Mariana Angoa-Perez - Academia.edu (original) (raw)

Papers by Mariana Angoa-Perez

Research paper thumbnail of Effects of Testosterone and Growth Hormone on Long-Term Retention and Extinction of a Passive Avoidance Response in Young and Aged Rats

International Journal of Neuroscience, 2007

Wistar rats were divided into two blocks: young and aged. Each block was then randomly divided in... more Wistar rats were divided into two blocks: young and aged. Each block was then randomly divided into the following groups: (1) Control (saline solution), (2) Growth Hormone (GH), (3) Testosterone enanthate, and (4) GH plus testosterone enanthate. Animals were trained on a one-trial passive avoidance conditioning and tested for retention 24 h after training and thereafter twice a week until the extinction response occurred. Results showed that GH, testosterone, and GH plus testosterone improved long-term memory in young rats. Both GH and testosterone delayed the extinction process in young and aged rats. The GH-testosterone interaction delayed the extinction only in young rats.

Research paper thumbnail of Effect of Growth Hormone on Cyclooxygenase-2 Expression in the Hippocampus of Rats Chronically Exposed to Ozone

International Journal of Neuroscience, 2008

The aim of this study was to determine GH-effects on Cyclooxygenase-2 (COX-2) expression on hippo... more The aim of this study was to determine GH-effects on Cyclooxygenase-2 (COX-2) expression on hippocampus alterations caused by ozone exposure. Seventy male rats were divided into: (1) control; (2) exposed to ozone for 7, 15, and 30 days; (3) exposed to ozone and treated with GH, for 7, 15, and 30 days. Results showed that lipoperoxidation levels and number of COX-2-positive cells increased in all groups exposed to ozone compared to control. In the groups treated with GH, COX-2 immunoreactive cell number decreased with respect to the ozone group. Therefore, GH could provide protection against damage induced by oxidative stress.

Research paper thumbnail of Oxidative damage in substantia nigra and striatum of rats chronically exposed to ozone

Journal of Chemical Neuroanatomy, 2006

The purpose of this work was to study if chronic low-dose ozone exposure could per se induce oxid... more The purpose of this work was to study if chronic low-dose ozone exposure could per se induce oxidative damage to neurons of striatum and substantia nigra. Thirty male Wistar rats were divided into three groups-Group 1: exposed to an air stream free of ozone; Group 2: exposed for 15 days to ozone; Group 3: exposed for 30 days to ozone. Ozone exposure was carried out daily for 4 h at a 0.25 ppm dose. Each group was then tested for (1) motor activity, (2) quantification of lipid peroxidation levels, (3) Klüver-Barrera staining, and (4) immunohistochemistry for tyrosine hydroxylase (TH), dopamine and adenosine 3 0 ,5 0-monophosphate-regulated phosphoprotein of 32kD (DARPP-32), inducible nitric oxide synthase (iNOS), and superoxide dismutase (SOD), to study neuronal alterations in striatum and substantia nigra. Results indicate that ozone exposure causes a significant decrease in motor activity. Ozone produced lipid peroxidation, morphological alterations, loss of fibers and cell death of the dopaminergic neurons. The DARPP-32, iNOS and SOD expression increased with repetitive ozone exposure. These alterations suggest that ozone causes oxidative stress which induces oxidative damage to substantia nigra and striatum of the rat.

Research paper thumbnail of A mouse model of human repetitive mild traumatic brain injury

Journal of Neuroscience Methods, 2012

A novel method for the study of repetitive mild traumatic brain injury (rmTBI) that models the mo... more A novel method for the study of repetitive mild traumatic brain injury (rmTBI) that models the most common form of head injury in humans is presented. Existing animal models of TBI impart focal, severe damage unlike that seen in repeated and mild concussive injuries, and few are configured for repetitive application. Our model is a modification of the Marmarou weight drop method and allows repeated head impacts to lightly anesthetized mice. A key facet of this method is the delivery of an impact to the cranium of an unrestrained subject allowing rapid acceleration of the free-moving head and torso, an essential characteristic known to be important for concussive injury in humans, and a factor that is missing from existing animal models of TBI. Our method does not require scalp incision, emplacement of protective skull helmets or surgery and the procedure can be completed in 1-2 minutes. Mice spontaneously recover the righting reflex and show no evidence of seizures, paralysis or impaired behavior. Skull fractures and intracranial bleeding are very rare. Minor deficits in motor coordination and locomotor hyperactivity recover over time. Histological analyses reveal mild astrocytic reactivity (increased expression of GFAP) and increased phospho-tau but a lack of blood-brain-barrier disruption, edema and microglial activation. This new animal model is simple and cost-effective and will facilitate characterization of the neurobiological and behavioral consequences of rmTBI. It is also ideal for high throughput screening of potential new therapies for mild concussive injuries as experienced by athletes and military personnel.

Research paper thumbnail of Dissociation between hypothermia and neurotoxicity caused by mephedrone and methcathinone in TPH2 knockout mice

Research paper thumbnail of Abuse potential and toxicity of the synthetic cathinones (i.e., “Bath salts”)

Neuroscience & Biobehavioral Reviews

Research paper thumbnail of Assessing the role of dopamine in the differential neurotoxicity patterns of methamphetamine, mephedrone, methcathinone and 4-methylmethamphetamine

Research paper thumbnail of Neuronal serotonin in the regulation of maternal behavior in rodents

Neurotransmitter (Houston, Tex.)

