were then estimated in MPFC-lesioned and sham-operated rats at PD59...
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 15, 1996
Neonatal, bilateral lesion of the ventral hippocampus (VH) in rats recently has been proposed as ... more Neonatal, bilateral lesion of the ventral hippocampus (VH) in rats recently has been proposed as a model of schizophrenia because these animals show postpubertal hypersensitivity to stress and to dopamine (DA) agonists that can be reversed by neuroleptic treatment. In search of the mechanisms of postpubertal emergence of hyperdopaminergic behavior in this model, we investigated developmental expressions of DA D1, D2, and D3 receptors in various striatal and limbic subregions of rats that had received bilateral ibotenic acid lesion of the VH at postnatal day 7 (PD7). D-Amphetamine-, apomorphine-, and stress-induced changes in locomotor activity were measured and, in accordance with previous reports, we observed an increased locomotor activity at PD56 in the hippocampal-lesioned group. The expression of DA D1, D2, and D3 receptors was then estimated in these rats by ligand autoradiography at PD41 and PD62. We observed that the levels of DA D3 receptors, as measured by tritiated 7-hydr...
We have studied, in spontaneously hypertensive (SH) rats at different ages (2, 4, and 8 months ol... more We have studied, in spontaneously hypertensive (SH) rats at different ages (2, 4, and 8 months old), the dendritic morphological changes of the pyramidal neurons of the medial prefrontal cortex (mPFC) and hippocampus and medium spiny neurons of the nucleus accumbens (NAcc) induced by the chronic effect of high-blood pressure. As control animals, we used Wistar-Kioto (WK) rats. Blood pressure was measured every 2 months to confirm the increase in arterial blood pressure. Spontaneous locomotor activity was assessed, and then brains were removed to study the dendritic morphology by the Golgi-Cox stain method followed by Sholl analysis. SH animals at 4 and 8 months of age showed decreased spine density in pyramidal neurons from the mPFC and in medium spiny cells from the NAcc. At 8 months of age as well the pyramidal neurons from the hippocampus exhibited a reduction in the number of dendritic spines. An increase in locomotion in a novel environment at all ages in the SH rats was observed. Our results indicate that high-blood pressure alters the neuronal dendrite morphology of the mPFC, hippocampus, and NAcc. The increased locomotion behavior supports the idea that dopaminergic transmission is altered in the SH rats. This could enhance our understanding of the consequences of chronic high-blood pressure on brain structure, which may implicate cognitive impairment in hypertensive patients.
International Journal of Medicinal Chemistry, 2011
The neonatal ventral hippocampal lesion (nVHL) has been widely used as an animal model for schizo... more The neonatal ventral hippocampal lesion (nVHL) has been widely used as an animal model for schizophrenia. Rats with an nVHL show several delayed behavioral alterations that mimic some symptoms of schizophrenia. Sprague-Dawley (SD) rats with an nVHL have a decrease in D3 receptors in limbic areas, but the expression of D3 receptors in Wistar (W) rats with an nVHL is unknown. The 7-Hydroxy-2-(N,N-di-n-propylamino) tetralin (7-OH-DPAT) has been reported as a D3-preferring agonist. Thus, we investigated the effect of (±)-7-OH-DPAT (0.25 mg/kg) on the motor activity in male adult W and SD rats after an nVHL. The 7-OH-DPAT caused a decrease in locomotion of W rats with an nVHL, but it did not change the locomotion of SD rats with this lesion. Our results suggest that the differential effect of 7-OH-DPAT between W and SD rats with an nVHL could be caused by a different expression of the D3 receptors. These results may have implications for modeling interactions of genetic and environmental factors involved in schizophrenia.
Proceedings of the National Academy of Sciences, 2016
A growing body of evidence indicates that treatments that typically impair memory consolidation b... more A growing body of evidence indicates that treatments that typically impair memory consolidation become ineffective when animals are given intense training. This effect has been obtained by treatments interfering with the neural activity of several brain structures, including the dorsal striatum. The mechanisms that mediate this phenomenon are unknown. One possibility is that intense training promotes the transfer of information derived from the enhanced training to a wider neuronal network. We now report that inhibitory avoidance (IA) induces mushroom spinogenesis in the medium spiny neurons (MSNs) of the dorsal striatum in rats, which is dependent upon the intensity of the foot-shock used for training; that is, the effect is seen only when high-intensity foot-shock is used in training. We also found that the relative density of thin spines was reduced. These changes were evident at 6 h after training and persisted for at least 24 h afterward. Importantly, foot-shock alone did not increase spinogenesis. Spine density in MSNs in the accumbens was also increased, but the increase did not correlate with the associative process involved in IA; rather, it resulted from the administration of the aversive stimulation alone. These findings suggest that mushroom spines of MSNs of the dorsal striatum receive afferent information that is involved in the integrative activity necessary for memory consolidation, and that intense training facilitates transfer of information from the dorsal striatum to other brain regions through augmented spinogenesis.
