A Computational Model for the Simulation of Prepulse Inhibition and Its Modulation by Cortical and Subcortical Units.

The sensorimotor gating is a nervous system function that modulates the acoustic startle response (ASR). Prepulse inhibition (PPI) phenomenon is an operational measure of sensorimotor gating, defined as the reduction of ASR when a high intensity sound (pulse) is preceded in milliseconds by a weaker stimulus (prepulse). Brainstem nuclei are associated with the mediation of ASR and PPI, whereas cortical and subcortical regions are associated with their modulation. However, it is still unclear how the modulatory units can influence PPI. In the present work, we developed a computational model of a neural circuit involved in the mediation (brainstem units) and modulation (cortical and subcortical units) of ASR and PPI. The activities of all units were modeled by the leaky-integrator formalism for neural population. The model reproduces basic features of PPI observed in experiments, such as the effects of changes in interstimulus interval, prepulse intensity, and habituation of ASR. The simulation of GABAergic and dopaminergic drugs impaired PPI by their effects over subcortical units activity. The results show that subcortical units constitute a central hub for PPI modulation. The presented computational model offers a valuable tool to investigate the neurobiology associated with disorder-related impairments in PPI.

Maternal depression and child development at 3 years of age: a longitudinal study in a Brazilian child development promotion program.

BACKGROUND: We tested the hypothesis that children of non-depressed mothers perform better in a developmental test at 3 years than children of depressed mothers. METHOD: Longitudinal analysis from a trial to assess the impact of a child development promotion program in 30 Brazilian municipalities. Mothers and children were appraised at first-year post-partum, 1 and 3 years after enrollment. Child development was assessed through the Ages and Stages Questionnaire (ASQ3) and maternal depression through the Edinburgh Postnatal Depression Scale (EPDS). Crude and adjusted beta coefficients were obtained by linear regression before and after multiple imputation. RESULTS: In total, 2098 mother/child dyads were included and 8.2% of the mothers had persistent depressive symptoms. There was a decrease in ASQ3 as the number of follow-ups with EPDS ≥ 10 increased (p for trend <0.001). In adjusted analysis, the direction of the association persisted but lost statistical significance. After multiple imputation, children from mothers with EPDS ≥ 10 in three follow-ups presented a decrease of about 14 points in ASQ3 (adjusted beta coefficient = -13.79; -22.59 to -5.00) (p for trend = 0.001). CONCLUSIONS: Identification of women at increased risk of depression should be among the primary health care sector priorities in maternal and child health in Brazil. IMPACT: In our population study, almost one in every ten women presented persistent depression symptoms across the first 3 years postpartum. In adjusted analysis there was a detrimental impact of persistent maternal depression on child development at 3 years of age. The persistent exposure to maternal depression across early childhood negatively influences children's development. Considering its prevalence, identification of women at increased risk of depression should be among the primary health care sector priorities in maternal and child health in Brazil.

Avaliação do Programa Criança Feliz: um estudo randomizado em 30 municípios brasileiros / Evaluation of the Happy Child Program: a randomized study in 30 Brazilian municipalities

Resumo O Programa Criança Feliz (PCF) atinge 1,4 milhão de crianças brasileiras menores de três anos com visitas domiciliares visando o desenvolvimento neuropsicomotor. Com base em modelo conceitual, avaliou-se implementação e impacto do PCF em estudo randomizado, em 30 municípios. Ao todo 3.242 crianças foram alocadas para o grupo intervenção (GI) ou controle (GC), sendo 80,0% acompanhadas prospectivamente durante três anos. O desenvolvimento foi avaliado pelo Ages and Stages Questionnaire (ASQ3). Análises por intenção de tratar mostraram escores médios de 203,3 no GI e 201,3 no GC. Análises adicionais com variáveis instrumentais e emparelhamento por escores de propensão tampouco mostraram efeito, uma vez que o número de contatos recebidos não esteve associado aos escores ASQ3. Tampouco foi observado impacto sobre estimulação, interações responsivas ou atributos psicológicos das crianças. As visitas foram interrompidas durante 12 meses devido à COVID-19, sendo substituídas por contatos virtuais. O estudo de implementação revelou baixa cobertura no GI, contaminação do GC, deficiências na gestão e baixa qualidade das visitas em muitos municípios. O estudo não demonstrou impacto do PCF implementado sob condições de rotina e fornece elementos para seu aprimoramento.