Maternal behavior is probably the most important pro-social behavior in female mammals, ensuring ... more Maternal behavior is probably the most important pro-social behavior in female mammals, ensuring both the development and survival of her offspring. Signals driving maternal behaviors are complex and involve several brain areas, most of which are innervated by serotonin. Serotonin transmission influences maternal processes indirectly through release of maternally-relevant hormones such as prolactin, oxytocin and vasopressin, but it can also have more direct effects on survival and the growth rate of offspring, as well as on maternal care, aggression and pup killing. This article aims to examine the basics of the components of maternal behaviors in rodents and the neural systems underpinning these maternal responses with special emphasis on the role of neural serotonin in the regulation of these behaviors.

Research paper thumbnail of Dissecting the influence of two structural substituents on the differential neurotoxic effects of methamphetamine and mephedrone on dopamine nerve endings with the use of 4-methylmethamphetamine and methcathinone

The Journal of pharmacology and experimental therapeutics, Jan 30, 2016

Mephedrone (MEPH) is a β-ketoamphetamine stimulant drug of abuse that is often a constituent of i... more Mephedrone (MEPH) is a β-ketoamphetamine stimulant drug of abuse that is often a constituent of illicit bath salts formulations. While MEPH bears remarkable similarities to methamphetamine (METH) in terms of chemical structure, as well as its neurochemical and behavioral effects, it has been shown to have a reduced neurotoxic profile compared to METH. The addition of a β-keto moiety and a 4-methyl ring substituent to METH yields MEPH, and a loss of direct neurotoxic potential. In the present study, 2 analogs of METH, methcathinone (MeCa) and 4-methylmethamphetamine (4MM), were assessed for their effects on mouse dopamine (DA) nerve endings to determine the relative contribution of each individual moiety to the loss of direct neurotoxicity in MEPH. Both MeCa and 4MM caused significant alterations in core body temperature as well as locomotor activity and stereotypy, but 4MM was found to elicit minimal dopaminergic toxicity only at the highest dose. By contrast, MeCa caused significan...

Research paper thumbnail of Prolonged Repetitive Head Trauma Induces a Singular Chronic Traumatic Encephalopathy–Like Pathology in White Matter Despite Transient Behavioral Abnormalities

The American Journal of Pathology, 2016

Research paper thumbnail of Neurotoxicology of Synthetic Cathinone Analogs

Neuropharmacology of New Psychoactive Substances (NPS), 2016

The present review briefly explores the neurotoxic properties of methcathinone, mephedrone, methy... more The present review briefly explores the neurotoxic properties of methcathinone, mephedrone, methylone, and methylenedioxypyrovalerone (MDPV), four synthetic cathinones most commonly found in "bath salts." Cathinones are β-keto analogs of the commonly abused amphetamines and display pharmacological effects resembling cocaine and amphetamines, but despite their commonalities in chemical structures, synthetic cathinones possess distinct neuropharmacological profiles and produce unique effects. Among the similarities of synthetic cathinones with their non-keto analogs are their targeting of monoamine systems, the release of neurotransmitters, and their stimulant properties. Most of the literature on synthetic cathinones has focused on describing their properties as psychostimulants, their behavioral effects on locomotion, memory, and potential for abuse, whereas descriptions of their neurotoxic properties are not abundant. The biochemical gauges of neurotoxicity induced by non-keto analogs are well studied in humans and experimental animals and include their ability to induce neuroinflammation, oxidative stress, excitotoxicity, temperature alterations as well as dysregulation of neurotransmitter systems and induce changes in monoamine transporters and receptors. These neurotoxicity gauges will serve as parameters to discuss the effects of the four previously mentioned synthetic cathinones alone or in combination with either another cathinone or with some of their non-keto analogs. Bath salts are not a defined combination of drugs and may consist of one synthetic cathinone compound or combinations of more cathinones. Furthermore, this review also presents some of the mechanisms that are thought to underlie this toxicity. A better understanding of the cellular and molecular mechanisms involved in the synthetic cathinones-induced neurotoxicity should contribute to generate modern therapeutic approaches to prevent or attenuate the adverse consequences of use of these drugs in humans.

Research paper thumbnail of Repeated mild traumatic brain injury causes focal response in lateral septum and hippocampus

Concussion, 2016

Aim: To advance our understanding of regional and temporal cellular responses to repeated mild tr... more Aim: To advance our understanding of regional and temporal cellular responses to repeated mild traumatic brain injury (rmTBI), we used a mouse model of rmTBI that incorporated acceleration, deceleration and rotational forces. Materials & methods: A modified weight-drop method was used to compare two inter-injury intervals, rmTBI-short (five hits delivered over 3 days) and rmTBI-long (five hits delivered over 15 days). Regional investigations of forebrain and midbrain histological alterations were performed at three post-injury time points (immediate, 2 weeks and 6 weeks). Results: The rmTBI-short protocol generated an immediate, localized microglial and astroglial response in the dorsolateral septum and hippocampus, with the astroglial response persisting in the dorsolateral septum. The rmTBI-long protocol showed only a transitory astroglial response in the dorsolateral septum. Conclusion: Our results indicate that the lateral septum and hippocampus are particularly vulnerable regio...

