RESUMO
BACKGROUND: Preclinical studies suggest that early exposure to anaesthesia alters the visual system in mice and non-human primates. We investigated whether exposure to general anaesthesia leads to visual attention processing changes in children, which could potentially impact essential life skills, including learning. METHODS: This was a post hoc analysis of data from the APprentissages EXécutifs et cerveau chez les enfants d'âge scolaire (APEX) cohort study. A total of 24 healthy 9-10-yr-old children who were or were not exposed to general anaesthesia (for surgery) by a mean age of 3.8 (2.6) yr performed a visual attention task to evaluate ability to process either local details or general global visual information. Whether children were distracted by visual interference during global and local information processing was also assessed. RESULTS: Participants included in the analyses (n=12 participants exposed to general anaesthesia and n=12 controls) successfully completed (>90% of correct answers) the trial tasks. Children from both groups were equally distracted by visual interference. However, children who had been exposed to general anaesthesia were more attracted to global visual information than were control children (P=0.03). CONCLUSIONS: These findings suggest lasting effects of early-life exposure to general anaesthesia on visuospatial abilities. Further investigations of the mechanisms by which general anaesthesia could have delayed effects on how children perceive their visual environment are needed.
Assuntos
Anestesia Geral , Atenção , Percepção Visual , Humanos , Criança , Feminino , Masculino , Atenção/efeitos dos fármacos , Estudos de Coortes , Percepção Visual/efeitos dos fármacos , Pré-EscolarRESUMO
The rapid serial visual presentation (RSVP) task and continuous performance tasks (CPT) are used to assess attentional impairments in patients with psychiatric and neurological conditions. This study developed a novel touchscreen task for rats based on the structure of a human RSVP task and used pharmacological manipulations to investigate their effects on different performance measures. Normal animals were trained to respond to a target image and withhold responding to distractor images presented within a continuous sequence. In a second version of the task, a false-alarm image was included, so performance could be assessed relative to two types of nontarget distractors. The effects of acute administration of stimulant and nonstimulant treatments for ADHD (amphetamine and atomoxetine) were tested in both tasks. Methylphenidate, ketamine, and nicotine were tested in the first task only. Amphetamine made animals more impulsive and decreased overall accuracy but increased accuracy when the target was presented early in the image sequence. Atomoxetine improved accuracy overall with a specific reduction in false-alarm responses and a shift in the attentional curve reflecting improved accuracy for targets later in the image sequence. However, atomoxetine also slowed responding and increased omissions. Ketamine, nicotine, and methylphenidate had no specific effects at the doses tested. These results suggest that stimulant versus nonstimulant treatments have different effects on attention and impulsive behaviour in this rat version of an RSVP task. These results also suggest that RSVP-like tasks have the potential to be used to study attention in rodents.
Assuntos
Anfetamina , Cloridrato de Atomoxetina , Atenção , Estimulantes do Sistema Nervoso Central , Ketamina , Metilfenidato , Nicotina , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/administração & dosagem , Cloridrato de Atomoxetina/farmacologia , Cloridrato de Atomoxetina/administração & dosagem , Atenção/efeitos dos fármacos , Atenção/fisiologia , Masculino , Ratos , Metilfenidato/farmacologia , Metilfenidato/administração & dosagem , Nicotina/farmacologia , Nicotina/administração & dosagem , Anfetamina/farmacologia , Anfetamina/administração & dosagem , Ketamina/farmacologia , Ketamina/administração & dosagem , Estimulação Luminosa/métodos , Inibidores da Captação Adrenérgica/farmacologia , Inibidores da Captação Adrenérgica/administração & dosagem , Aprendizagem Seriada/efeitos dos fármacos , Aprendizagem Seriada/fisiologia , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Percepção Visual/efeitos dos fármacos , Percepção Visual/fisiologia , Ratos Sprague-DawleyRESUMO
Opioid peptides and their receptors are expressed in the mammalian retina; however, little is known about how they might affect visual processing. The melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs), which mediate important non-image-forming visual processes such as the pupillary light reflex (PLR), express ß-endorphin-preferring, µ-opioid receptors (MORs). The objective of the present study was to elucidate if opioids, endogenous or exogenous, modulate pupillary light reflex (PLR) via MORs expressed by ipRGCs. MOR-selective agonist [D-Ala2, MePhe4, Gly-ol5]-enkephalin (DAMGO) or antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) was administered via intravitreal injection. PLR was recorded in response to light stimuli of various intensities. DAMGO eliminated PLR evoked by light with intensities below melanopsin activation threshold but not that evoked by bright blue irradiance that activated melanopsin signaling, although in the latter case, DAMGO markedly slowed pupil constriction. CTAP or genetic ablation of MORs in ipRGCs slightly enhanced dim-light-evoked PLR but not that evoked by a bright blue stimulus. Our results suggest that endogenous opioid signaling in the retina contributes to the regulation of PLR. The slowing of bright light-evoked PLR by DAMGO is consistent with the observation that systemically applied opioids accumulate in the vitreous and that patients receiving chronic opioid treatment have slow PLR.