Abstract The Happy Child Program (Programa Criança Feliz - PCF, in Portuguese) reaches 1.4 million Brazilian children under three years of age with home visits aimed at promoting neuropsychomotor development. Based on a conceptual model, PCF implementation and impact were evaluated in a randomized study in 30 municipalities. A total of 3,242 children were allocated to the intervention (IG) or control (CG) group, 80.0% of whom were prospectively followed up from late 2018 to late 2021. Development was assessed by the Ages and Stages Questionnaire (ASQ3). During the three-year study period, visits were replaced by virtual contacts for an average of 12 months due to COVID-19. At the endline survey, intent-to-treat analyses showed mean scores of 203.3 in the IG and 201.3 in the CG. Additional analyses using instrumental variables and propensity scores matching also showed no effect, since the number of contacts with the program was not associated with ASQ3 scores. No impact was observed on stimulation, responsive interactions or psychological attributes of children. The implementation study revealed low coverage in the IG, contamination of the CG, deficiencies in management and low quality of visits in many municipalities. The study did not demonstrate an impact of PCF implemented under routine conditions, but provides elements for its improvement.

Evaluation of the Happy Child Program: a randomized study in 30 Brazilian municipalities. / Avaliação do Programa Criança Feliz: um estudo randomizado em 30 municípios brasileiros.

The Happy Child Program (Programa Criança Feliz - PCF, in Portuguese) reaches 1.4 million Brazilian children under three years of age with home visits aimed at promoting neuropsychomotor development. Based on a conceptual model, PCF implementation and impact were evaluated in a randomized study in 30 municipalities. A total of 3,242 children were allocated to the intervention (IG) or control (CG) group, 80.0% of whom were prospectively followed up from late 2018 to late 2021. Development was assessed by the Ages and Stages Questionnaire (ASQ3). During the three-year study period, visits were replaced by virtual contacts for an average of 12 months due to COVID-19. At the endline survey, intent-to-treat analyses showed mean scores of 203.3 in the IG and 201.3 in the CG. Additional analyses using instrumental variables and propensity scores matching also showed no effect, since the number of contacts with the program was not associated with ASQ3 scores. No impact was observed on stimulation, responsive interactions or psychological attributes of children. The implementation study revealed low coverage in the IG, contamination of the CG, deficiencies in management and low quality of visits in many municipalities. The study did not demonstrate an impact of PCF implemented under routine conditions, but provides elements for its improvement.

O Programa Criança Feliz (PCF) atinge 1,4 milhão de crianças brasileiras menores de três anos com visitas domiciliares visando o desenvolvimento neuropsicomotor. Com base em modelo conceitual, avaliou-se implementação e impacto do PCF em estudo randomizado, em 30 municípios. Ao todo 3.242 crianças foram alocadas para o grupo intervenção (GI) ou controle (GC), sendo 80,0% acompanhadas prospectivamente durante três anos. O desenvolvimento foi avaliado pelo Ages and Stages Questionnaire (ASQ3). Análises por intenção de tratar mostraram escores médios de 203,3 no GI e 201,3 no GC. Análises adicionais com variáveis instrumentais e emparelhamento por escores de propensão tampouco mostraram efeito, uma vez que o número de contatos recebidos não esteve associado aos escores ASQ3. Tampouco foi observado impacto sobre estimulação, interações responsivas ou atributos psicológicos das crianças. As visitas foram interrompidas durante 12 meses devido à COVID-19, sendo substituídas por contatos virtuais. O estudo de implementação revelou baixa cobertura no GI, contaminação do GC, deficiências na gestão e baixa qualidade das visitas em muitos municípios. O estudo não demonstrou impacto do PCF implementado sob condições de rotina e fornece elementos para seu aprimoramento.