Research paper thumbnail of Acciones protectoras de los estrógenos en el sistema nervioso central

En el cerebro de los mamíferos, los estrógenos juegan un papel crucial en varias funciones no rep... more En el cerebro de los mamíferos, los estrógenos juegan un papel crucial en varias funciones no reproductivas, tales como la modulación de la excitabilidad neuronal, plasticidad sináptica, inducción de la sobrevivencia neuronal, expresión de respuestas regenerativas, neurogénesis regional en el adulto, regulación de la diferenciación y desarrollo neuronal. Además se ha demostrado su participación en otras funciones del sistema nervioso central (SNC), entre las cuales se encuentran el control de la actividad neuronal relacionada con los procesos de cognición, la modulación del estado de ánimo y otros estados mentales, así como el mejoramiento del aprendizaje y la memoria. Las acciones de los estrógenos incluyen diferentes mecanismos: tales como efectos genómicos clásicos asociados a receptores de estrógenos (ER); efectos no genómicos, que involucran sistemas de segundos mensajeros y vías de proteínas cinasas; y efectos antioxidantes independientes de receptor. 1 Efectos genómicos: Las ...

Research paper thumbnail of The sleep-wake cycle and motor activity, but not temperature, are disrupted over the light-dark cycle in mice genetically depleted of serotonin

AJP: Regulatory, Integrative and Comparative Physiology, 2014

We examined the role that serotonin has in the modulation of sleep and wakefulness across a 12-h:... more We examined the role that serotonin has in the modulation of sleep and wakefulness across a 12-h:12-h light-dark cycle and determined whether temperature and motor activity are directly responsible for potential disruptions to arousal state. Telemetry transmitters were implanted in 24 wild-type mice (Tph2+/+) and 24 mice with a null mutation for tryptophan hydroxylase 2 (Tph2−/−). After surgery, electroencephalography, core body temperature, and motor activity were recorded for 24 h. Temperature for a given arousal state (quiet and active wake, non-rapid eye movement, and paradoxical sleep) was similar in the Tph2+/+ and Tph2−/− mice across the light-dark cycle. The percentage of time spent in active wakefulness, along with motor activity, was decreased in the Tph2+/+ compared with the Tph2−/− mice at the start and end of the dark cycle. This difference persisted into the light cycle. In contrast, the time spent in a given arousal state was similar at the remaining time points. Desp...

Research paper thumbnail of Mice Genetically Depleted of Brain Serotonin Do Not Display a Depression-like Behavioral Phenotype

ACS Chemical Neuroscience, 2014

Reductions in function within the serotonin (5HT) neuronal system have long been proposed as etio... more Reductions in function within the serotonin (5HT) neuronal system have long been proposed as etiological factors in depression. Selective serotonin reuptake inhibitors (SSRIs) are the most common treatment for depression, and their therapeutic effect is generally attributed to their ability to increase the synaptic levels of 5HT. Tryptophan hydroxylase 2 (TPH2) is the initial and rate-limiting enzyme in the biosynthetic pathway of 5HT in the CNS, and losses in its catalytic activity lead to reductions in 5HT production and release. The time differential between the onset of 5HT reuptake inhibition by SSRIs (minutes) and onset of their antidepressant efficacy (weeks to months), when considered with their overall poor therapeutic effectiveness, has cast some doubt on the role of 5HT in depression. Mice lacking the gene for TPH2 are genetically depleted of brain 5HT and were tested for a depression-like behavioral phenotype using a battery of valid tests for affective-like disorders in animals. The behavior of TPH2(-/-) mice on the sucrose preference test, tail suspension test, and forced swim test and their responses in the unpredictable chronic mild stress and learned helplessness paradigms was the same as wild-type controls. While TPH2(-/-) mice as a group were not responsive to SSRIs, a subset responded to treatment with SSRIs in the same manner as wild-type controls with significant reductions in immobility time on the tail suspension test, indicative of antidepressant drug effects. The behavioral phenotype of the TPH2(-/-) mouse questions the role of 5HT in depression. Furthermore, the TPH2(-/-) mouse may serve as a useful model in the search for new medications that have therapeutic targets for depression that are outside of the 5HT neuronal system.

Research paper thumbnail of A Novel Model of Mild Traumatic Brain Injury for Juvenile Rats

Journal of Visualized Experiments, 2014

Despite growing evidence that childhood represents a major risk period for mild traumatic brain i... more Despite growing evidence that childhood represents a major risk period for mild traumatic brain injury (mTBI) from sports-related concussions, motor vehicle accidents, and falls, a reliable animal model of mTBI had previously not been developed for this important aspect of development. The modified weight-drop technique employs a glancing impact to the head of a freely moving rodent transmitting acceleration, deceleration, and rotational forces upon the brain. When applied to juvenile rats, this modified weight-drop technique induced clinically relevant behavioural outcomes that were representative of post-concussion symptomology. The technique is a rapidly applied procedure with an extremely low mortality rate, rendering it ideal for high-throughput studies of therapeutics. In addition, because the procedure involves a mild injury to a closed head, it can easily be used for studies of repetitive brain injury. Owing to the simplistic nature of this technique, and the clinically relevant biomechanics of the injury pathophysiology, the modified weight-drop technique provides researchers with a reliable model of mTBI that can be used in a wide variety of behavioural, molecular, and genetic studies.