Assuntos
Peptídeos Opioides/genética , Receptores Opioides mu/genética , Retina/metabolismo , Percepção Visual/genética , Animais , Ala(2)-MePhe(4)-Gly(5)-Encefalina/farmacologia , Encefalinas/antagonistas & inibidores , Encefalinas/genética , Humanos , Luz , Camundongos , Peptídeos/farmacologia , Receptores Opioides/genética , Receptores Opioides mu/antagonistas & inibidores , Reflexo/genética , Retina/patologia , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/fisiologia , Transdução de Sinais/efeitos dos fármacos , Percepção Visual/efeitos dos fármacos , beta-Endorfina/genéticaRESUMO
Nicotine increases the output of every major neurotransmitter. In previous studies designed to identify the secondary neurotransmitter systems mediating nicotine's attention-enhancing effects in a rat model, the ß-adrenoceptor antagonist propranolol blocked these effects. The present study was designed to test whether this mechanism held true in humans, thus guiding development of novel nicotinic agonists for cognitive enhancement. Twenty-six nonsmokers completed a nicotine (7 mg/24 h transdermally) x propranolol (40 mg p.o., body weight-adjusted) interaction study. Over four test days, each participant received double-placebo, nicotine only, propranolol only, and nicotine plus propranolol in randomized sequence before cognitive testing. No drug effects were seen in a visuospatial attention task. In the Rapid Visual Information Processing Task, performed in two 15-min blocks, neither drug alone significantly affected hit rate, but both drugs combined acted synergistically to alleviate its decrement over time in the first block and displayed additive beneficial effects in the second. In a change detection task, propranolol enhanced accuracy and reduced reaction time independent of nicotine presence. Propranolol also enhanced subjective self-reports of vigor. Overall, the findings were contrary to those hypothesized. Propranolol displayed beneficial effects on cognition, especially on sustaining performance over time. ß-adrenoceptor activation by nicotine-induced noradrenaline release appeared to limit performance-enhancing effects of nicotine, because they were unmasked by ß-adrenoceptor antagonism. The results suggest that cognitive effects of changes in ß-adrenoceptor tone are context-dependent; contrary to rodent paradigms, human cognitive paradigms require no physical orienting in space but prolonged periods of remaining stationary while sustaining predictable processing demands.
Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Atenção/efeitos dos fármacos , Agonistas Colinérgicos/farmacologia , Nicotina/farmacologia , Propranolol/farmacologia , Desempenho Psicomotor/efeitos dos fármacos , Receptores Adrenérgicos beta/efeitos dos fármacos , Percepção Espacial/efeitos dos fármacos , Percepção Visual/efeitos dos fármacos , Antagonistas Adrenérgicos beta/administração & dosagem , Adulto , Agonistas Colinérgicos/administração & dosagem , Sinergismo Farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nicotina/administração & dosagem , Propranolol/administração & dosagem , Adulto JovemRESUMO
The purpose of this study was to characterize acute changes in inflammatory pathways in the mouse eye after blast-mediated traumatic brain injury (bTBI) and to determine whether modulation of these pathways could protect the structure and function of retinal ganglion cells (RGC). The bTBI was induced in C57BL/6J male mice by exposure to three 20 psi blast waves directed toward the head with the body shielded, with an inter-blast interval of one hour. Acute cytokine expression in retinal tissue was measured through reverse transcription-quantitative polymerase chain reaction (RT-qPCR) four hours post-blast. Increased retinal expression of interleukin (lL)-1ß, IL-1α, IL-6, and tumor necrosis factor (TNF)α was observed in bTBI mice exposed to blast when compared with shams, which was associated with activation of microglia and macroglia reactivity, assessed via immunohistochemistry with ionized calcium binding adaptor molecule 1 and glial fibrillary acidic protein, respectively, one week post-blast. Blockade of the IL-1 pathway was accomplished using anakinra, an IL-1RI antagonist, administered intra-peritoneally for one week before injury and continuing for three weeks post-injury. Retinal function and RGC layer thickness were evaluated four weeks post-injury using pattern electroretinogram (PERG) and optical coherence tomography (OCT), respectively. After bTBI, anakinra treatment resulted in a preservation of RGC function and RGC structure when compared with saline treated bTBI mice. Optic nerve integrity analysis demonstrated a trend of decreased damage suggesting that IL-1 blockade also prevents axonal damage after blast. Blast exposure results in increased retinal inflammation including upregulation of pro-inflammatory cytokines and activation of resident microglia and macroglia. This may explain partially the RGC loss we observed in this model, as blockade of the acute inflammatory response after injury with the IL-1R1 antagonist anakinra resulted in preservation of RGC function and RGC layer thickness.
