RESUMEN
Anxiety is an emotional state that affects the quality of human life. Several neurotransmitters are involved in the regulation of anxiety, including glutamate. The major actions of glutamate are mediated by N-methyl-d-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). The present study performed a behavioral and neurochemical analysis of Carioca High-conditioned Freezing (CHF) and Carioca Low-conditioned Freezing (CLF) rats compared with control rats. We evaluated thermal nociception, anxiety-like behavior, depressive-like behavior, spatial memory, habituation memory, and the content and localization of different glutamatergic receptor subunits and postsynaptic density-95 (PSD-95), a postsynaptic protein. The CHF group exhibited an anxious-like phenotype, impairments in habituation and spatial memory, and a depressive-like phenotype compared with the control group. In the ventral hippocampus, an increase in the PSD-95, GluN1 and GluA1 subunits and a decrease in the GluN2A subunit of glutamatergic receptors. The CLF group exhibited a less anxious-like phenotype, hyperlocomotion and habituation impairments. Also, CLF animals, presented, in the ventral hippocampus, an increase in the PSD-95, GluN1 and GluA2 subunits and a decrease in the GluN2B subunit. These results suggest that the differential composition of NMDAR and AMPAR subunits may be related to the modulation of different phenotypes in CHF and CLF rats, which may help identify new targets for therapeutic interventions for anxiety disorders and other comorbidities.
Asunto(s)
Hipocampo , Receptores de N-Metil-D-Aspartato , Animales , Ansiedad , Ácido Glutámico , Hipocampo/metabolismo , Ratas , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Memoria Espacial , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol PropiónicoRESUMEN
Attention deficit and hyperactivity disorder (ADHD) is characterized by impaired levels of hyperactivity, impulsivity, and inattention. Adenosine and endocannabinoid systems tightly interact in the modulation of dopamine signaling, involved in the neurobiology of ADHD. In this study, we evaluated the modulating effects of the cannabinoid and adenosine systems in a tolerance to delay of reward task using the most widely used animal model of ADHD. Spontaneous Hypertensive Rats (SHR) and Wistar-Kyoto rats were treated chronically or acutely with caffeine, a non-selective adenosine receptor antagonist, or acutely with a cannabinoid agonist (WIN55212-2, WIN) or antagonist (AM251). Subsequently, animals were tested in the tolerance to delay of reward task, in which they had to choose between a small, but immediate, or a large, but delayed, reward. Treatment with WIN decreased, whereas treatment with AM251 increased the choices of the large reward, selectively in SHR rats, indicating a CB1 receptor-mediated increase in impulsive behavior. An acute pre-treatment with caffeine blocked WIN effects. Conversely, a chronic treatment with caffeine increased the impulsive phenotype and potentiated the WIN effects. The results indicate that both cannabinoid and adenosine receptors modulate impulsive behavior in SHR: the antagonism of cannabinoid receptors might be effective in reducing impulsive symptoms present in ADHD; in addition, caffeine showed the opposite effects on impulsive behavior depending on the length of treatment. These observations are of particular importance to consider when therapeutic manipulation of CB1 receptors is applied to ADHD patients who consume coffee.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Cafeína/farmacología , Agonistas de Receptores de Cannabinoides/farmacología , Antagonistas de Receptores de Cannabinoides/farmacología , Conducta Impulsiva/efectos de los fármacos , Psicotrópicos/farmacología , Animales , Benzoxazinas/farmacología , Modelos Animales de Enfermedad , Masculino , Morfolinas/farmacología , Naftalenos/farmacología , Piperidinas/farmacología , Antagonistas de Receptores Purinérgicos P1/farmacología , Pirazoles/farmacología , Distribución Aleatoria , Ratas Endogámicas SHR , Ratas Endogámicas WKYRESUMEN
Neonatal handling has an impact on adult behavior of experimental animals and is associated with rapid and increased palatable food ingestion, impaired behavioral flexibility, and fearless behavior to novel environments. These symptoms are characteristic features of impulsive trait, being controlled by the medial prefrontal cortex (mPFC). Impulsive behavior is a key component of many psychiatric disorders such as attention deficit hyperactivity disorder (ADHD), manic behavior, and schizophrenia. Others have reported a methylphenidate (MPH)-induced enhancement of mPFC functioning and improvements in behavioral core symptoms of ADHD patients. The aims of the present study were: (i) to find in vivo evidence for an association between neonatal handling and the development of impulsive behavior in adult Wistar rats and (ii) to test whether neonatal handling could have an impact on monoamine levels in the mPFC and the pharmacological response to MPH in vivo. Therefore, experimental animals (litters) were classified as: "non-handled" and "handled" (10[Formula: see text]min/day, postnatal days 1-10). After puberty, they were exposed to either a larger and delayed or smaller and immediate reward (tolerance to delay of reward task). Acute MPH (3[Formula: see text]mg/Kg. i.p.) was used to suppress and/or regulate impulsive behavior. Our results show that only neonatally handled male adult Wistar rats exhibit impulsive behavior with no significant differences in monoamine levels in the medial prefrontal cortex, together with a decreased response to MPH. On this basis, we postulate that early life interventions may have long-term effects on inhibitory control mechanisms and affect the later response to pharmacological agents during adulthood.