The Antioxidant N-Acetyl-L-Cysteine Restores the Behavioral Deficits in a Neurodevelopmental Model of Schizophrenia Through a Mechanism That Involves Nitric Oxide.

The disruption of neurodevelopment is a hypothesis for the emergence of schizophrenia. Some evidence supports the hypothesis that a redox imbalance could account for the developmental impairments associated with schizophrenia. Additionally, there is a deficit in glutathione (GSH), a main antioxidant, in this disorder. The injection of metilazoximetanol acetate (MAM) on the 17th day of gestation in Wistar rats recapitulates the neurodevelopmental and oxidative stress hypothesis of schizophrenia. The offspring of rats exposed to MAM treatment present in early adulthood behavioral and neurochemical deficits consistent with those seen in schizophrenia. The present study investigated if the acute and chronic (250 mg/kg) treatment during adulthood with N-acetyl-L-cysteine (NAC), a GSH precursor, can revert the behavioral deficits [hyperlocomotion, prepulse inhibition (PPI), and social interaction (SI)] in MAM rats and if the NAC-chronic-effects could be canceled by L-arginine (250 mg/kg, i.p, for 5 days), nitric oxide precursor. Analyses of markers involved in the inflammatory response, such as astrocytes (glial fibrillary acid protein, GFAP) and microglia (binding adapter molecule 1, Iba1), and parvalbumin (PV) positive GABAergic, were conducted in the prefrontal cortex [PFC, medial orbital cortex (MO) and prelimbic cortex (PrL)] and dorsal and ventral hippocampus [CA1, CA2, CA3, and dentate gyrus (DG)] in rats under chronic treatment with NAC. MAM rats showed decreased time of SI and increased locomotion, and both acute and chronic NAC treatments were able to recover these behavioral deficits. L-arginine blocked NAC behavioral effects. MAM rats presented increases in GFAP density at PFC and Iba1 at PFC and CA1. NAC increased the density of Iba1 cells at PFC and of PV cells at MO and CA1 of the ventral hippocampus. The results indicate that NAC recovered the behavioral deficits observed in MAM rats through a mechanism involving nitric oxide. Our data suggest an ongoing inflammatory process in MAM rats and support a potential antipsychotic effect of NAC.

Early Schizophrenia and Bipolar Disorder Patients Display Reduced Neural Prepulse Inhibition.

BACKGROUND: Altered sensorimotor gating has been demonstrated by Prepulse Inhibition (PPI) tests in patients with psychosis. Recent advances in signal processing methods allow assessment of neural PPI through electroencephalogram (EEG) recording during acoustic startle response measures (classic muscular PPI). Simultaneous measurements of muscular (eye-blink) and neural gating phenomena during PPI test may help to better understand sensorial processing dysfunctions in psychosis. In this study, we aimed to assess simultaneously muscular and neural PPI in early bipolar disorder and schizophrenia patients. METHOD: Participants were recruited from a population-based case-control study of first episode psychosis. PPI was measured using electromyography (EMG) and EEG in pulse alone and prepulse + pulse with intervals of 30, 60, and 120 ms in early bipolar disorder (n = 18) and schizophrenia (n = 11) patients. As control group, 15 socio-economically matched healthy subjects were recruited. All subjects were evaluated with Rating Scale, Hamilton Rating Scale for Depression, and Young Mania Rating Scale questionnaires at recruitment and just before PPI test. Wilcoxon ranked sum tests were used to compare PPI test results between groups. RESULTS: In comparison to healthy participants, neural PPI was significantly reduced in PPI 30 and PPI60 among bipolar and schizophrenia patients, while muscular PPI was reduced in PPI60 and PPI120 intervals only among patients with schizophrenia. CONCLUSION: The combination of muscular and neural PPI evaluations suggested distinct impairment patterns among schizophrenia and bipolar disorder patients. Simultaneous recording may contribute with novel information in sensory gating investigations.