Assuntos
Lesões Encefálicas Traumáticas/imunologia , Imunidade/imunologia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Receptores de Interleucina-1/antagonistas & inibidores , Retina/imunologia , Percepção Visual/imunologia , Animais , Traumatismos por Explosões/diagnóstico por imagem , Traumatismos por Explosões/tratamento farmacológico , Traumatismos por Explosões/imunologia , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Lesões Encefálicas Traumáticas/tratamento farmacológico , Eletrorretinografia/métodos , Imunidade/efeitos dos fármacos , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Retina/diagnóstico por imagem , Retina/efeitos dos fármacos , Tomografia de Coerência Óptica/métodos , Resultado do Tratamento , Percepção Visual/efeitos dos fármacosRESUMO
A synthetic monomeric peptide triple receptor agonist, termed "Triagonist" that incorporates glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon (Gcg) actions, was previously developed to improve upon metabolic and glucose regulatory benefits of single and dual receptor agonists in rodent models of diet-induced obesity and type 2 diabetes. In the current study, the neurotrophic and neuroprotective actions of this Triagonist were probed in cellular and mouse models of mild traumatic brain injury (mTBI), a prevalent cause of neurodegeneration in both the young and elderly. Triagonist dose- and time-dependently elevated cyclic AMP levels in cultured human SH-SY5Y neuronal cells, and induced neurotrophic and neuroprotective actions, mitigating oxidative stress and glutamate excitotoxicity. These actions were inhibited only by the co-administration of antagonists for all three receptor types, indicating the balanced co-involvement of GLP-1, GIP and Gcg receptors. To evaluate physiological relevance, a clinically translatable dose of Triagonist was administered subcutaneously, once daily for 7â¯days, to mice following a 30â¯g weight drop close head injury. Triagonist fully mitigated mTBI-induced visual and spatial memory deficits, evaluated at 7 and 30â¯days post injury. These results establish Triagonist as a novel neurotrophic/protective agent worthy of further evaluation as a TBI treatment strategy.
Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Polipeptídeo Inibidor Gástrico/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Glucagon/agonistas , Fármacos Neuroprotetores/uso terapêutico , Nootrópicos/uso terapêutico , Animais , Lesões Encefálicas Traumáticas/psicologia , Linhagem Celular , AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Ácido Glutâmico/toxicidade , Humanos , Injeções Subcutâneas , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fármacos Neuroprotetores/administração & dosagem , Nootrópicos/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Percepção Espacial/efeitos dos fármacos , Percepção Visual/efeitos dos fármacosRESUMO
ABSTRACT Objective There is controversy regarding cognitive function in patients with congenital adrenal hyperplasia (CAH). This study is aimed at the assessment of cognitive functions in children with CAH, and their relation to hydrocortisone (HC) therapy and testosterone levels. Subjects and methods Thirty children with CAH due to 21 hydroxylase deficiency were compared with twenty age- and sex-matched healthy controls. HC daily and cumulative doses were calculated, the socioeconomic standard was assessed, and free testosterone was measured. Cognitive function assessment was performed using the Wechsler Intelligence Scale - Revised for Children and Adults (WISC), the Benton Visual Retention Test, and the Wisconsin Card Sorting Test (WCST). Results The mean age (SD) of patients was 10.22 (3.17) years [11 males (36.7%), 19 females (63.3%)]. Mean (SD) HC dose was 15.78 (4.36) mg/m 2 /day. Mean (SD) cumulative HC dose 44,689. 9 (26,892.02) mg. Patients had significantly lower scores in all domains of the WISC test, performed significantly worse in some components of the Benton Visual Retention Test, as well as in the Wisconsin Card Sorting Test. There was no significant difference in cognitive performance when patients were subdivided according to daily HC dose (< 10, 10 - 15, > 15 mg/m 2 /day). A positive correlation existed between cumulative HC dose and worse results of the Benton test. No correlation existed between free testosterone and any of the three tests. Conclusion Patients with CAH are at risk of some cognitive impairment. Hydrocortisone therapy may be implicated. This study highlights the need to assess cognitive functions in CAH.
Assuntos
Humanos , Masculino , Feminino , Criança , Adolescente , Hidrocortisona/administração & dosagem , Cognição/efeitos dos fármacos , Hiperplasia Suprarrenal Congênita/psicologia , Anti-Inflamatórios/administração & dosagem , Fatores Socioeconômicos , Testosterona/sangue , Percepção Visual/efeitos dos fármacos , Escalas de Wechsler , Hidrocortisona/farmacologia , Estudos de Casos e Controles , Transtornos Cognitivos/diagnóstico , Hiperplasia Suprarrenal Congênita/metabolismo , Hiperplasia Suprarrenal Congênita/sangue , Relação Dose-Resposta a Droga , Deficiência Intelectual/diagnóstico , Anti-Inflamatórios/farmacologia , Testes NeuropsicológicosRESUMO
Neovascular retinal diseases are the leading causes of blindness in advanced countries. To date, anti-VEGF (vascular endothelial growth factor) drugs are clinically effective and widely used for these diseases. However, recent animal and clinical studies reported that potent and long-term VEGF antagonism may induce chorioretinal atrophy. Thus, physiological amount of VEGF is required for the homeostasis in the retina. Hypoxia-inducible factors (HIFs) are transcription factors located upstream of VEGF. We hypothesized that ectopically stabilized HIFs induce pathological amount of VEGF involved with retinal neovascularization. Therefore, HIF inhibition could be an alternative therapeutic candidate targeting the pathological amount of VEGF while holding a physiological amount of VEGF. To test this hypothesis, topotecan and doxorubicin, HIF inhibitors with different mechanisms were administered to the murine oxygen-induced retinopathy (OIR) model. We found that both topotecan and doxorubicin significantly prevented pathological but not physiological neovascularization in OIR. Furthermore, impaired visual function observed in OIR can also be suppressed by administering topotecan. These data suggested that HIF inhibition may be effective for pathological angiogenesis and neurodegeneration of the retina.