Asunto(s)
Estimulantes del Sistema Nervioso Central/farmacología , Manejo Psicológico , Conducta Impulsiva/efectos de los fármacos , Conducta Impulsiva/fisiología , Metilfenidato/farmacología , Factores de Edad , Análisis de Varianza , Animales , Animales Recién Nacidos , Monoaminas Biogénicas/metabolismo , Peso Corporal/efectos de los fármacos , Condicionamiento Operante , Modelos Animales de Enfermedad , Femenino , Masculino , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Embarazo , Ratas , Ratas Wistar , Refuerzo en Psicología , Factores Sexuales , Factores de TiempoRESUMEN
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high heterogeneity that can affect individuals of any age. It is characterized by three main symptoms: inattention, hyperactivity, and impulsivity. These neurobehavioral alterations and neurochemical and pharmacological findings are mainly attributed to unbalanced catecholaminergic signaling, especially involving dopaminergic pathways within prefrontal and striatal areas. Dopamine receptors and transporters are not solely implicated in this imbalance, as evidence indicates that the dopaminergic signaling is modulated by adenosine activity. To this extent, alterations in adenosinergic signaling are probably involved in ADHD. Here, we review the current knowledge about adenosine's role in the modulation of chemical, behavioral and cognitive parameters of ADHD, especially regarding dopaminergic signaling. Current literature usually links adenosine receptors signaling to the dopaminergic imbalance found in ADHD, but there is evidence that equilibrative nucleoside transporters (ENTs) could also be implicated as players in dopaminergic signaling alterations seen in ADHD, since their involvement in other neurobehavioral impairments.
Asunto(s)
Adenosina , Trastorno por Déficit de Atención con Hiperactividad , Proteínas de Transporte de Nucleósidos , Receptores Purinérgicos P1 , Humanos , Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Animales , Proteínas de Transporte de Nucleósidos/metabolismo , Receptores Purinérgicos P1/metabolismo , Adenosina/metabolismo , Dopamina/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiopatología , Transducción de Señal/fisiologíaRESUMEN
Abnormal cognitive and sensorial properties have been reported in patients with psychiatric and neurodevelopmental conditions, such as attention deficit hyperactivity disorder (ADHD). ADHD patients exhibit impaired dopaminergic signaling and plasticity in brain areas related to cognitive and sensory processing. The spontaneous hypertensive rat (SHR), in comparison to the Wistar Kyoto rat (WKY), is the most used genetic animal model to study ADHD. Brain neurotrophic factor (BDNF), critical for midbrain and hippocampal dopaminergic neuron survival and differentiation, is reduced in both ADHD subjects and SHR. Physical exercise (e.g. swimming) promotes neuroplasticity and improves cognition by increasing BDNF and irisin. Here we investigate the effects of gestational swimming on sensorial and behavioral phenotypes, striatal dopaminergic parameters, and hippocampal FNDC5/irisin and BDNF levels observed in WKY and SHR. Gestational swimming improved nociception in SHR rats (p = 0.006) and increased hippocampal BDNF levels (p = 0.02) in a sex-dependent manner in adolescent offspring. Sex differences were observed in hippocampal FNDC5/irisin levels (p = 0.002), with females presenting lower levels than males. Our results contribute to the notion that swimming during pregnancy is a promising alternative to improve ADHD phenotypes in the offspring.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad , Humanos , Ratas , Femenino , Masculino , Animales , Adolescente , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Fibronectinas , Nocicepción , Encéfalo/metabolismo , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Modelos Animales de EnfermedadRESUMEN
Caffeine and anabolic-androgenic steroids (AAS) are commonly used to improve muscle mass and athletic performance. Nandrolone Decanoate (ND) is one of the most abused AAS worldwide, leading to behavioral changes in both humans and rodents. Caffeine, the most widely consumed psychostimulant globally, is present in various thermogenic and gym supplements. Low and moderate doses of caffeine antagonize adenosine receptors and have been linked to improved memory and pain relief. We have previously demonstrated that consuming caffeine prevents the risk-taking behavior triggered by nandrolone. In this study, we aimed to investigate the long-term effects of ND and caffeine, either alone or in combination, on passive avoidance memory and nociception. We used the step-down and hot-plate tasks in male and female Lister Hooded rats. Our results confirmed the antinociceptive effect of caffeine and indicated that chronic administration of the ND-caffeine association promotes the evocation of aversive memory in female rats.