Research paper thumbnail of Soman increases neuronal COX-2 levels: Possible link between seizures and protracted neuronal damage

NeuroToxicology, 2010

Nerve agent-induced seizures cause neuronal damage in brain limbic and cortical circuits leading ... more Nerve agent-induced seizures cause neuronal damage in brain limbic and cortical circuits leading to persistent behavioral and cognitive deficits. Without aggressive anticholinergic and benzodiazepine therapy, seizures can be prolonged and neuronal damage progresses for extended periods of time. The objective of this study was to determine the effects of the nerve agent soman on expression of cyclooxygenase-2 (COX-2), the initial enzyme in the biosynthetic pathway of the proinflammatory prostaglandins and a factor that has been implicated in seizure initiation and propagation. Rats were exposed to a toxic dose of soman and scored behaviorally for seizure intensity. Expression of COX-2 was determined throughout brain from 4 hr to 7 days after exposure by immunohistochemistry and immunoblotting. Microglial activation and astrogliosis were assessed microscopically over the same time-course. Soman increased COX-2 expression in brain regions known to be damaged by nerve agents (e.g., hippocampus, amygdala, piriform cortex and thalamus). COX-2 expression was induced in neurons, and not in microglia or astrocytes, and remained elevated through 7 days. The magnitude of COX-2 induction was correlated with seizure intensity. COX-1 expression was not changed by soman. Increased expression of neuronal COX-2 by soman is a late-developing response relative to other signs of acute physiological distress caused by nerve agents. COX-2-mediated production of prostaglandins is a consequence of the seizure-induced neuronal damage, even after survival of the

Research paper thumbnail of Estrogen counteracts ozone-induced oxidative stress and nigral neuronal death

NeuroReport, 2006

Oxidative stress is implicated in the premature death of dopamine neurons in substantia nigra in ... more Oxidative stress is implicated in the premature death of dopamine neurons in substantia nigra in Parkinson's disease. The incidence of Parkinson's disease is higher in men than in women, and estrogen may provide neuroprotection against oxidative damage. We examined the protective effects of estrogen on rat nigral death after chronic ozone inhalation. Ozone inhalation produced impaired nigral cell morphology and loss of dopamine neurons in ovariectomized rats. This was counteracted after 60 days of 17beta-estradiol treatment, when blood levels were highest. These results indicate that ozone exposure may be a useful Parkinson's disease model and neuroprotection afforded by 17beta-estradiol is dependent on the high levels achieved after its prolonged administration.

Research paper thumbnail of Animal models of sports-related head injury: bridging the gap between pre-clinical research and clinical reality

Journal of Neurochemistry, 2014

Sports-related head impact and injury has become a very highly contentious public health and medi... more Sports-related head impact and injury has become a very highly contentious public health and medico-legal issue. Near-daily news accounts describe the travails of concussed athletes as they struggle with depression, sleep disorders, mood swings, and cognitive problems. Some of these individuals have developed chronic traumatic encephalopathy, a progressive and debilitating neurodegenerative disorder. Animal models have always been an integral part of the study of traumatic brain injury in humans but, historically, they have concentrated on acute, severe brain injuries. This review will describe a small number of new and emerging animal models of sports-related head injury that have the potential to increase our understanding of how multiple mild head impacts, starting in adolescence, can have serious psychiatric, cognitive and histopathological outcomes much later in life. Sports-related head injury (SRHI) has emerged as a significant public health issue as athletes can develop psychiatric and neurodegenerative disorders later in life. Animal models have always been an integral part of the study of human TBI but few existing methods are valid for studying SRHI. In this review, we propose criteria for effective animal models of SRHI. Movement of the head upon impact is judged to be of primary importance in leading to concussion and persistent CNS dysfunction.

Research paper thumbnail of Genetic depletion of brain 5HT reveals a common molecular pathway mediating compulsivity and impulsivity

Journal of Neurochemistry, 2012

Neuropsychiatric disorders characterized by behavioral disinhibition, including disorders of comp... more Neuropsychiatric disorders characterized by behavioral disinhibition, including disorders of compulsivity (e.g. obsessive-compulsive disorder; OCD) and impulse-control (e.g. impulsive aggression), are severe, highly prevalent and chronically disabling. Treatment options for these diseases are extremely limited. The pathophysiological bases of disorders of behavioral disinhibition are poorly understood but it has been suggested that serotonin dysfunction may play a role. Mice lacking the gene encoding brain tryptophan hydroxylase 2 (Tph2-/-), the initial and rate-limiting enzyme in the synthesis of serotonin, were tested in numerous behavioral assays that are well known for their utility in modeling human neuropsychiatric diseases. Mice lacking Tph2 (and brain 5HT) show intense compulsive and impulsive behaviors to include extreme aggression. The impulsivity is motor in form and not cognitive because Tph2-/- mice show normal acquisition and reversal learning on a spatial learning task. Restoration of 5HT levels by treatment of Tph2-/- mice with its immediate precursor 5-hydroxytryptophan attenuated compulsive and impulsive-aggressive behaviors. Surprisingly, in Tph2-/- mice, the lack of 5HT was not associated with anxiety-like behaviors. The results indicate that 5HT mediates behavioral disinhibition in the mammalian brain independent of anxiogenesis.