Assuntos
Hiperóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neovascularização Retiniana/tratamento farmacológico , Neovascularização Retiniana/metabolismo , Percepção Visual/fisiologia , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Feminino , Hiperóxia/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Retiniana/patologia , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/uso terapêutico , Topotecan/farmacologia , Topotecan/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismo , Percepção Visual/efeitos dos fármacosRESUMO
In this study we investigated the ability of zebrafish to discriminate visual signs and associate them with a reward in an associative-learning protocol including distractors. Moreover, we studied the effects of caffeine on animal performance in the task. After being trained to associate a specific image pattern with a reward (food) in the presence of other, distractor images, the fish were challenged to locate the exact cue associated with the reward. The distractors were same-colored pattern images similar to the target. Both the target and distractors were continually moved around the tank. Fish were exposed to three caffeine concentrations for 14 days: 0 mg/L (control, n = 12), 10 mg/L (n = 14), and 50 mg/L (n = 14). Zebrafish spent most of the time close to the target (where the reward was offered) under the effects of 0 and 10 mg/L caffeine, and the shortest latency to reach the target was observed for the 10-mg/L caffeine group. Both caffeine treatments (10 and 50 mg/L) increased the average speed and distance traveled when compared to the control group. This study confirms previous results showing that zebrafish demonstrate conditioned learning ability; however, low-dose caffeine exposure seems to favor visual cue discrimination and to increase zebrafish performance in a multicue discrimination task, in which primarily focus and attention are required in order to obtain the reward.
Assuntos
Aprendizagem por Associação/efeitos dos fármacos , Atenção/efeitos dos fármacos , Cafeína/administração & dosagem , Antagonistas de Receptores Purinérgicos P1/administração & dosagem , Peixe-Zebra , Animais , Comportamento Animal/efeitos dos fármacos , Cafeína/farmacologia , Café , Condicionamento Psicológico/efeitos dos fármacos , Discriminação Psicológica/efeitos dos fármacos , Antagonistas de Receptores Purinérgicos P1/farmacologia , Recompensa , Percepção Visual/efeitos dos fármacosRESUMO
This study investigated the efficacy of components of licorice root to alter performance on two different recognition tasks, a hippocampus-sensitive metric change in object location (MCOL) task and a striatum-sensitive double object recognition (DOR) task. Isoliquiritigenin (ISL), licorice root extract (LRE), and whole licorice root powder (LRP) were assessed. Young adult female rats were ovariectomized (OVX) and exposed to ISL, LRE or LRP at 0.075%, 0.5% or 5% respectively in the diet. An estradiol group was included as a positive control based on our prior findings. Rats were allowed to explore two objects for three 5-min study trials (separated by 3-min intervals) before a fourth 5-min test trial where the objects were moved closer together (MCOL task) or replaced with two new objects (DOR task). Rats typically habituate to the objects across the three study trials. An increase in object exploration time in the test trial suggests the rat detected the change. Estradiol improved MCOL performance and impaired DOR performance, similar to previously shown effects of estradiol and other estrogens, which tend to improve learning and memory on hippocampus-sensitive tasks and impair striatum-sensitive cognition. LRP had no effect on recognition while exposure to ISL and LRE improved MCOL performance. Exposure to ISL, LRE and LRP failed to attenuate DOR, contrary to effects of estradiol shown here and to previous reports in young-adult OVX rats. These findings suggest components of licorice root may prove to be effective therapies targeting memory enhancement without unintended deleterious cognitive effects.
Assuntos
Estrogênios/farmacologia , Glycyrrhiza/química , Extratos Vegetais/farmacologia , Raízes de Plantas/química , Reconhecimento Psicológico/efeitos dos fármacos , Percepção Visual/efeitos dos fármacos , Animais , Estradiol/farmacologia , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Memória/efeitos dos fármacos , Ovariectomia , Ratos , Ratos Long-Evans , Navegação Espacial/efeitos dos fármacosRESUMO
Elevations of sex steroids induced by social cues can rapidly modulate social behavior, but we know little about where they act within the nervous system to produce such effects. In male goldfish, testosterone (T) rapidly increases approach responses to the visual cues of females through its conversion to estradiol. Because aromatase is expressed in the retina, we tested if T can acutely influence retina responses to visual stimuli, and investigated the receptor mechanisms that may mediate such effects. Specifically, we measured FOS protein immunoreactivity to determine if T affects cellular responses to visual stimuli that include females, and used electrophysiology to investigate whether T can generally affect light sensitivity. We found that T acutely increased FOS responses to the simultaneous onset of light and the presence of female visual stimuli, both of which would normally be associated with early morning spawning, and increased electrophysiological responses to low intensity light pulses. Both effects were blocked by an estrogen receptor beta (ERß) antagonist, indicating that T is likely being converted to estradiol (E2) and acting through an ERß mediated mechanism to acutely modulate visual processing. Changes in sensory processing could subsequently influence approach behavior to increase reproductive success in competitive mating environments.