The synthesis of (E)-6,8-dioxo-7-propyl-9-styrylcarboxa- mido-1,3,4,6,7,8-hexahydro-2H-pyrimido(1... more The synthesis of (E)-6,8-dioxo-7-propyl-9-styrylcarboxa- mido-1,3,4,6,7,8-hexahydro-2H-pyrimido(1,6-a)pyrimidine (9) from 6-aminouracil (4) using a chemo- and regioselective pathway is des- cribed herein. Additionally we report the pharmaco-biological evalua- tion of the compound 9 using the anxiolitic test plus maze elevator and the effect of 9 over the locomotor activity in the Wistar rats. The results suggest that compound 9 exhibit a significant anxiolitic
Schizophrenia, a severe and debilitating disorder with a high social burden, affects 1% of the ad... more Schizophrenia, a severe and debilitating disorder with a high social burden, affects 1% of the adult world population. Available therapies are unable to treat all the symptoms, and result in strong side effects. For this reason, numerous animal models have been generated to elucidate the pathophysiology of this disorder. All these models present neuronal remodeling and abnormalities in spine stability. It is well known that the complexity in dendritic arborization determines the number of receptive synaptic contacts. Also the loss of dendritic spines and arbor stability are strongly associated with schizophrenia. This review evaluates changes in spine density and dendritic arborization in animal models of schizophrenia. By understanding these changes, pharmacological treatments can be designed to target specific neural systems to attenuate neuronal remodeling and associated behavioral deficits.
Accumulated evidence suggests that neuropeptide Y (NPY) is involved in emotional disorders by act... more Accumulated evidence suggests that neuropeptide Y (NPY) is involved in emotional disorders by acting on Y1 and Y2 receptors. This hypothesis is based on animal studies carried out in naïve normal animals but not in animal models of depression, including the olfactory bulbectomized (OBX) rat. The OBX rat produces a wide array of symptoms that mimic several aspects of human depression and anxiety disorders. In the present study, we aimed to investigate the effects of sustained (2 weeks) intracerebroventricular administration of NPY Y1 and Y2 agonists and antagonists in a battery of behavioral tests including the open field, forced swim test (FST) and social interaction (SI) tests in OBX rats. The levels of Y1 and Y2 receptors in the hippocampus and basolateral amygdala (BLA) were also evaluated. Treatment with the Y1-like receptor agonist, [Leu31Pro34]PYY, decreased both depressive- and anxiogenic-like behaviors. The Y2 receptor antagonist, BIIE0246, decreased the immobility time in the FST in OBX animals and increased active contacts in the SI test in sham rats. The Y2 agonist, PYY3-36, increased the immobility time in the FST in OBX rats. Additionally, increased levels of Y2 receptor binding were quantified in the dorsal hippocampus and BLA in OBX rats. Taken together, the autoradiographic results add further evidence that the NPYergic system is altered in disturbed emotional states. Moreover, we demonstrate a differential role for NPY Y1 and Y2 receptors in emotional processes under control and challenged conditions.This article is part of a Special Issue entitled ‘Anxiety and Depression’.► The neuropeptide Y mediates emotional behaviors by modulating Y1 and Y2 receptors. ► Emotional behaviors were evaluated in the OBX model of depression. ► Y1 agonist decreases depression and anxiogenic behaviors in the OBX rat. ► Y2 antagonist acts as antidepressant in OBX and as anxiolytic in control animals. ► The Y1 and Y2 receptors have a differential role in emotional processes.
The animal model of streptozotocin-induced diabetes mellitus type 1 (DM1) is used to study neuron... more The animal model of streptozotocin-induced diabetes mellitus type 1 (DM1) is used to study neuronal and behavioral changes produced by an increase in blood-glucose levels. Our previous report showed that chronic streptozotocin administration induced atrophy of dendritic morphology of pyramidal neurons of the CA1 dorsal hippocampus. In addition, we showed that Cerebrolysin (Cbl), a neurotrophic peptide mixture, reduces the dendritic atrophy in animal models of aging. This study aimed to determine whether Cbl was capable of reducing behavioral and neuronal alterations, after 6 weeks of hyperglycemia in mice (streptozotocin-induced DM1). The levels of glucose in the blood were evaluated before and after streptozotocin administration and only animals with more than 240 mg/dL of blood-levels of glucose were used. After streptozotocin treatment, the mice received 6 weeks of Cbl, locomotor activity was measured and dendritic morphological changes were evaluated using Golgi-Cox stain proced...