Asunto(s)
Reacción de Prevención , Cafeína , Memoria , Nandrolona Decanoato , Nocicepción , Animales , Cafeína/farmacología , Femenino , Masculino , Ratas , Nocicepción/efectos de los fármacos , Nandrolona Decanoato/farmacología , Memoria/efectos de los fármacos , Reacción de Prevención/efectos de los fármacos , Nandrolona/farmacología , Nandrolona/análogos & derivados , Estimulantes del Sistema Nervioso Central/farmacología , Anabolizantes/farmacologíaRESUMEN
Anabolic-androgenic steroids (AAS) and caffeine can induce several behavioral alterations in humans and rodents. Administration of nandrolone decanoate is known to affect defensive responses to aversive stimuli, generally decreasing inhibitory control and increasing aggressivity but whether caffeine intake influences behavioral changes induced by AAS is unknown. The present study aimed to investigate behavioral effects of caffeine (a non-selective antagonist of adenosine receptors) alone or combined with nandrolone decanoate (one of the most commonly AAS abused) in female and male Lister Hooded rats. Our results indicated that chronic administration of nandrolone decanoate (10 mg/kg, i.m., once a week for 8 weeks) decreased risk assessment/anxiety-like behaviors (in the elevated plus maze test), regardless of sex. These effects were prevented by combined caffeine intake (0.1 g/L, p.o., ad libitum). Overall, the present study heralds a key role for caffeine intake in the modulation of nandrolone decanoate-induced behavioral changes in rats, suggesting adenosine receptors as candidate targets to manage impact of AAS on brain function and behavior.
Asunto(s)
Anabolizantes , Esteroides Anabólicos Androgénicos , Nandrolona Decanoato , Receptores Purinérgicos P1 , Animales , Femenino , Masculino , Ratas , Anabolizantes/farmacología , Esteroides Anabólicos Androgénicos/farmacología , Ansiedad/inducido químicamente , Cafeína/farmacología , Nandrolona Decanoato/farmacología , Receptores Purinérgicos P1/metabolismoRESUMEN
Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor that has recently been implicated in several psychiatric conditions related to monoaminergic dysfunction, such as schizophrenia, substance use disorders, and mood disorders. Although attention-deficit/hyperactivity disorder (ADHD) is also related to changes in monoaminergic neurotransmission, studies that assess whether TAAR1 participates in the neurobiology of ADHD are lacking. We hypothesized that TAAR1 plays an important role in ADHD and might represent a potential therapeutic target. Here, we investigate if TAAR1 modulates behavioral phenotypes in Spontaneously Hypertensive Rats (SHR), the most validated animal model of ADHD, and Wistar Kyoto rats (WKY, used as a control strain). Our results showed that TAAR1 is downregulated in ADHD-related brain regions in SHR compared with WKY. While intracerebroventricular (i.c.v.) administration of the selective TAAR1 antagonist EPPTB impaired cognitive performance in SHR, i.c.v. administration of highly selective TAAR1 full agonist RO5256390 decreased motor hyperactivity, novelty-induced locomotion, and induced an anxiolytic-like behavior. Overall, our findings show that changes in TAAR1 levels/activity underlie behavior in SHR, suggesting that TAAR1 plays a role in the neurobiology of ADHD. Although additional confirmatory studies are required, TAAR1 might be a potential pharmacological target for individuals with this disorder.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad , Receptores Acoplados a Proteínas G , Animales , Ansiedad/tratamiento farmacológico , Trastorno por Déficit de Atención con Hiperactividad/psicología , Conducta Animal , Cognición , Modelos Animales de Enfermedad , Hipercinesia , Agitación Psicomotora , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Receptores Acoplados a Proteínas G/genéticaRESUMEN