Assuntos
Receptor beta de Estrogênio/metabolismo , Proteínas de Peixes/metabolismo , Carpa Dourada/metabolismo , Retina/metabolismo , Testosterona/metabolismo , Percepção Visual/fisiologia , Animais , Comportamento Competitivo/fisiologia , Antagonistas do Receptor de Estrogênio/farmacologia , Receptor beta de Estrogênio/antagonistas & inibidores , Feminino , Proteínas de Peixes/antagonistas & inibidores , Masculino , Proteínas Proto-Oncogênicas c-fos/metabolismo , Reprodução/fisiologia , Retina/efeitos dos fármacos , Comportamento Sexual Animal/fisiologia , Percepção Visual/efeitos dos fármacosRESUMO
In order to develop a test battery based on a variety of neurological systems in fish, three sensory systems (vision, olfaction, and lateral line) as well as nerve transmission (acetylcholine esterase) were analyzed in zebrafish (Danio rerio) embryos with respect to their suitability as a model for the screening of neurotoxic trace substances in aquatic ecosystems. As a selection of known or putative neurotoxic compounds, amidotrizoic acid, caffeine, cypermethrin, dichlorvos, 2,4-dinitrotoluene, 2,4-dichlorophenol, 4-nonylphenol, perfluorooctanoic acid, and perfluorooctane sulfonic acid were tested in the fish embryo test (OECD test guideline 236) to determine EC10 values, which were then used as maximum test concentration in subsequent neurotoxicity tests. Whereas inhibition of acetylcholinesterase was investigated biochemically both in vivo and in vitro (ex vivo), the sensory organs were studied in vivo by means of fluorescence microscopy and histopathology in 72- or 96-h-old zebrafish embryos, which are not regarded as protected developmental stages in Europe and thus - at least de jure - represent alternative test methods. Various steps of optimization allowed this neurotoxicity battery to identify neurotoxic potentials for five out of the nine compounds: Cypermethrin and dichlorvos could be shown to specifically modulate acetylcholinesterase activity; dichlorvos, 2,4-dichlorophenol, 4-nonylphenol, and perfluorooctane sulfonic acid led to a degeneration of neuromasts, whereas both vision and olfaction proved quite resistant to concentrations ≤ EC10 of all of the model neurotoxicants tested. Comparison of neurotoxic effects on acetylcholinesterase activity following in vivo and in vitro (ex vivo) exposure to cypermethrin provided hints to a specific enzyme-modulating activity of pyrethroid compounds. Enhancement of the neuromast assay by applying a simultaneous double-staining procedure and implementing a 4-scale scoring system (Stengel et al. 2017) led to reduced variability of results and better statistical resolution and allowed to differentiate location-dependent effects in single neuromasts. Since acetylcholinesterase inhibition and neuromast degeneration can be analyzed in 72- and 96-h-old zebrafish embryos exposed to neurotoxicants according to the standard protocol of the fish embryo toxicity test (OECD TG 236), the fish embryo toxicity test can be enhanced to serve as a sensitive neurotoxicity screening test in non-protected stages of vertebrates.
Assuntos
Sistema da Linha Lateral/efeitos dos fármacos , Neurotoxinas/toxicidade , Percepção Olfatória/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Testes de Toxicidade/métodos , Percepção Visual/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo , Acetilcolinesterase/metabolismo , Animais , Embrião não Mamífero/efeitos dos fármacos , Proteínas de Peixes/metabolismo , Peixe-Zebra/crescimento & desenvolvimentoRESUMO
BACKGROUND: Metabotropic glutamate receptor 4 (mGluR4) and dopamine D2 receptors are specifically expressed within the indirect pathway neurons of the striato-pallidal-subthalamic pathway. This unique expression profile suggests that mGluR4 and D2 receptors may play a cooperative role in the regulation and inhibitory control of behaviour. We investigated this possibility by testing the effects of a functionally-characterised positive allosteric mGluR4 modulator, 4-((E)-styryl)-pyrimidin-2-ylamine (Cpd11), both alone and in combination with the D2 receptor antagonist eticlopride, on two distinct forms of impulsivity. METHODS: Rats were trained on the five-choice serial reaction time task (5-CSRTT) of sustained visual attention and segregated according to low, mid, and high levels of motor impulsivity (LI, MI and HI, respectively), with unscreened rats used as an additional control group. A separate group of rats was trained on a delay discounting task (DDT) to assess choice impulsivity. RESULTS: Systemic administration of Cpd11 dose-dependently increased motor impulsivity and impaired attentional accuracy on the 5-CSRTT in all groups tested. Eticlopride selectively attenuated the increase in impulsivity induced by Cpd11, but not the accompanying attentional impairment, at doses that had no significant effect on behavioural performance when administered alone. Cpd11 also decreased choice impulsivity on the DDT (i.e. increased preference for the large, delayed reward) and decreased locomotor activity. CONCLUSIONS: These findings demonstrate that mGluR4s, in conjunction with D2 receptors, affect motor- and choice-based measures of impulsivity, and therefore may be novel targets to modulate impulsive behaviour associated with a number of neuropsychiatric syndromes.