Research paper thumbnail of Effects of Testosterone and Growth Hormone on Long-Term Retention and Extinction of a Passive Avoidance Response in Young and Aged Rats

International Journal of Neuroscience, 2007

Wistar rats were divided into two blocks: young and aged. Each block was then randomly divided in... more Wistar rats were divided into two blocks: young and aged. Each block was then randomly divided into the following groups: (1) Control (saline solution), (2) Growth Hormone (GH), (3) Testosterone enanthate, and (4) GH plus testosterone enanthate. Animals were trained on a one-trial passive avoidance conditioning and tested for retention 24 h after training and thereafter twice a week until the extinction response occurred. Results showed that GH, testosterone, and GH plus testosterone improved long-term memory in young rats. Both GH and testosterone delayed the extinction process in young and aged rats. The GH-testosterone interaction delayed the extinction only in young rats.

Research paper thumbnail of Effect of Growth Hormone on Cyclooxygenase-2 Expression in the Hippocampus of Rats Chronically Exposed to Ozone

International Journal of Neuroscience, 2008

The aim of this study was to determine GH-effects on Cyclooxygenase-2 (COX-2) expression on hippo... more The aim of this study was to determine GH-effects on Cyclooxygenase-2 (COX-2) expression on hippocampus alterations caused by ozone exposure. Seventy male rats were divided into: (1) control; (2) exposed to ozone for 7, 15, and 30 days; (3) exposed to ozone and treated with GH, for 7, 15, and 30 days. Results showed that lipoperoxidation levels and number of COX-2-positive cells increased in all groups exposed to ozone compared to control. In the groups treated with GH, COX-2 immunoreactive cell number decreased with respect to the ozone group. Therefore, GH could provide protection against damage induced by oxidative stress.

Research paper thumbnail of Oxidative damage in substantia nigra and striatum of rats chronically exposed to ozone

Journal of Chemical Neuroanatomy, 2006

The purpose of this work was to study if chronic low-dose ozone exposure could per se induce oxid... more The purpose of this work was to study if chronic low-dose ozone exposure could per se induce oxidative damage to neurons of striatum and substantia nigra. Thirty male Wistar rats were divided into three groups-Group 1: exposed to an air stream free of ozone; Group 2: exposed for 15 days to ozone; Group 3: exposed for 30 days to ozone. Ozone exposure was carried out daily for 4 h at a 0.25 ppm dose. Each group was then tested for (1) motor activity, (2) quantification of lipid peroxidation levels, (3) Klüver-Barrera staining, and (4) immunohistochemistry for tyrosine hydroxylase (TH), dopamine and adenosine 3 0 ,5 0-monophosphate-regulated phosphoprotein of 32kD (DARPP-32), inducible nitric oxide synthase (iNOS), and superoxide dismutase (SOD), to study neuronal alterations in striatum and substantia nigra. Results indicate that ozone exposure causes a significant decrease in motor activity. Ozone produced lipid peroxidation, morphological alterations, loss of fibers and cell death of the dopaminergic neurons. The DARPP-32, iNOS and SOD expression increased with repetitive ozone exposure. These alterations suggest that ozone causes oxidative stress which induces oxidative damage to substantia nigra and striatum of the rat.

Research paper thumbnail of A mouse model of human repetitive mild traumatic brain injury

Journal of Neuroscience Methods, 2012

A novel method for the study of repetitive mild traumatic brain injury (rmTBI) that models the mo... more A novel method for the study of repetitive mild traumatic brain injury (rmTBI) that models the most common form of head injury in humans is presented. Existing animal models of TBI impart focal, severe damage unlike that seen in repeated and mild concussive injuries, and few are configured for repetitive application. Our model is a modification of the Marmarou weight drop method and allows repeated head impacts to lightly anesthetized mice. A key facet of this method is the delivery of an impact to the cranium of an unrestrained subject allowing rapid acceleration of the free-moving head and torso, an essential characteristic known to be important for concussive injury in humans, and a factor that is missing from existing animal models of TBI. Our method does not require scalp incision, emplacement of protective skull helmets or surgery and the procedure can be completed in 1-2 minutes. Mice spontaneously recover the righting reflex and show no evidence of seizures, paralysis or impaired behavior. Skull fractures and intracranial bleeding are very rare. Minor deficits in motor coordination and locomotor hyperactivity recover over time. Histological analyses reveal mild astrocytic reactivity (increased expression of GFAP) and increased phospho-tau but a lack of blood-brain-barrier disruption, edema and microglial activation. This new animal model is simple and cost-effective and will facilitate characterization of the neurobiological and behavioral consequences of rmTBI. It is also ideal for high throughput screening of potential new therapies for mild concussive injuries as experienced by athletes and military personnel.

Research paper thumbnail of Dissociation between hypothermia and neurotoxicity caused by mephedrone and methcathinone in TPH2 knockout mice

Research paper thumbnail of Abuse potential and toxicity of the synthetic cathinones (i.e., “Bath salts”)

Neuroscience & Biobehavioral Reviews

Research paper thumbnail of Assessing the role of dopamine in the differential neurotoxicity patterns of methamphetamine, mephedrone, methcathinone and 4-methylmethamphetamine

Research paper thumbnail of Neuronal serotonin in the regulation of maternal behavior in rodents

Neurotransmitter (Houston, Tex.)