Vaccination coverage in children up to 2 years old, receiving financial support from the Family Income Transfer Program, Brazil. / Cobertura vacinal em crianças de até 2 anos de idade beneficiárias do Programa Bolsa Família, Brasil.

OBJECTIVE: To assess vaccination coverage, based on the National Immunization Program schedule, among children receiving financial support from the Family Income Transfer Program, Brazil, according to the family socioeconomic status and maternal characteristics. METHODS: 3,242 children under 12 months old were assessed between August/2018 and April/2019, of whom 3,008 were reassessed between September/2019 and January/2020. The analyses were performed using multilevel models (level 3, Federative Unit; level 2, municipality; level 1, children). RESULTS: Vaccination coverage was 2.5 fold higher in the first follow-up (61.0% - 95% CI 59.3;62.6%), compared to the second follow-up (24.8% - 95% CI 22.8;25.9%) (p<0.001). In the first follow-up, coverage was higher in the richest quintile (67.9%) and in children whose mothers had ≥9 years of schooling (63.3%). In the second follow-up, there were no differences. The highest coverage occurred between 0.5-2.5 (93.5%) and 12.5-15.5 months (34.4%), respectively, first and second follow-ups. CONCLUSION: Low coverage was found, both in the first and second year of life.

Vaccination coverage of children up to two years of age, benefiting from the Bolsa Família Program, Brazil / Cobertura de vacunación de niños hasta dos años, beneficiarios del Programa Bolsa Família, Brasil / Cobertura vacinal em crianças de até dois anos de idade beneficiárias do Programa Bolsa Família, Brasil

Objective: Evaluate the vaccinal coverage in agreement with the Brazilian National Immunization Program, among children benefiting from the Bolsa Familia Program, Brazil, according to the family's socioeconomic level and maternal characteristics. Methods: 3242 children were assessed between August/2018 and April/2019, of which 3008 were reassessed between September/2019 and January/2020. Multilevel models (level 3, state; level 2: municipality, level 1, children) were employed. Results: Coverage was 2.5 times higher in the first (61.0% ­ 95%CI 59.3;62.6%) than in the second follow-up (24.8% ­ 95%CI 22.8;25.9%) (p<0.001). In the first follow-up, coverage was higher in children in the richest quintile (67.9%) and whose mothers had ≥9 years of schooling (63.3%). There were no differences in the second follow-up. The highest coverage occurred between 0.5-2.5 months (93.5%) and 12.5-15.5 months (34.4%), respectively in the first and second follow-ups. Conclusion: The coverage of adequate vaccination was low, both in the first and second year of life.

Objetivo: Avaliar a cobertura vacinal, conforme o calendário do Programa Nacional de Imunizações, entre crianças beneficiárias do Programa Bolsa Família, Brasil, segundo nível socioeconômico da família e características maternas. Métodos: Foram avaliadas 3.242 crianças menores de 12 meses de vida entre agosto/2018 e abril/2019, sendo 3.008 delas reavaliadas entre setembro/2019 e janeiro/2020. As análises foram realizadas utilizando-se modelos multiníveis (nível 3, Unidade da Federação; nível 2, município; nível 1, crianças). Resultados: A cobertura vacinal foi 2,5 vezes maior no primeiro (61,0% ­ IC95% 59,3;62,6%), comparado ao segundo acompanhamento (24,8% ­ IC95% 22,8;25,9%) (p<0,001). No primeiro acompanhamento, a cobertura foi maior no quintil mais rico (67,9%) e nas crianças cujas mães tinham ≥9 anos de escolaridade (63,3%). No segundo acompanhamento, não houve diferenças. As maiores coberturas ocorreram entre 0,5-2,5 (93,5%) e 12,5-15,5 meses (34,4%), respectivamente primeiro e segundo acompanhamentos. Conclusão: Encontrou-se baixa cobertura, tanto no primeiro quanto no segundo ano de vida.