Assuntos
Antagonistas dos Receptores de Dopamina D2/farmacologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Comportamento Impulsivo/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Pirimidinas/farmacologia , Salicilamidas/farmacologia , Estirenos/farmacologia , Animais , Atenção/efeitos dos fármacos , Atenção/fisiologia , AMP Cíclico/metabolismo , Desvalorização pelo Atraso/efeitos dos fármacos , Desvalorização pelo Atraso/fisiologia , Antagonistas dos Receptores de Dopamina D2/sangue , Relação Dose-Resposta a Droga , Agonistas de Aminoácidos Excitatórios/sangue , Agonistas de Aminoácidos Excitatórios/líquido cefalorraquidiano , Comportamento Impulsivo/fisiologia , Masculino , Atividade Motora/fisiologia , Psicotrópicos/farmacologia , Pirimidinas/sangue , Pirimidinas/líquido cefalorraquidiano , Ratos , Receptores de Dopamina D2/metabolismo , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/metabolismo , Salicilamidas/sangue , Estirenos/sangue , Estirenos/líquido cefalorraquidiano , Percepção Visual/efeitos dos fármacos , Percepção Visual/fisiologiaRESUMO
Naltrexone reduces drinking among individuals with alcohol use disorders (AUDs), but it is not effective for everyone. Variability in its effects on reward-related brain activation, genetic variation, and/or cigarette smoking may account for this mixed response profile. This randomized clinical trial tested the effects of naltrexone on drinking and alcohol cue-elicited brain activation, evaluated whether OPRM1 A118G genotype or smoking moderated these effects, and explored whether the effects of medication on cue-elicited activation predicted subsequent drinking. One hundred and fifty-two treatment-seeking individuals with alcohol dependence, half preselected to carry at least one A118G G (Asp) allele, were randomized to naltrexone (50 mg) or placebo for 16 weeks and administered an fMRI alcohol cue reactivity task at baseline and after 2 weeks of treatment. Naltrexone, relative to placebo, significantly reduced alcohol cue-elicited activation of the right ventral striatum (VS) between baseline and week 2 and reduced heavy drinking over 16 weeks. OPRM1 genotype did not significantly moderate these effects, but G-allele carriers who received naltrexone had an accelerated return to heavy drinking after medication was stopped. Smoking moderated the effects of medication on drinking, such that naltrexone was superior to placebo only among smokers. The degree of reduction in right VS activation between scans interacted with medication in predicting subsequent drinking, such that individuals with greater reduction in activation who received naltrexone, but not placebo, experienced the least heavy drinking during the following 14 weeks. These data replicate previous findings that naltrexone reduces heavy drinking and reward-related brain activation among treatment-seeking individuals with AUDs, and indicate that smoking and the magnitude of reduction in cue-elicited brain activation may predict treatment response.
Assuntos
Alcoolismo/tratamento farmacológico , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Alcoolismo/genética , Alcoolismo/fisiopatologia , Alcoolismo/psicologia , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Mapeamento Encefálico , Sinais (Psicologia) , Feminino , Seguimentos , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Variantes Farmacogenômicos , Prognóstico , Receptores Opioides mu/genética , Recompensa , Índice de Gravidade de Doença , Método Simples-Cego , Fumar/genética , Fumar/fisiopatologia , Fumar/psicologia , Percepção Visual/efeitos dos fármacos , Percepção Visual/fisiologiaRESUMO
The nucleus accumbens (NAc) is thought to be a site of integration of positively and negatively valenced information and action selection. Functional differentiation in valence processing has previously been found along the rostrocaudal axis of the shell region of the NAc in assessments of unconditioned motivation. Given that the core region of the NAc has been implicated in the elicitation of motivated behavior in response to conditioned cues, we sought to assess the role of caudal, intermediate, and rostral sites within this subregion in cue-elicited approach-avoidance decisions. Rats were trained to associate visuo-tactile cues with appetitive, aversive, and neutral outcomes. Following the successful acquisition of the cue-outcome associations, rats received microinfusions of GABAA and GABAB receptor agonists (muscimol/baclofen) or saline into the caudal, intermediate, or rostral NAc core and were then exposed to a superimposition of appetitively and aversively valenced cues versus neutral cues in a "conflict test," as well as to the appetitive versus neutral cues, and aversive cues versus neutral cues, in separate conditioned preference/avoidance tests. Disruption of activity in the intermediate to caudal parts of the NAc core resulted in a robust avoidance bias in response to motivationally conflicting cues, as well as a potentiated avoidance of aversive cues as compared with control animals, coupled with an attenuated conditioned preference for the appetitive cue. These results suggest that the caudal NAc core may have the capacity to exert bidirectional control over appetitively and aversively motivated responses to valence signals.