Maternal behavior is probably the most important pro-social behavior in female mammals, ensuring ... more Maternal behavior is probably the most important pro-social behavior in female mammals, ensuring both the development and survival of her offspring. Signals driving maternal behaviors are complex and involve several brain areas, most of which are innervated by serotonin. Serotonin transmission influences maternal processes indirectly through release of maternally-relevant hormones such as prolactin, oxytocin and vasopressin, but it can also have more direct effects on survival and the growth rate of offspring, as well as on maternal care, aggression and pup killing. This article aims to examine the basics of the components of maternal behaviors in rodents and the neural systems underpinning these maternal responses with special emphasis on the role of neural serotonin in the regulation of these behaviors.

Research paper thumbnail of Dissecting the influence of two structural substituents on the differential neurotoxic effects of methamphetamine and mephedrone on dopamine nerve endings with the use of 4-methylmethamphetamine and methcathinone

The Journal of pharmacology and experimental therapeutics, Jan 30, 2016

Mephedrone (MEPH) is a β-ketoamphetamine stimulant drug of abuse that is often a constituent of i... more Mephedrone (MEPH) is a β-ketoamphetamine stimulant drug of abuse that is often a constituent of illicit bath salts formulations. While MEPH bears remarkable similarities to methamphetamine (METH) in terms of chemical structure, as well as its neurochemical and behavioral effects, it has been shown to have a reduced neurotoxic profile compared to METH. The addition of a β-keto moiety and a 4-methyl ring substituent to METH yields MEPH, and a loss of direct neurotoxic potential. In the present study, 2 analogs of METH, methcathinone (MeCa) and 4-methylmethamphetamine (4MM), were assessed for their effects on mouse dopamine (DA) nerve endings to determine the relative contribution of each individual moiety to the loss of direct neurotoxicity in MEPH. Both MeCa and 4MM caused significant alterations in core body temperature as well as locomotor activity and stereotypy, but 4MM was found to elicit minimal dopaminergic toxicity only at the highest dose. By contrast, MeCa caused significan...

Research paper thumbnail of Prolonged Repetitive Head Trauma Induces a Singular Chronic Traumatic Encephalopathy–Like Pathology in White Matter Despite Transient Behavioral Abnormalities

The American Journal of Pathology, 2016

Research paper thumbnail of Neurotoxicology of Synthetic Cathinone Analogs

Neuropharmacology of New Psychoactive Substances (NPS), 2016

The present review briefly explores the neurotoxic properties of methcathinone, mephedrone, methy... more The present review briefly explores the neurotoxic properties of methcathinone, mephedrone, methylone, and methylenedioxypyrovalerone (MDPV), four synthetic cathinones most commonly found in "bath salts." Cathinones are β-keto analogs of the commonly abused amphetamines and display pharmacological effects resembling cocaine and amphetamines, but despite their commonalities in chemical structures, synthetic cathinones possess distinct neuropharmacological profiles and produce unique effects. Among the similarities of synthetic cathinones with their non-keto analogs are their targeting of monoamine systems, the release of neurotransmitters, and their stimulant properties. Most of the literature on synthetic cathinones has focused on describing their properties as psychostimulants, their behavioral effects on locomotion, memory, and potential for abuse, whereas descriptions of their neurotoxic properties are not abundant. The biochemical gauges of neurotoxicity induced by non-keto analogs are well studied in humans and experimental animals and include their ability to induce neuroinflammation, oxidative stress, excitotoxicity, temperature alterations as well as dysregulation of neurotransmitter systems and induce changes in monoamine transporters and receptors. These neurotoxicity gauges will serve as parameters to discuss the effects of the four previously mentioned synthetic cathinones alone or in combination with either another cathinone or with some of their non-keto analogs. Bath salts are not a defined combination of drugs and may consist of one synthetic cathinone compound or combinations of more cathinones. Furthermore, this review also presents some of the mechanisms that are thought to underlie this toxicity. A better understanding of the cellular and molecular mechanisms involved in the synthetic cathinones-induced neurotoxicity should contribute to generate modern therapeutic approaches to prevent or attenuate the adverse consequences of use of these drugs in humans.

Research paper thumbnail of Repeated mild traumatic brain injury causes focal response in lateral septum and hippocampus

Concussion, 2016

Aim: To advance our understanding of regional and temporal cellular responses to repeated mild tr... more Aim: To advance our understanding of regional and temporal cellular responses to repeated mild traumatic brain injury (rmTBI), we used a mouse model of rmTBI that incorporated acceleration, deceleration and rotational forces. Materials & methods: A modified weight-drop method was used to compare two inter-injury intervals, rmTBI-short (five hits delivered over 3 days) and rmTBI-long (five hits delivered over 15 days). Regional investigations of forebrain and midbrain histological alterations were performed at three post-injury time points (immediate, 2 weeks and 6 weeks). Results: The rmTBI-short protocol generated an immediate, localized microglial and astroglial response in the dorsolateral septum and hippocampus, with the astroglial response persisting in the dorsolateral septum. The rmTBI-long protocol showed only a transitory astroglial response in the dorsolateral septum. Conclusion: Our results indicate that the lateral septum and hippocampus are particularly vulnerable regio...