Cobertura vacinal em crianças de até 2 anos de idade beneficiárias do Programa Bolsa Família, Brasil / Cobertura de vacunación de niños hasta 2 años, beneficiarios del Programa Bolsa Familia, Brasil / Vaccination coverage in children up to 2 years old, receiving financial support from the Family Income Transfer Program, Brazil

Objetivo: Avaliar a cobertura vacinal, conforme o calendário do Programa Nacional de Imunizações, entre crianças beneficiárias do Programa Bolsa Família, Brasil, segundo nível socioeconômico da família e características maternas. Métodos: Foram avaliadas 3.242 crianças menores de 12 meses de vida entre agosto de 2018 e abril de 2019, sendo 3.008 delas reavaliadas entre setembro de 2019 e janeiro de 2020. As análises foram realizadas utilizando-se modelos multiníveis (nível 3, Unidade da Federação; nível 2, município; nível 1, crianças). Resultados: A cobertura vacinal foi 2,5 vezes maior no primeiro (61,0% - IC95% 59,3;62,6%), comparado ao segundo acompanhamento (24,8% - IC95% 22,8;25,9%) (p<0,001). No primeiro acompanhamento, a cobertura foi maior no quintil mais rico (67,9%) e entre as crianças cujas mães tinham ≥9 anos de escolaridade (63,3%). No segundo acompanhamento, não houve diferenças. As maiores coberturas ocorreram entre 0,5-2,5 (93,5%) e 12,5-15,5 meses (34,4%), respectivamente primeiro e segundo acompanhamentos. Conclusão: Encontrou-se baixa cobertura, tanto no primeiro quanto no segundo ano de vida.

Objetivo: Evaluar la cobertura de vacunación según el Programa Nacional de Inmunizaciones, entre los niños beneficiarios del Programa Bolsa Familia, Brasil, según el nivel socioeconómico familiar y características maternas. Métodos: Analizamos 3.242 niños menores de 12 meses entre agosto/2018 y abril/2019 y se reevaluaron 3.008 entre septiembre/2019 y enero/2020. Se utilizaron modelos multinivel (nivel 3, estado; nivel 2, municipio; nivel 1, niños). Resultados: La cobertura fue 2,5 veces mayor en el primer seguimiento (61,0% - IC95% 59,3;62,6%) que en el segundo (24,8% - IC95% 22,8;25,9%) (p<0,001). En el primer seguimiento, la cobertura fue mayor en el quintil más rico (67,9%) y entre aquellos cuyas madres tenían ≥9 años de escolaridad (63,3%). En el segundo seguimiento no hubo diferencias. La mayor cobertura ocurrió entre los 0,5-2,5 (93,5%) y 12,5-15,5 meses (34,4%), respectivamente, en el primero y el segundo seguimiento. Conclusión: Se encontró baja cobertura en el primero y en el segundo año de vida.

Objective: To assess vaccination coverage, based on the National Immunization Program schedule, among children receiving financial support from the Family Income Transfer Program, Brazil, according to the family socioeconomic status and maternal characteristics. Methods: 3,242 children under 12 months old were assessed between August/2018 and April/2019, of whom 3,008 were reassessed between September/2019 and January/2020. The analyses were performed using multilevel models (level 3, Federative Unit; level 2, municipality; level 1, children). Results: Vaccination coverage was 2.5 fold higher in the first follow-up (61.0% - 95% CI 59.3;62.6%), compared to the second follow-up (24,8% - IC95% 22,8;25,9%) (p<0,001). In the first follow-up, coverage was higher in the richest quintile (67.9%) and in children whose mothers had ≥9 years of schooling (63.3%). In the second follow-up, there were no differences. The highest coverage occurred between 0.5-2.5 (93.5%) and 12.5-15.5 months (34.4%), respectively, first and second follow-ups. Conclusion: Low coverage was found, both in the first and second year of life.