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 15, 1996
Functional and structural abnormalities in the medial prefrontal cortex (MPFC) and overactive dop... more Functional and structural abnormalities in the medial prefrontal cortex (MPFC) and overactive dopamine (DA) neurotransmission are thought to be the key pathologies in schizophrenia. To understand the role of MPFC in the pre- and postpubertal development of the subcortical DA system, the effects of neonatal [postnatal day 7 (PD7)] MPFC excitotoxic lesions on locomotor behaviors and the expression of DA receptor subtypes and DA transporter were investigated in Sprague Dawley rats at PD35 and PD56, respectively. No significant differences in the novelty of d-amphetamine-induced locomotion were observed between sham-operated and ibotenic acid-lesioned rats at PD35. Postpubertally (at PD56), however, the locomotor activity of lesioned rats in the novel environment and after d-amphetamine administration was enhanced significantly compared with controls. The expressions of DA D1, D2, D3, and D4 receptors and DA transporter were then estimated in MPFC-lesioned and sham-operated rats at PD59...
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 15, 1996
Neonatal, bilateral lesion of the ventral hippocampus (VH) in rats recently has been proposed as ... more Neonatal, bilateral lesion of the ventral hippocampus (VH) in rats recently has been proposed as a model of schizophrenia because these animals show postpubertal hypersensitivity to stress and to dopamine (DA) agonists that can be reversed by neuroleptic treatment. In search of the mechanisms of postpubertal emergence of hyperdopaminergic behavior in this model, we investigated developmental expressions of DA D1, D2, and D3 receptors in various striatal and limbic subregions of rats that had received bilateral ibotenic acid lesion of the VH at postnatal day 7 (PD7). D-Amphetamine-, apomorphine-, and stress-induced changes in locomotor activity were measured and, in accordance with previous reports, we observed an increased locomotor activity at PD56 in the hippocampal-lesioned group. The expression of DA D1, D2, and D3 receptors was then estimated in these rats by ligand autoradiography at PD41 and PD62. We observed that the levels of DA D3 receptors, as measured by tritiated 7-hydr...
We have studied, in spontaneously hypertensive (SH) rats at different ages (2, 4, and 8 months ol... more We have studied, in spontaneously hypertensive (SH) rats at different ages (2, 4, and 8 months old), the dendritic morphological changes of the pyramidal neurons of the medial prefrontal cortex (mPFC) and hippocampus and medium spiny neurons of the nucleus accumbens (NAcc) induced by the chronic effect of high-blood pressure. As control animals, we used Wistar-Kioto (WK) rats. Blood pressure was measured every 2 months to confirm the increase in arterial blood pressure. Spontaneous locomotor activity was assessed, and then brains were removed to study the dendritic morphology by the Golgi-Cox stain method followed by Sholl analysis. SH animals at 4 and 8 months of age showed decreased spine density in pyramidal neurons from the mPFC and in medium spiny cells from the NAcc. At 8 months of age as well the pyramidal neurons from the hippocampus exhibited a reduction in the number of dendritic spines. An increase in locomotion in a novel environment at all ages in the SH rats was observed. Our results indicate that high-blood pressure alters the neuronal dendrite morphology of the mPFC, hippocampus, and NAcc. The increased locomotion behavior supports the idea that dopaminergic transmission is altered in the SH rats. This could enhance our understanding of the consequences of chronic high-blood pressure on brain structure, which may implicate cognitive impairment in hypertensive patients.
International Journal of Medicinal Chemistry, 2011
The neonatal ventral hippocampal lesion (nVHL) has been widely used as an animal model for schizo... more The neonatal ventral hippocampal lesion (nVHL) has been widely used as an animal model for schizophrenia. Rats with an nVHL show several delayed behavioral alterations that mimic some symptoms of schizophrenia. Sprague-Dawley (SD) rats with an nVHL have a decrease in D3 receptors in limbic areas, but the expression of D3 receptors in Wistar (W) rats with an nVHL is unknown. The 7-Hydroxy-2-(N,N-di-n-propylamino) tetralin (7-OH-DPAT) has been reported as a D3-preferring agonist. Thus, we investigated the effect of (±)-7-OH-DPAT (0.25 mg/kg) on the motor activity in male adult W and SD rats after an nVHL. The 7-OH-DPAT caused a decrease in locomotion of W rats with an nVHL, but it did not change the locomotion of SD rats with this lesion. Our results suggest that the differential effect of 7-OH-DPAT between W and SD rats with an nVHL could be caused by a different expression of the D3 receptors. These results may have implications for modeling interactions of genetic and environmental factors involved in schizophrenia.
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Papers by Gonzalo Flores