Prepulse inhibition of the acoustic startle reflex impairment by 5-HT2A receptor activation in the inferior colliculus is prevented by GABAA receptor blockade in the pedunculopontine tegmental nucleus.

The relationship between serotonin dysfunction and schizophrenia commenced with the discovery of the effects of lysergic acid diethylamide (LSD) that has high affinity for 5-HT2A receptors. Activation of these receptors produces perceptual and behavioural changes such as illusions, visual hallucinations and locomotor hyperactivity. Using prepulse inhibition (PPI) of the acoustic startle, which is impaired in schizophrenia,we aimed to investigate:i) the existence of a direct and potentially inhibitory neural pathway between the inferior colliculus (IC) and the pedunculopontine tegmental nucleus (PPTg) involved in the mediation of PPI responses by a neural tract tracing procedure;ii) if the microinjection of the 5-HT2A receptors agonist DOI in IC would activate neurons in this structure and in the PPTg by a c-Fos protein immunohistochemistry study;iii) whether the deficits in PPI responses, observed after the administration of DOI in the IC, could be prevented by the concomitant microinjection of the GABAA receptor antagonist bicuculline in the PPTg.Male Wistar rats were used in this study. An IC-PPTg reciprocated neuronal pathway was identified by neurotracing. The number of c-Fos labelled cells was lower in the DOI group in IC and PPTg, suggesting that this decrease could be due to the high levels of GABA in both structures. The concomitant microinjections of bicuculline in PPTg and DOI in IC prevented the PPI deficit observed after the IC microinjection of DOI. Our findings suggest that IC 5-HT2A receptors may be at least partially involved in the regulation of inhibitory pathways mediating PPI response in IC and PPTg structures.

Clozapine prevented social interaction deficits and reduced c-Fos immunoreactivity expression in several brain areas of rats exposed to acute restraint stress.

In the present study, we evaluate the effect of acute restraint stress (15 min) of male Wistar rats on social interaction measurements and c-Fos immunoreactivity (c-Fos-ir) expression, a marker of neuronal activity, in areas involved with the modulation of acute physical restraint in rats, i.e., the paraventricular nucleus of the hypothalamus (PVN), median raphe nucleus (MnR), medial prefrontal cortex (mPFC), cingulate prefrontal cortex (cPFC), nucleus accumbens (NaC), hippocampus (CA3), lateral septum (LS) and medial amygdala (MeA). We considered the hypothesis that restraint stress exposure could promote social withdrawal induced by the activation of the hypothalamic-pituitary-adrenocortical (HPA) axis, and increase c-Fos expression in these limbic forebrain areas investigated. In addition, we investigated whether pretreatment with the atypical antipsychotic clozapine (5 mg/kg; I.P.) could attenuate or block the effects of restraint on these responses. We found that restraint stress induced social withdrawal, and increased c-Fos-ir in these areas, demonstrating that a single 15 min session of physical restraint of rats effectively activated the HPA axis, representing an effective tool for the investigation of neuronal activity in brain regions sensitive to stress. Conversely, pretreatment with clozapine, prevented social withdrawal and reduced c-Fos expression. We suggest that treatment with clozapine exerted a preventive effect in the social interaction deficit, at least in part, by blocking the effect of restraint stress in brain regions that are known to regulate the HPA-axis, including the cerebral cortex, hippocampus, hypothalamus, septum and amygdala. Further experiments will be done to confirm this hypothesis.

Haloperidol rescues the schizophrenia-like phenotype in adulthood after rotenone administration in neonatal rats.

Neuropsychiatric disorders are multifactorial disturbances that encompass several hypotheses, including changes in neurodevelopment. It is known that brain development disturbances during early life can predict psychosis in adulthood. As we have previously demonstrated, rotenone, a mitochondrial complex I inhibitor, could induce psychiatric-like behavior in 60-day-old rats after intraperitoneal injections from the 5th to the 11th postnatal day. Because mitochondrial deregulation is related to psychiatric disorders and the establishment of animal models is a high-value preclinical tool, we investigated the responsiveness of the rotenone (Rot)-treated newborn rats to pharmacological agents used in clinical practice, haloperidol (Hal), and methylphenidate (MPD). Taken together, our data show that Rot-treated animals exhibit hyperlocomotion, decreased social interaction, and diminished contextual fear conditioning response at P60, consistent with positive, negative, and cognitive deficits of schizophrenia (SZ), respectively, that were reverted by Hal, but not MPD. Rot-treated rodents also display a prodromal-related phenotype at P35. Overall, our results seem to present a new SZ animal model as a consequence of mitochondrial inhibition during a critical neurodevelopmental period. Therefore, our study is crucial not only to elucidate the relevance of mitochondrial function in the etiology of SZ but also to fulfill the need for new and trustworthy experimentation models and, likewise, provide possibilities to new therapeutic avenues for this burdensome disorder.

Inhibition of Toll Like Signaling Pathway Is Associated With Genomic Instability in Rat Liver Exposed to Crack Cocaine.