Meta-Analysis of Sensorimotor Gating Deficits in Patients With Schizophrenia Evaluated by Prepulse Inhibition Test.

Prepulse inhibition (PPI) of startle is an operational measure of sensorimotor gating that is often impaired in patients with schizophrenia. Despite the large number of studies, there is considerable variation in PPI outcomes reported. We conducted a systematic review and meta-analysis investigating PPI impairment in patients with schizophrenia compared with healthy control subjects, and examined possible explanations for the variation in results between studies. Major databases were screened for observational studies comparing healthy subjects and patients with schizophrenia for the prepulse and pulse intervals of 60 and 120 ms as primary outcomes, ie, PPI-60 and PPI-120. Standardized mean difference (SMD) and 95% confidence intervals (CI) were extracted and pooled using random effects models. We then estimated the mean effect size of these measures with random effects meta-analyses and evaluated potential PPI heterogeneity moderators, using sensitivity analysis and meta-regressions. Sixty-seven primary studies were identified, with 3685 healthy and 4290 patients with schizophrenia. The schizophrenia group showed reduction in sensorimotor gating for both PPI-60 (SMD = -0.50, 95% CI = [-0.61, -0.39]) and PPI-120 (SMD = -0.44, 95% CI = [-0.54, -0.33]). The sensitivity and meta-regression analysis showed that sample size, gender proportion, imbalance for gender, source of control group, and study continent were sources of heterogeneity (P < .05) for both PPI-60 and PPI-120 outcomes. Our findings confirm a global sensorimotor gating deficit in schizophrenia patients, with overall moderate effect size for PPI-60 and PPI-120. Methodological consistency should decrease the high level of heterogeneity of PPI results between studies.

A Method for Simultaneous Evaluation of Muscular and Neural Prepulse Inhibition.

Prepulse inhibition (PPI) test has been widely used to evaluate sensorimotor gating. In humans, deficits in this mechanism are measured through the orbicularis muscle response using electromyography (EMG). Although this mechanism can be modulated by several brain structures and is impaired in some pathologies as schizophrenia and bipolar disorder, neural PPI evaluation is rarely performed in humans. Since eye blinks are a consequence of PPI stimulation, they strongly contaminate the electroencephalogram (EEG) signal. This paper describes a method to reduce muscular artifacts and enable neural PPI assessment through EEG in parallel to muscular PPI evaluation using EMG. Both types of signal were simultaneously recorded in 22 healthy subjects. PPI was evaluated by the acoustical startle response with EMG and by the P2-N1 event-related potential (ERP) using EEG in Fz, Cz, and Pz electrodes. In order to remove EEG artifacts, Independent Component Analysis (ICA) was performed using two methods. Firstly, visual inspection discarded components containing artifact characteristics as ocular and tonic muscle artifacts. The second method used visual inspection as gold standard to validate parameters in an automated component selection using the SASICA algorithm. As an outcome, EEG artifacts were effectively removed and equivalent neural PPI evaluation performance was obtained using both methods, with subjects exhibiting consistent neural as well as muscular PPI. This novel method improves PPI test, enabling neural gating mechanisms assessment within the latency of 100-200 ms, which is not evaluated by other sensory gating tests as P50 and mismatch negativity.

Dorsal striatum D1-expressing neurons are involved with sensorimotor gating on prepulse inhibition test.