Assuntos
Aprendizagem da Esquiva/fisiologia , Comportamento de Escolha/fisiologia , Sinais (Psicologia) , Núcleo Accumbens/fisiologia , Animais , Aprendizagem por Associação/efeitos dos fármacos , Aprendizagem por Associação/fisiologia , Aprendizagem da Esquiva/efeitos dos fármacos , Baclofeno/farmacologia , Comportamento de Escolha/efeitos dos fármacos , Condicionamento Psicológico/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Conflito Psicológico , Agonistas GABAérgicos/farmacologia , Masculino , Motivação/efeitos dos fármacos , Motivação/fisiologia , Muscimol/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Long-Evans , Receptores de GABA-A/metabolismo , Receptores de GABA-B/metabolismo , Percepção do Tato/efeitos dos fármacos , Percepção do Tato/fisiologia , Percepção Visual/efeitos dos fármacos , Percepção Visual/fisiologiaRESUMO
RATIONALE: Zebrafish have a sophisticated color- and shape-sensitive visual system, so we examined color cue-based novel object recognition in zebrafish. We evaluated preference in the absence or presence of drugs that affect attention and memory retention in rodents: nicotine and the histone deacetylase inhibitor (HDACi) phenylbutyrate (PhB). OBJECTIVES: The objective of this study was to evaluate whether nicotine and PhB affect innate preferences of zebrafish for familiar and novel objects after short- and long-retention intervals. METHODS: We developed modified object recognition (OR) tasks using neutral novel and familiar objects in different colors. We also tested objects which differed with respect to the exploratory behavior they elicited from naïve zebrafish. RESULTS: Zebrafish showed an innate preference for exploring red or green objects rather than yellow or blue objects. Zebrafish were better at discriminating color changes than changes in object shape or size. Nicotine significantly enhanced or changed short-term innate novel object preference whereas PhB had similar effects when preference was assessed 24 h after training. Analysis of other zebrafish behaviors corroborated these results. CONCLUSIONS: Zebrafish were innately reluctant or prone to explore colored novel objects, so drug effects on innate preference for objects can be evaluated changing the color of objects with a simple geometry. Zebrafish exhibited recognition memory for novel objects with similar innate significance. Interestingly, nicotine and PhB significantly modified innate object preference.
Assuntos
Comportamento Exploratório/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Reconhecimento Visual de Modelos/efeitos dos fármacos , Fenilbutiratos/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Feminino , Masculino , Memória/efeitos dos fármacos , Reconhecimento Psicológico/efeitos dos fármacos , Tempo , Percepção Visual/efeitos dos fármacos , Peixe-ZebraRESUMO
INTRODUCTION: The influence of n-3 long-chain polyunsaturated fatty acids (LCPUFA) supplementation on brain functioning is debated. Some studies have found positive effects on cognition in children with learning difficulties, elderly people with cognitive impairment and depression scores in depressed individuals. Other studies have found null or negative effects. Observational studies in adolescents have found positive associations between fish consumption (containing n-3 LCPUFAs) and academic achievement. However, intervention studies in typically developing adolescents are missing. OBJECTIVE: The goal of this study is to determine the influence of increasing Omega-3 Index on cognitive functioning, academic achievement and mental well-being of typically developing adolescents. METHODS AND DATA ANALYSIS: Double-blind, randomised, placebo controlled intervention; 264 adolescents (age 13-15â years) attending lower general secondary education started daily supplementation of 400â mg eicosapentaenoic acid and docosahexaenoic acid (EPA+DHA) in cohort I (n=130) and 800â mg EPA+DHA in cohort II (n=134) or a placebo for 52â weeks. Recruitment took place according to a low Omega-3 Index (<5%). The Omega-3 Index was monitored via a finger prick at baseline and after 3, 6 and 12â months. The supplement dose was adjusted after 3â months (placebo analogously) to reach an Omega-3 Index of 8-11%. At baseline, 6 and 12â months, a neuropsychological test battery, a number of questionnaires and a standardised math test (baseline and 12â months) were administered. School grades were collected. In a subsample, sleep quality and quantity data (n=64) and/or eye-tracking data (n=33) were collected. ETHICS AND DISSEMINATION: Food2Learn is performed according to Good Clinical Practice. All data collected are linked to participant number only. The results will be disseminated on group level to participants and schools. The results will be presented at conferences and published in peer-reviewed journals. The study is approved by the Medical Ethical Committee of Atrium-Orbis-Zuyd Hospital and is registered at the Netherlands Trial Register (NTR4082). TRIAL REGISTRATION NUMBERS: NTR4082 and NCT02240264; Pre-results.