Research paper thumbnail of Acciones protectoras de los estrógenos en el sistema nervioso central

En el cerebro de los mamíferos, los estrógenos juegan un papel crucial en varias funciones no rep... more En el cerebro de los mamíferos, los estrógenos juegan un papel crucial en varias funciones no reproductivas, tales como la modulación de la excitabilidad neuronal, plasticidad sináptica, inducción de la sobrevivencia neuronal, expresión de respuestas regenerativas, neurogénesis regional en el adulto, regulación de la diferenciación y desarrollo neuronal. Además se ha demostrado su participación en otras funciones del sistema nervioso central (SNC), entre las cuales se encuentran el control de la actividad neuronal relacionada con los procesos de cognición, la modulación del estado de ánimo y otros estados mentales, así como el mejoramiento del aprendizaje y la memoria. Las acciones de los estrógenos incluyen diferentes mecanismos: tales como efectos genómicos clásicos asociados a receptores de estrógenos (ER); efectos no genómicos, que involucran sistemas de segundos mensajeros y vías de proteínas cinasas; y efectos antioxidantes independientes de receptor. 1 Efectos genómicos: Las ...

Research paper thumbnail of The sleep-wake cycle and motor activity, but not temperature, are disrupted over the light-dark cycle in mice genetically depleted of serotonin

AJP: Regulatory, Integrative and Comparative Physiology, 2014

We examined the role that serotonin has in the modulation of sleep and wakefulness across a 12-h:... more We examined the role that serotonin has in the modulation of sleep and wakefulness across a 12-h:12-h light-dark cycle and determined whether temperature and motor activity are directly responsible for potential disruptions to arousal state. Telemetry transmitters were implanted in 24 wild-type mice (Tph2+/+) and 24 mice with a null mutation for tryptophan hydroxylase 2 (Tph2−/−). After surgery, electroencephalography, core body temperature, and motor activity were recorded for 24 h. Temperature for a given arousal state (quiet and active wake, non-rapid eye movement, and paradoxical sleep) was similar in the Tph2+/+ and Tph2−/− mice across the light-dark cycle. The percentage of time spent in active wakefulness, along with motor activity, was decreased in the Tph2+/+ compared with the Tph2−/− mice at the start and end of the dark cycle. This difference persisted into the light cycle. In contrast, the time spent in a given arousal state was similar at the remaining time points. Desp...

Research paper thumbnail of Mice Genetically Depleted of Brain Serotonin Do Not Display a Depression-like Behavioral Phenotype

ACS Chemical Neuroscience, 2014

Reductions in function within the serotonin (5HT) neuronal system have long been proposed as etio... more Reductions in function within the serotonin (5HT) neuronal system have long been proposed as etiological factors in depression. Selective serotonin reuptake inhibitors (SSRIs) are the most common treatment for depression, and their therapeutic effect is generally attributed to their ability to increase the synaptic levels of 5HT. Tryptophan hydroxylase 2 (TPH2) is the initial and rate-limiting enzyme in the biosynthetic pathway of 5HT in the CNS, and losses in its catalytic activity lead to reductions in 5HT production and release. The time differential between the onset of 5HT reuptake inhibition by SSRIs (minutes) and onset of their antidepressant efficacy (weeks to months), when considered with their overall poor therapeutic effectiveness, has cast some doubt on the role of 5HT in depression. Mice lacking the gene for TPH2 are genetically depleted of brain 5HT and were tested for a depression-like behavioral phenotype using a battery of valid tests for affective-like disorders in animals. The behavior of TPH2(-/-) mice on the sucrose preference test, tail suspension test, and forced swim test and their responses in the unpredictable chronic mild stress and learned helplessness paradigms was the same as wild-type controls. While TPH2(-/-) mice as a group were not responsive to SSRIs, a subset responded to treatment with SSRIs in the same manner as wild-type controls with significant reductions in immobility time on the tail suspension test, indicative of antidepressant drug effects. The behavioral phenotype of the TPH2(-/-) mouse questions the role of 5HT in depression. Furthermore, the TPH2(-/-) mouse may serve as a useful model in the search for new medications that have therapeutic targets for depression that are outside of the 5HT neuronal system.

Research paper thumbnail of A Novel Model of Mild Traumatic Brain Injury for Juvenile Rats

Journal of Visualized Experiments, 2014

Despite growing evidence that childhood represents a major risk period for mild traumatic brain i... more Despite growing evidence that childhood represents a major risk period for mild traumatic brain injury (mTBI) from sports-related concussions, motor vehicle accidents, and falls, a reliable animal model of mTBI had previously not been developed for this important aspect of development. The modified weight-drop technique employs a glancing impact to the head of a freely moving rodent transmitting acceleration, deceleration, and rotational forces upon the brain. When applied to juvenile rats, this modified weight-drop technique induced clinically relevant behavioural outcomes that were representative of post-concussion symptomology. The technique is a rapidly applied procedure with an extremely low mortality rate, rendering it ideal for high-throughput studies of therapeutics. In addition, because the procedure involves a mild injury to a closed head, it can easily be used for studies of repetitive brain injury. Owing to the simplistic nature of this technique, and the clinically relevant biomechanics of the injury pathophysiology, the modified weight-drop technique provides researchers with a reliable model of mTBI that can be used in a wide variety of behavioural, molecular, and genetic studies.