Prepulse inhibition (PPI) is a behavioral test in which the startle reflex response to a high-intensity stimulus (pulse) is inhibited by the prior presentation of a weak stimulus (prepulse). The classic neural circuitry that mediates startle response is localized in the brainstem; however, recent studies point to the contribution of structures involved in higher cognitive functions in regulating the sensorimotor gating, particularly forebrain regions innervated by dopaminergic nuclei. The aim of the present study was to verify the role of dorsal striatum (DS) and dopaminergic transmitting mediated by D1 and D2 receptors on PPI test in rats. DS inactivation induced by muscimol injection did not affect PPI (%PPI and startle response), although it impaired the locomotor activity and caused catalepsy. Infusion of D1-like antagonist SCH23390 impaired %PPI but did not disturb the startle response and locomotor activity evaluated immediately after PPI test. D2 antagonist microinjection (sulpiride) did not affect %PPI and startle response, but impaired motor activity. These results point to an important role of DS, probably mediated by direct basal ganglia pathway, on modulation of sensorimotor gating, in accordance with clinical studies showing PPI deficits in schizophrenia, Tourette syndrome, and compulsive disorders - pathologies related to basal ganglia dysfunctions.

Signaling Mechanisms in the Nitric Oxide Donor- and Amphetamine-Induced Dopamine Release in Mesencephalic Primary Cultured Neurons.

Previous research has shown that nitric oxide (NO) synthase inhibitors prevent rodents' sensorimotor gating impairments induced by dopamine releasing drugs, such as amphetamine (Amph) and methylphenidate. The mechanisms of this effect have not been entirely understood. In the present work, we investigated some possible mechanisms by which the NO donor, NOC-12 (3-ethyl-3-(ethylaminoethyl)-1-hydroxy-2-oxo-1-triazene), influence spontaneous and Amph-induced dopamine release, using rat mesencephalic primary cultured neurons preparations. Our results showed that NOC-12 increased dopamine release in a concentration-dependent manner and potentiated the Amph-induced one. Dopamine release induced by NOC-12 was disrupted by N-acetyl-L-cystein (NAC-a free radical scavenger) and MK-801, a NMDA (N-methyl-D-aspartate) non-competitive antagonist, and was concentration dependently affected by oxadiazolo[4,3]quinoxalin-1-one, an inhibitor of the soluble guanylate cyclase (sGC). In contrast, dopamine released by Amph was facilitated by NAC and by MK-801 and not affected by nifedipine (a L-type-Ca(+2) channel blocker), which enhanced NOC-12-induced dopamine release. The present work demonstrates that DA release induced by NOC-12 is partially dependent on sGC and on NMDA activation, and is modulated by L-type Ca(+2) channel and the antioxidant NAC. This mechanism differs from the Amph-induced one, which appears not to depend on L-type Ca(+2) channel and seems to be facilitated by NMDA channel blocking and by NAC. These results suggest that Amph and NOC-12 induce dopamine release through complementary pathways, which may explain the potentiation of Amph-induced dopamine release by NOC-12. These findings contribute to understand the involvement of NO in dopamine-related neuropsychiatric and neurodegenerative diseases.

Simultaneous evaluation of prepulse inhibition with EMG and EEG using advanced artifact removal techniques.

Prepulse inhibition (PPI) consists of a reduction of the acoustic startle reflex (SR) magnitude (measured with EMG) when a startling stimulus is preceded by a non-startling one. This behavior has been extensively investigated in studies related to schizophrenia, since sensory-motor deficit plays a central role in its pathophysiology. However, the same auditory stimuli that trigger the SR also provoke intense auditory evoked responses (AEP), which can be measured with EEG. Comparing these two types of responses, acquired simultaneously, is a great opportunity to investigate the dependence and interdependence of their neural pathways. Nonetheless, so far very few studies have dared to perform such simultaneous recordings, because SR produces strong eye blinks and muscle contraction artifacts that contaminate EEG electrodes placed on the scalp. In this study we investigated the possibility of simultaneously obtaining both the acoustic SR (using EMG) and the AEP (using EEG) measures, through the use of advanced artifact removal techniques, to better characterize PPI in healthy humans.

Pleiotrophin receptor RPTP-zeta/beta expression is up-regulated by L-DOPA in striatal medium spiny neurons of parkinsonian rats.