Adolescence is a period of increased sensitivity to stress and vulnerability to the manifestation of psychiatric disorders, such as attention-deficit/hyperactivity disorder (ADHD). Nevertheless, the relationship between stress during adolescence and ADHD is still unclear. Knowing that stress can have long-term consequences, the aim of this study was to evaluate the impact of a single episode of restraint stress during adolescence on locomotion, risk behaviour and short-term memory in adult spontaneously hypertensive rats (SHR), a validated animal model of ADHD. A single episode of stress during adolescence increased risk behaviour and impaired short-term recognition memory, but did not alter locomotion in adult SHR. These findings show that stress during adolescence, even acute, may lead to long-term behavioural consequences in an animal model of ADHD.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad , Adolescente , Animales , Modelos Animales de Enfermedad , Humanos , Memoria a Corto Plazo , Ratas , Ratas Endogámicas SHR , Asunción de RiesgosRESUMEN
The hallmarks of Alzheimer's disease include the deposition of beta-amyloid (Abeta), neuroinflammation, and cognitive deficits. The accumulation of activated glial cells in cognitive-related areas is critical for these alterations, although little is known about the mechanisms driving this event. Herein we used macrophage inflammatory protein-1alpha (MIP-1alpha(-/-))- or CC-chemokine receptor 5 (CCR5(-/-))-deficient mice to address the role played by chemokines in molecular and behavioral alterations induced by Abeta(1-40). Abeta(1-40) induced a time-dependent increase of MIP-1alpha mRNA followed by accumulation of activated glial cells in the hippocampus of wild-type mice. MIP-1alpha(-/-) and CCR5(-/-) mice displayed reduced astrocytosis and microgliosis in the hippocampus after Abeta(1-40) administration that was associated with decreased expression of cyclooxygenase-2 and inducible nitric oxide synthase, as well as reduced activation of nuclear factor-kappaB, activator protein-1 and cyclic AMP response element-binding protein. Furthermore, MIP-1alpha(-/-) and CCR5(-/-) macrophages showed impaired chemotaxis in vitro, although cytokine production in response to Abeta(1-40) was unaffected. Notably, the cognitive deficits and synaptic dysfunction induced by Abeta(1-40) were also attenuated in MIP-1alpha(-/-) and CCR5(-/-) mice. Collectively, these results indicate that the MIP-1alpha/CCR5 signaling pathway is critical for the accumulation of activated glial cells in the hippocampus and, therefore, for the inflammation and cognitive failure induced by Abeta(1-40). Our data suggest MIP-1alpha and CCR5 as potential therapeutic targets for Alzheimer's disease treatment.
Asunto(s)
Péptidos beta-Amiloides/toxicidad , Quimiocina CCL3/metabolismo , Trastornos del Conocimiento/metabolismo , Inflamación/metabolismo , Sistema Nervioso/patología , Fragmentos de Péptidos/toxicidad , Receptores CCR5/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Movimiento Celular/efectos de los fármacos , Trastornos del Conocimiento/patología , Ciclooxigenasa 2/metabolismo , Eliminación de Gen , Hipocampo/efectos de los fármacos , Hipocampo/enzimología , Hipocampo/patología , Humanos , Inflamación/patología , Masculino , Memoria/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Sistema Nervioso/efectos de los fármacos , Neuroglía/efectos de los fármacos , Neuroglía/metabolismo , Neuroglía/patología , Óxido Nítrico Sintasa de Tipo II/metabolismo , Sinapsis/efectos de los fármacos , Sinapsis/patología , Factores de Transcripción/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Coronavirus disease 2019 (COVID-19) is caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The impacts of the disease may be beyond the respiratory system, also affecting mental health. Several factors may be involved in the association between COVID-19 and psychiatric outcomes, such as fear inherent in the pandemic, adverse effects of treatments, as well as financial stress, and social isolation. Herein we discuss the growing evidence suggesting that the relationship between SARS-CoV-2 and host may also trigger changes in brain and behavior. Based on the similarity of SARS-CoV-2 with other coronaviruses, it is conceivable that changes in endocrine and immune response in the periphery or in the central nervous system may be involved in the association between SARS-CoV-2 infection and impaired mental health. This is likely to be further enhanced, since millions of people worldwide are isolated in quarantine to minimize the transmission of SARS-CoV-2 and social isolation can also lead to neuroendocrine-immune changes. Accordingly, we highlight here the hypothesis that neuroendocrine-immune interactions may be involved in negative impacts of SARS-CoV-2 infection and social isolation on psychiatric issues.