Assuntos
Desempenho Acadêmico , Comportamento do Adolescente/efeitos dos fármacos , Cognição/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Aprendizagem/efeitos dos fármacos , Percepção Visual/efeitos dos fármacos , Absenteísmo , Adolescente , Afeto/efeitos dos fármacos , Animais , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/sangue , Método Duplo-Cego , Ácido Eicosapentaenoico/sangue , Euphausiacea , Ácidos Graxos Ômega-3/sangue , Ácidos Graxos Ômega-3/farmacologia , Feminino , Óleos de Peixe , Humanos , Masculino , Motivação/efeitos dos fármacos , Países Baixos , Testes Neuropsicológicos , AutoimagemRESUMO
Identifying statistical patterns between environmental stimuli enables organisms to respond adaptively when cues are later observed. However, stimuli are often obscured from detection, necessitating behavior under conditions of ambiguity. Considerable evidence indicates decisions under ambiguity rely on inference processes that draw on past experiences to generate predictions under novel conditions. Despite the high demand for this process and the observation that it deteriorates disproportionately with age, the underlying mechanisms remain unknown. We developed a rodent model of decision-making during ambiguity to examine features of experience that contribute to inference. Rats learned either a simple (positive patterning) or complex (negative patterning) instrumental discrimination between the illumination of one or two lights. During test, only one light was lit while the other relevant light was blocked from physical detection (covered by an opaque shield, rendering its status ambiguous). We found experience with the complex negative patterning discrimination was necessary for rats to behave sensitively to the ambiguous test situation. These rats behaved as if they inferred the presence of the hidden light, responding differently than when the light was explicitly absent (uncovered and unlit). Differential expression profiles of the immediate early gene cFos indicated hippocampal involvement in the inference process while localized microinfusions of the muscarinic antagonist, scopolamine, into the dorsal hippocampus caused rats to behave as if only one light was present. That is, blocking cholinergic modulation prevented the rat from inferring the presence of the hidden light. Collectively, these results suggest cholinergic modulation mediates recruitment of hippocampal processes related to past experiences and transfer of these processes to make decisions during ambiguous situations. Our results correspond with correlations observed between human brain function and inference abilities, suggesting our experiments may inform interventions to alleviate or prevent cognitive dysfunction. © 2015 Wiley Periodicals, Inc.
Assuntos
Acetilcolina/metabolismo , Tomada de Decisões/fisiologia , Hipocampo/metabolismo , Aprendizagem/fisiologia , Animais , Cateteres de Demora , Tomada de Decisões/efeitos dos fármacos , Discriminação Psicológica/efeitos dos fármacos , Discriminação Psicológica/fisiologia , Feminino , Hipocampo/efeitos dos fármacos , Imuno-Histoquímica , Aprendizagem/efeitos dos fármacos , Antagonistas Muscarínicos/farmacologia , Testes Neuropsicológicos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Long-Evans , Escopolamina/farmacologia , Percepção Visual/efeitos dos fármacos , Percepção Visual/fisiologiaRESUMO
A fundamental question in vision neuroscience is how parallel processing of Retinal Ganglion Cell (RGC) signals is integrated at the level of the visual thalamus. It is well-known that parallel ON-OFF pathways generate output signals from the retina that are conveyed to the dorsal lateral geniculate nucleus (dLGN). However, it is unclear how these signals distribute onto thalamic cells and how these two pathways interact. Here, by electrophysiological recordings and c-Fos expression analysis, we characterized the effects of pharmacological manipulations of the retinal circuit aimed at inducing either a selective activation of a single pathway, OFF RGCs [intravitreal L-(+)-2-Amino-4-phosphonobutyric, L-AP4] or an unregulated activity of all classes of RGCs (intravitreal 4-Aminopyridine, 4-AP). In in vivo experiments, the analysis of c-Fos expression in the dLGN showed that these two manipulations recruited active cells from the same area, the lateral edge of the dLGN. Despite this similarity, the unregulated co-activation of both ON and OFF pathways by 4-AP yielded a much stronger recruitment of GABAergic interneurons in the dLGN when compared to L-AP4 pure OFF activation. The increased activation of an inhibitory thalamic network by a high level of unregulated discharge of ON and OFF RGCs might suggest that cross-inhibitory pathways between opposing visual channels are presumably replicated at multiple levels in the visual pathway, thus increasing the filtering ability for non-informative or noisy visual signals.
Assuntos
Neurônios GABAérgicos/fisiologia , Células Ganglionares da Retina/fisiologia , Tálamo/fisiologia , Vias Visuais/fisiologia , Percepção Visual/fisiologia , 4-Aminopiridina/farmacologia , Potenciais de Ação , Aminobutiratos/farmacologia , Animais , Potenciais Evocados Visuais , Agonistas de Aminoácidos Excitatórios/farmacologia , Interneurônios/fisiologia , Masculino , Modelos Neurológicos , Método de Monte Carlo , Estimulação Luminosa , Bloqueadores dos Canais de Potássio/farmacologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Sprague-Dawley , Células Ganglionares da Retina/citologia , Células Ganglionares da Retina/efeitos dos fármacos , Processamento de Sinais Assistido por Computador , Técnicas de Cultura de Tecidos , Vias Visuais/efeitos dos fármacos , Percepção Visual/efeitos dos fármacosRESUMO
Cannabis use in adolescence may be characterized by differences in the neural basis of affective processing. In this study, we used an fMRI affective face processing task to compare a large group (n=70) of 14-year olds with a history of cannabis use to a group (n=70) of never-using controls matched on numerous characteristics including IQ, SES, alcohol and cigarette use. The task contained short movies displaying angry and neutral faces. Results indicated that cannabis users had greater reactivity in the bilateral amygdalae to angry faces than neutral faces, an effect that was not observed in their abstinent peers. In contrast, activity levels in the cannabis users in cortical areas including the right temporal-parietal junction and bilateral dorsolateral prefrontal cortex did not discriminate between the two face conditions, but did differ in controls. Results did not change after excluding subjects with any psychiatric symptomology. Given the high density of cannabinoid receptors in the amygdala, our findings suggest cannabis use in early adolescence is associated with hypersensitivity to signals of threat. Hypersensitivity to negative affect in adolescence may place the subject at-risk for mood disorders in adulthood.