Research paper thumbnail of Soman increases neuronal COX-2 levels: Possible link between seizures and protracted neuronal damage

NeuroToxicology, 2010

Nerve agent-induced seizures cause neuronal damage in brain limbic and cortical circuits leading ... more Nerve agent-induced seizures cause neuronal damage in brain limbic and cortical circuits leading to persistent behavioral and cognitive deficits. Without aggressive anticholinergic and benzodiazepine therapy, seizures can be prolonged and neuronal damage progresses for extended periods of time. The objective of this study was to determine the effects of the nerve agent soman on expression of cyclooxygenase-2 (COX-2), the initial enzyme in the biosynthetic pathway of the proinflammatory prostaglandins and a factor that has been implicated in seizure initiation and propagation. Rats were exposed to a toxic dose of soman and scored behaviorally for seizure intensity. Expression of COX-2 was determined throughout brain from 4 hr to 7 days after exposure by immunohistochemistry and immunoblotting. Microglial activation and astrogliosis were assessed microscopically over the same time-course. Soman increased COX-2 expression in brain regions known to be damaged by nerve agents (e.g., hippocampus, amygdala, piriform cortex and thalamus). COX-2 expression was induced in neurons, and not in microglia or astrocytes, and remained elevated through 7 days. The magnitude of COX-2 induction was correlated with seizure intensity. COX-1 expression was not changed by soman. Increased expression of neuronal COX-2 by soman is a late-developing response relative to other signs of acute physiological distress caused by nerve agents. COX-2-mediated production of prostaglandins is a consequence of the seizure-induced neuronal damage, even after survival of the

Research paper thumbnail of Estrogen counteracts ozone-induced oxidative stress and nigral neuronal death

NeuroReport, 2006

Oxidative stress is implicated in the premature death of dopamine neurons in substantia nigra in ... more Oxidative stress is implicated in the premature death of dopamine neurons in substantia nigra in Parkinson's disease. The incidence of Parkinson's disease is higher in men than in women, and estrogen may provide neuroprotection against oxidative damage. We examined the protective effects of estrogen on rat nigral death after chronic ozone inhalation. Ozone inhalation produced impaired nigral cell morphology and loss of dopamine neurons in ovariectomized rats. This was counteracted after 60 days of 17beta-estradiol treatment, when blood levels were highest. These results indicate that ozone exposure may be a useful Parkinson's disease model and neuroprotection afforded by 17beta-estradiol is dependent on the high levels achieved after its prolonged administration.

Research paper thumbnail of Animal models of sports-related head injury: bridging the gap between pre-clinical research and clinical reality

Journal of Neurochemistry, 2014

Sports-related head impact and injury has become a very highly contentious public health and medi... more Sports-related head impact and injury has become a very highly contentious public health and medico-legal issue. Near-daily news accounts describe the travails of concussed athletes as they struggle with depression, sleep disorders, mood swings, and cognitive problems. Some of these individuals have developed chronic traumatic encephalopathy, a progressive and debilitating neurodegenerative disorder. Animal models have always been an integral part of the study of traumatic brain injury in humans but, historically, they have concentrated on acute, severe brain injuries. This review will describe a small number of new and emerging animal models of sports-related head injury that have the potential to increase our understanding of how multiple mild head impacts, starting in adolescence, can have serious psychiatric, cognitive and histopathological outcomes much later in life. Sports-related head injury (SRHI) has emerged as a significant public health issue as athletes can develop psychiatric and neurodegenerative disorders later in life. Animal models have always been an integral part of the study of human TBI but few existing methods are valid for studying SRHI. In this review, we propose criteria for effective animal models of SRHI. Movement of the head upon impact is judged to be of primary importance in leading to concussion and persistent CNS dysfunction.

Research paper thumbnail of Genetic depletion of brain 5HT reveals a common molecular pathway mediating compulsivity and impulsivity

Journal of Neurochemistry, 2012

Neuropsychiatric disorders characterized by behavioral disinhibition, including disorders of comp... more Neuropsychiatric disorders characterized by behavioral disinhibition, including disorders of compulsivity (e.g. obsessive-compulsive disorder; OCD) and impulse-control (e.g. impulsive aggression), are severe, highly prevalent and chronically disabling. Treatment options for these diseases are extremely limited. The pathophysiological bases of disorders of behavioral disinhibition are poorly understood but it has been suggested that serotonin dysfunction may play a role. Mice lacking the gene encoding brain tryptophan hydroxylase 2 (Tph2-/-), the initial and rate-limiting enzyme in the synthesis of serotonin, were tested in numerous behavioral assays that are well known for their utility in modeling human neuropsychiatric diseases. Mice lacking Tph2 (and brain 5HT) show intense compulsive and impulsive behaviors to include extreme aggression. The impulsivity is motor in form and not cognitive because Tph2-/- mice show normal acquisition and reversal learning on a spatial learning task. Restoration of 5HT levels by treatment of Tph2-/- mice with its immediate precursor 5-hydroxytryptophan attenuated compulsive and impulsive-aggressive behaviors. Surprisingly, in Tph2-/- mice, the lack of 5HT was not associated with anxiety-like behaviors. The results indicate that 5HT mediates behavioral disinhibition in the mammalian brain independent of anxiogenesis.