Asunto(s)
Infecciones por Coronavirus/psicología , Trastornos Mentales/etiología , Salud Mental , Neumonía Viral/psicología , Encéfalo , COVID-19 , Infecciones por Coronavirus/inmunología , Enfermedades del Sistema Endocrino/virología , Humanos , Enfermedades del Sistema Nervioso/virología , Sistemas Neurosecretores , Pandemias , Neumonía Viral/inmunología , Aislamiento SocialRESUMEN
Neuropeptide S (NPS) is a recently discovered peptide signalling through its receptor NPSR, which is expressed throughout the brain. Since NPSR activation increases dopaminergic transmission, we now tested if NPSR modulates behavioural and neurochemical alterations displayed by an animal model of attention-deficit/hyperactivity disorder (ADHD), Spontaneous Hypertensive Rats (SHR), compared to its control strain, Wistar Kyoto rats (WKY). NPS (0.1 and 1â¯nmol, intracerebroventricularly (icv)) did not modify the performance in the open field test in both strains; however, NPSR antagonism with [tBu-d-Gly5]NPS (3â¯nmol, icv) increased, per se, the total distance travelled by WKY. In the elevated plus-maze, NPS (1â¯nmol, icv) increased the percentage of entries in the open arms (%EO) only in WKY, an effect prevented by pretreatment with [tBu-d-Gly5]NPS (3â¯nmol, icv), which decreased per se the %EO in WKY and increased their number of entries in the closed arms. Immunoblotting of frontal cortical extracts showed no differences of NPSR density, although SHR had a lower NPS content than WKY. SHR showed higher activity of dopamine uptake than WKY, and NPS (1â¯nmol, icv) did not change this profile. Overall, the present work shows that the pattern of functioning of the NPS system is distinct in WKY and SHR, suggesting that this system may contribute to the pathophysiology of ADHD.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad , Neuropéptidos , Animales , Modelos Animales de Enfermedad , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKYRESUMEN
Oxidative stress is implicated in retinal cell injury associated with glaucoma and other retinal diseases. However, the mechanism by which oxidative stress leads to retinal damage is not completely understood. Transient receptor potential ankyrin 1 (TRPA1) is a redox-sensitive channel that, by amplifying the oxidative stress signal, promotes inflammation and tissue injury. Here, we investigated the role of TRPA1 in retinal damage evoked by ischemia (1 hour) and reperfusion (I/R) in mice. In wild-type mice, retinal cell numbers and thickness were reduced at both day-2 and day-7 after I/R. By contrast, mice with genetic deletion of TRPA1 were protected from the damage seen in their wild-type littermates. Daily instillation of eye drops containing two different TRPA1 antagonists, an oxidative stress scavenger, or a NADPH oxidase-1 inhibitor also protected the retinas of C57BL/6J mice exposed to I/R. Mice with genetic deletion of the proinflammatory TRP channels, vanilloid 1 (TRPV1) or vanilloid 4 (TRPV4), were not protected from I/R damage. Surprisingly, genetic deletion or pharmacological blockade of TRPA1 also attenuated the increase in the number of infiltrating macrophages and in the levels of the oxidative stress biomarker, 4-hydroxynonenal, and of the apoptosis biomarker, active caspase-3, evoked by I/R. These findings suggest that TRPA1 mediates the oxidative stress burden and inflammation that result in murine retinal cell death. We also found that TRPA1 (both mRNA and protein) is expressed by human retinal cells. Thus, it is possible that inhibition of a TRPA1-dependent pathway could also attenuate glaucoma-related retinal damage.
Asunto(s)
Daño por Reperfusión/metabolismo , Retina/metabolismo , Canal Catiónico TRPA1/metabolismo , Animales , Muerte Celular , Inflamación , Isquemia , Masculino , Ratones , Ratones Endogámicos C57BL , NADPH Oxidasa 1/metabolismo , Estrés Oxidativo/fisiología , Reperfusión , Daño por Reperfusión/fisiopatología , Retina/fisiología , Enfermedades de la Retina , Canal Catiónico TRPA1/genética , Canal Catiónico TRPA1/fisiología , Canales Catiónicos TRPV/metabolismo , Canales de Potencial de Receptor Transitorio/genéticaRESUMEN
Cocaine (COC) is a psychostimulant that acts by increasing catecholaminergic neurotransmission mainly due to its effects on the dopamine transporter (DAT). However, other neurotransmitter systems may also be regulated by COC, including the GABAergic system. Since the effect of COC in modulating gamma-aminobutyric acid (GABA) reuptake is not defined, we investigated the molecular mechanisms related to the increase in GABA uptake induced by acute COC exposure and its effects on locomotor activity in adolescent mice. Behavioral experiments showed that COC increased locomotor activity and decreased immobilization time in mice. A single COC exposure reduced both GABA uptake and GAT-1 protein levels. On the other hand, cyclic adenosine monophosphate (cAMP) levels increased after a COC challenge. The major changes induced by acute COC on behavioral and neurochemical assays were avoided by previous treatment with the selective D1 receptor antagonist SCH-23390 (0.5 mg/kg). Our findings suggest that GABA uptake naturally decreases during mice development from preadolescence until adulthood and that dopamine (DA) D1-like receptors are key players in the regulation of GABA uptake levels following a single COC exposure in adolescent mice.