L-DOPA is still the drug of choice to treat Parkinson's disease although adverse side effects appear after several years of treatment. These are thought to be the consequence of plastic re-arrangements of the nigrostriatal connections, such as sprouting of the dopaminergic terminals or post-synaptic changes. Pleiotrophin, a trophic factor that we have shown to be up-regulated in the striatum of parkinsonian rats after long-term L-DOPA treatment may play a role in these plastic changes. To determine whether one of the three known pleiotrophin receptors [N-syndecan, receptor protein tyrosine phosphatase type zeta beta (RPTP-zeta/beta) and anaplastic lymphoma kinase] might be implicated in these putative plastic effects, we quantified their expression levels by real-time RT-PCR in the striatum and mesencephalon of rats with partial lesions of the nigrostriatal pathway undergoing L-DOPA treatment. Both pleiotrophin and RPTP-zeta/beta expression was up-regulated in the striatum but not in the mesencephalon of lesioned rats and RPTP-zeta/beta expression was even further increased by L-DOPA. The levels of the RPTP-zeta/beta protein were also increased in the striatum of L-DOPA-treated lesioned rats. Immunofluorescence labeling showed the protein to be constitutively expressed in striatal medium spiny neurons, which are innervated by both the corticostriatal glutamatergic and nigrostriatal dopaminergic systems. RPTP-zeta/beta might therefore be implicated in the plastic changes triggered by L-DOPA treatment and might merit further study as a potential candidate for Parkinon's disease therapy.

Modulation of dopamine uptake by nitric oxide in cultured mesencephalic neurons.

Strong evidence obtained from in vivo and ex-vivo studies suggests the existence of interaction between dopaminergic and nitrergic systems. Some of the observations suggest a possible implication of nitric oxide (NO) in dopamine (DA) uptake mechanism. The present work investigated the interaction between both systems by examining the effect of an NO donor, sodium nitroprusside (SNP), associated with the indirect DA agonist, amphetamine (AMPH) on tritiated DA uptake in cultures of embryonic mesencephalic neurons. Consistent with the literature, both AMPH (1, 3 and 10 microM) and SNP (300 microM and 1 mM) inhibited DA uptake in a dose-dependent manner. In addition, the inhibition of DA uptake by AMPH (1 and 3 microM) was significantly increased by the previous addition of SNP (300 microM). The implication of NO in this interaction was supported by the fact that the free radical scavenger N-acetyl-L-Cysteine (500 microM) significantly increased DA uptake and completely abolished the effect of SNP, leaving unaffected that from AMPH on DA uptake. Further, double-labeling immunohistochemistry showed the presence of tyrosine hydroxylase- (TH, marker for dopaminergic neurons) and neuronal NO synthase- (nNOS, marker for NO containing neurons) expressing neurons in mesencephalic cultures. Some dopaminergic neurons also express nNOS giving further support for a pre-synaptic interaction between both systems. This is the first work demonstrating in mesencephalic cultured neurons a combined effect of an NO donor and an indirect DA agonist on specific DA uptake.

Conflict as a determinant of rat behavior in three types of elevated plus-maze.

Three groups of rats were tested in different types of elevated plus-mazes, a normal one (two closed and two open arms), a totally closed one (four closed arms) and a totally open (four open arms). Closed arms were surrounded by 40-cm high wooden walls and open arms were surrounded by 0.5-cm high transparent Plexiglas ledges. As expected, in the closed maze rats explored equally all the arms, both in terms of time and frequency of entries, as well as in exploration of the extremities. Rats in the totally open maze also presented a similar pattern of exploration, that is, no significant differences were found between the results obtained with the closed and the open mazes in terms of central and extremities exploration. It is suggested that the typical behavior of rats in the conventional elevated plus-maze is caused by the contrasting characteristics of open and closed arms rather than by the physical aversive characteristics of the open arms per se. Results also confirm a prediction made by a computer model simulating rat exploratory behavior in virtual mazes, normal, totally open and totally closed.