Asunto(s)
Cocaína/farmacología , Dopamina/metabolismo , Lóbulo Frontal/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Ácido gamma-Aminobutírico/efectos de los fármacos , Animales , Estimulantes del Sistema Nervioso Central/farmacología , Cocaína/administración & dosificación , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/efectos de los fármacos , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Inhibidores de Captación de Dopamina/farmacología , Lóbulo Frontal/metabolismo , Ratones , Actividad Motora/efectos de los fármacos , Ácido gamma-Aminobutírico/metabolismoRESUMEN
The strain of spontaneously hypertensive rats (SHR) is considered a genetic model for the study of attention-deficit hyperactivity disorder (ADHD), as it displays hyperactivity, impulsivity and poorly sustained attention. Recently, we have shown the involvement of adenosinergic neuromodulation in the SHR's short-term and long-term memory impairments. In this study, we investigated the performance of male and female SHR in a modified version of the object-recognition task (using objects with different structural complexity) and compared them with Wistar rats, a widely used outbred rat strain for the investigation of learning processes. The suitability of the SHR strain to represent an animal model of ADHD, as far as mnemonic deficits are concerned, was pharmacologically validated by the administration of methylphenidate, the first-choice drug for the treatment of ADHD patients. The role of adenosine A1 and A2A receptors in object discrimination was investigated by the administration of caffeine (nonselective antagonist) or selective adenosine receptor antagonists. Wistar rats discriminated all the objects used (cube vs. pyramid; cube vs. T-shaped object), whereas SHR only discriminated the most structurally distinct pairs of objects (cube vs. pyramid). Pretraining administration of methylphenidate [2 mg/kg, intraperitoneal (i.p.)], caffeine (1-10 mg/kg, i.p.), the selective adenosine receptor antagonists DPCPX (8-cyclopenthyl-1,3-dipropylxanthine; A1 antagonist, 5 mg/kg, i.p.) and ZM241385 (A2A antagonist, 1.0 mg/kg, i.p.), or the association of ineffective doses of DPCPX (3 mg/kg) and ZM241385 (0.5 mg/kg), improved the performance of SHR in the object-recognition task. These findings show that the discriminative learning impairments of SHR can be attenuated by the blockade of either A1 or A2A adenosine receptors, suggesting that adenosinergic antagonists might represent potentially interesting drugs for the treatment of ADHD.
Asunto(s)
Antagonistas del Receptor de Adenosina A1 , Antagonistas del Receptor de Adenosina A2 , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Memoria a Corto Plazo/efectos de los fármacos , Ratas Endogámicas SHR/fisiología , Reconocimiento en Psicología/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Cafeína/farmacología , Modelos Animales de Enfermedad , Femenino , Masculino , Memoria a Corto Plazo/fisiología , Metilfenidato/farmacología , Ratas , Ratas Wistar , Receptor de Adenosina A1/fisiología , Receptores de Adenosina A2/fisiología , Reconocimiento en Psicología/fisiología , Triazinas/administración & dosificación , Triazinas/farmacología , Triazoles/administración & dosificación , Triazoles/farmacología , Xantinas/administración & dosificación , Xantinas/farmacologíaRESUMEN
Increased brain deposition of amyloid beta protein (Abeta) and cognitive deficits are classical signals of Alzheimer's disease (AD) that have been highly associated with inflammatory alterations. The present work was designed to determine the correlation between tumor necrosis factor-alpha (TNF-alpha)-related signaling pathways and inducible nitric oxide synthase (iNOS) expression in a mouse model of AD, by means of both in vivo and in vitro approaches. The intracerebroventricular injection of Abeta(1-40) in mice resulted in marked deficits of learning and memory, according to assessment in the water maze paradigm. This cognition impairment seems to be related to synapse dysfunction and glial cell activation. The pharmacological blockage of either TNF-alpha or iNOS reduced the cognitive deficit evoked by Abeta(1-40) in mice. Similar results were obtained in TNF-alpha receptor 1 and iNOS knock-out mice. Abeta(1-40) administration induced an increase in TNF-alpha expression and oxidative alterations in prefrontal cortex and hippocampus. Likewise, Abeta(1-40) led to activation of both JNK (c-Jun-NH2-terminal kinase)/c-Jun and nuclear factor-kappaB, resulting in iNOS upregulation in both brain structures. The anti-TNF-alpha antibody reduced all of the molecular and biochemical alterations promoted by Abeta(1-40). These results provide new insights in mouse models of AD, revealing TNF-alpha and iNOS as central mediators of Abeta action. These pathways might be targeted for AD drug development.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/administración & dosificación , Modelos Animales de Enfermedad , Óxido Nítrico Sintasa de Tipo II/biosíntesis , Transducción de Señal/fisiología , Factor de Necrosis Tumoral alfa/fisiología , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/fisiología , Animales , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica/fisiología , Inyecciones Intraventriculares , Masculino , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/enzimología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Óxido Nítrico Sintasa de Tipo II/genética , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Adenosine A2A receptors (A2ARs) were recently described to control synaptic plasticity and network activity in the prefrontal cortex (PFC). We now probed the role of these PFC A2AR by evaluating the behavioral performance (locomotor activity, anxiety-related behavior, cost-benefit decision making and working memory) of rats upon downregulation of A2AR selectively in the prelimbic medial PFC (PLmPFC) via viral small hairpin RNA targeting the A2AR (shA2AR). The most evident alteration observed in shA2AR-treated rats, when compared to sh-control (shCTRL)-treated rats, was a decrease in the choice of the large reward upon an imposed delay of 15 s assessed in a T-maze-based cost-benefit decision-making paradigm, suggestive of impulsive decision making. Spontaneous locomotion in the open field was not altered, suggesting no changes in exploratory behavior. Furthermore, rats treated with shA2AR in the PLmPFC also displayed a tendency for higher anxiety levels in the elevated plus maze (less entries in the open arms), but not in the open field test (time spent in the center was not affected). Finally, working memory performance was not significantly altered, as revealed by the spontaneous alternation in the Y-maze test and the latency to reach the platform in the repeated trial Morris water maze. These findings constitute the first direct demonstration of a role of PFC A2AR in the control of behavior in physiological conditions, showing their major contribution for the control of delay-based cost-benefit decisions.
RESUMEN
Stress response can be modulated by neonatal/childhood events. Neonatal handling (NH) is an animal model in which the animals are subjected to brief separations from the dam during the first days of life, and it leads to lower emotionality and behavioral changes in adulthood. The aim of this study was to observe if early events, such as (NH), may program associative learning and behavioral flexibility in adult male rats and if these changes could be related to altered neurochemistry in the medial prefrontal cortex (mPFC). We evaluated proteins related to synaptic plasticity (brain-derived neurotrophic factor [BDNF] and synaptophysin [SYP]) as well as Na+/K+-ATPase activity. Additionally, we evaluated proteins related to the dopaminergic system (tyrosine hydroxylase [TH] and phosphorylated TH [pTH]), since this system appears to be affected in some neonatal interventions. Neonatally handled animals exhibited impairment in simple discrimination and intradimensional shift but not in reversal or compound discrimination; in addition, no alteration in switching from an egocentric spatial to a cued strategy was observed. These effects were accompanied by a decrease in SYP levels and Na+/K+-ATPase activity, suggesting reduced synaptic function. These results indicate that NH increases attention to irrelevant stimuli and/or impairs associative learning, and this is accompanied by neurochemical alterations in the (mPFC).
Asunto(s)
Manejo Psicológico , Discapacidades para el Aprendizaje/metabolismo , Plasticidad Neuronal/fisiología , Corteza Prefrontal/crecimiento & desarrollo , Corteza Prefrontal/metabolismo , Estrés Psicológico/metabolismo , Animales , Animales Recién Nacidos , Atención/fisiología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Función Ejecutiva/fisiología , Aprendizaje/fisiología , Discapacidades para el Aprendizaje/etiología , Masculino , Distribución Aleatoria , Ratas Wistar , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Sinaptofisina/metabolismo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Malathion is an organophosphate widely used as an insecticide in agriculture and in public health programs, causing risk to human health. As was recently reported, malathion induces depressant-like behavior and oxidative damage to the brain of rodents. Given the relevance of searching for neuroprotective agents against such damage, this study was therefore undertaken to investigate the neuroprotective potential of zinc in dealing with malathion-related toxicity. Female Wistar rats were exposed to malathion (50 and 100 mg/kg, ip) and/or zinc chloride (ZnCl2; 5 mg/kg, ip) for 3 days. Malathion produced a depressant-like effect, observed by the increased immobility time in the forced swimming test (FST), without affecting total locomotor activity and rearing in the open-field. However, malathion administered at 50 mg/kg reduced the central time in the arena and at the dose of 100 mg/kg reduced the central locomotion. These effects were completely reversed by ZnCl2. Exposure to malathion (50 mg/kg, ip) and/or ZnCl2 did not affect AChE activity in the hippocampus, cerebral cortex, and blood. Malathion (50 mg/kg, ip) alone caused some harmful effects, such as (1) an increase in lipid peroxidation and a reduction of glutathione peroxidase activity in the cerebral cortex, (2) reduction of glutathione reductase activity in the hippocampus, and (3) changes in the structure of chromatin in the dentate gyrus, all effects attenuated by ZnCl2. In conclusion, these results clearly show that zinc administration is able to attenuate some neurochemical, morphological, and behavioral effects induced by malathion, notably the malathion-induced depressant-like effect in the FST.
Asunto(s)
Antidepresivos/farmacología , Antioxidantes/farmacología , Conducta Animal/efectos de los fármacos , Encéfalo/metabolismo , Cloruros/farmacología , Depresión/prevención & control , Fármacos Neuroprotectores/farmacología , Compuestos de Zinc/farmacología , Acetilcolinesterasa/sangre , Acetilcolinesterasa/metabolismo , Animales , Ansiolíticos/farmacología , Antidepresivos/uso terapéutico , Antioxidantes/uso terapéutico , Ansiedad/inducido químicamente , Ansiedad/metabolismo , Ansiedad/prevención & control , Encéfalo/efectos de los fármacos , Encéfalo/enzimología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Cloruros/uso terapéutico , Ensamble y Desensamble de Cromatina/efectos de los fármacos , Giro Dentado/efectos de los fármacos , Giro Dentado/metabolismo , Depresión/inducido químicamente , Depresión/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Glutatión Peroxidasa/metabolismo , Glutatión Reductasa/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Locomoción/efectos de los fármacos , Malatión , Fármacos Neuroprotectores/uso terapéutico , Ratas , Ratas Wistar , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Compuestos de Zinc/uso terapéuticoRESUMEN
Considerable evidence supports the role of oxidative stress in the pathogenesis of Alzheimer's disease (AD). Previous studies suggest that the central nervous system (CNS) administration of beta-amyloid peptide, the major constituent of senile plaque in AD, induces oxidative stress in rodents which may contribute to the learning and memory deficits verified in the beta-amyloid model of AD. In the present study, we compared the effects of a single intracerebroventricular (i.c.v.) injection of aggregated beta-amyloid peptide-(1-40) (Abeta(1-40)) (400pmol/mouse) on spatial learning and memory performance, synaptic density and the glutathione (GSH)-dependent antioxidant status in adult male C57BL/6 and Swiss albino mice. Seven days after Abeta(1-40) administration, C57BL/6 and Swiss mice presented similar spatial learning and memory impairments, as evaluated in the water maze task, although these impairments were not found in Abeta(40-1)-treated mice. Moreover, a similar decline of synaptophysin levels was observed in the hippocampus (HC) and prefrontal cortex (PFC) of both Swiss and C57BL/6 mice treated with Abeta(1-40), which suggests synaptic loss. C57BL/6 mice presented lower levels of glutathione-related antioxidant defences (total glutathione (GSH-t) levels, glutathione peroxidase (GPx) and glutathione reductase (GR) activity) in the HC and PFC in comparison to Swiss mice. Despite the reduced basal GSH-dependent antioxidant defences observed in C57BL/6 mice, Abeta(1-40) administration induced significant alterations in the brain antioxidant parameters only in Swiss mice, decreasing GSH-t levels and increasing GPx and GR activity in the HC and PFC 24h after treatment. These results indicate strain differences in the susceptibility to Abeta(1-40)-induced changes in the GSH-dependent antioxidant defences in mice, which should be taken into account in further studies using the Abeta model of AD in mice. In addition, the present findings suggest that the spatial learning and memory deficits induced by beta-amyloid peptides in rodents may not be entirely related to glutathione-dependent antioxidant response.