BACKGROUND/AIM: The aim of the present study was to investigate the biological effects of subacute crack cocaine exposure in rat liver. MATERIAL AND METHODS: A total of 32 rats were distributed into four groups (n=8): Experimental group 1 (G1) and Experimental group 2 (G2): rats received 18 mg/kg of body weight (b.w) of crack cocaine for 5 days, once a day, group G2 remained 72 h without exposure after the experimental period (5 days)(abstinence); Experimental group 3 (G3): rats received 36 mg/kg of body weight (b.w) of crack cocaine for 5 days, once a day; Control Group (CTRL): rats received only the vehicle (DMSO) administered by the intraperitoneal (i.p) route for 5 days, once a day. RESULTS: All groups exposed to crack cocaine had an increase in the number of micronucleated hepatocytes and binucleated cells only in the highest tested dose (36 mg/kg). Karyolysis had an increase in the 18 mg/kg dose, in the abstinence group (G2), and 36 mg/kg group (G3); whereas pyknotic nuclei had an increase in the G2 group. The group exposed to 18 mg/kg of crack cocaine also showed high 8 OHdG expression. The p-NF-κB p65 protein decreased in the groups exposed to crack cocaine at doses of 18 and 36 mg/kg, as well as in the abstinence group. MyD88 was also found decreased in the group exposed to crack cocaine at 18 mg/kg. CONCLUSION: Crack cocaine inhibited toll like signaling pathway whilst being associated with genomic instability in rat liver cells.

Dimethoate induces genotoxicity as a result of oxidative stress: in vivo and in vitro studies.

Dimethoate ([O,O-dimethyl S-(N-methylcarbamoylmethyl) phosphorodithioate]) is an organophosphate insecticide and acaricide widely used for agricultural purposes. Genotoxicity refers to the ability of a chemical agent interact directly to DNA or act indirectly leading to DNA damage by affecting spindle apparatus or enzymes involved in DNA replication, thereby causing mutations. Taking into consideration the importance of genotoxicity induced by dimethoate, the purpose of this manuscript was to provide a mini review regarding genotoxicity induced by dimethoate as a result of oxidative stress. The present study was conducted on studies available in MEDLINE, PUBMED, EMBASE, and Google scholar for all kind of articles (all publications published until May, 2020) using the following key words: dimethoate, omethoate, DNA damage, genetic damage, oxidative stress, genotoxicity, mutation, and mutagenicity. The results showed that many studies were published in the scientific literature; the approach was clearly demonstrated in multiple tissues and organs, but few papers were designed in humans. In summary, new studies within the field are important for better understanding the pathobiological events of genotoxicity on human cells, particularly to explain what cells and/or tissues are more sensitive to genotoxic insult induced by dimethoate.

Does Panoramic X-ray Induce Cytogenetic Damage to Oral Cells? A Systematic Review With Meta-analysis.

AIM: The aim of this review was to evaluate the scientific literature regarding the cytogenetic damage in oral exfoliated cells of adult patients submitted to panoramic X-ray. MATERIALS AND METHODS: An extensive search of the literature was conducted on PubMed, Scopus and Web of Science databases for all studies published until April 2021 using combinations of the following keywords: "panoramic X-ray," "DNA damage," "genetic damage", "genotoxicity", "mutagenicity", cytotoxicity", "buccal cells", "oral mucosa", "tongue", "gingiva", "micronucleus assay", according to the PRISMA guidelines. All clinical studies in English language were included in the study. A total of 10 studies were identified. RESULTS: As expected, the results regarding the cytogenetic damage induced by panoramic X-ray are conflicting. Some authors have demonstrated that panoramic X-ray induces mutagenesis in oral cells, whereas others did not. After reviewing the 10 studies, two were classified as strong, four were considered moderate, and four were considered weak, according to the quality assessment components of the Effective Public Health Practice Project (EPHPP). Meta-analysis data revealed a negative response related to mutagenicity in oral cells by panoramic X-ray. CONCLUSION: Taken together, this review failed to demonstrate the association between micronucleus frequency and panoramic X-ray.

A comparative study on the effects of the benzodiazepine midazolam and the dopamine agents, apomorphine and sulpiride, on rat behavior in the two-way avoidance test.

In recent years, studies in behavioral pharmacology have shown the involvement of dopaminergic mechanisms in avoidance behavior as assessed by the two-way active avoidance test (CAR). Changes in dopaminergic transmission also occur in response to particularly threatening challenges. However, studies on the effects of benzodiazepine (BZD) drugs in this test are still unclear. Given the interplay of dopamine and other neurotransmitters in the neurobiology of anxiety and schizophrenia the aim of this work was to evaluate the effects of systemic administration of midazolam, the dopaminergic agonist apomorphine, and the D2 receptor antagonist sulpiride using the CAR, a test that shows good sensitivity to typical neuroleptic drugs. Whereas midazolam did not alter the avoidance response, apomorphine increased and sulpiride reduced them in this test. Escape was not affected by any drug treatments. Heightened avoidance was not associated with the increased motor activity caused by apomorphine. In contrast with the benzodiazepine midazolam, activation of post-synaptic D2 receptors with apomorphine facilitates, whereas the D2 receptor antagonism with sulpiride inhibited the acquisition of the avoidance behavior. Together, these results bring additional evidence for a role of D2 mechanisms in the acquisition of the active avoidance.

Could male reproductive system be the main target of subchronic exposure to manganese in adult animals?

Manganese (Mn) is one of the most common chemical elements on Earth and an essential micronutrient in animal organism. However, in supraphysiological levels and long-term exposures, it is a potential toxicant. Although nervous system is the most studied in relation to Mn toxicity, other tissues can have their function impaired by Mn in high doses. The present study investigated the possible adverse effects of subchronic exposure to supraphysiologic level of Mn (5 mg/kg or 15 mg/kg, intraperitoneally) on reproductive, neurobehavioral, renal and hepatic parameters of male rats. For the first time, the vulnerability of these parameters to Mn was concomitantly investigated. While our results demonstrate that Mn treatments were not sufficient to produce a marked effect of neurotoxic, hepatotoxic or renal toxicity in adult rats, we found typical indicators of reproductive toxicity such as histopathological changes (major in testes and epididymis) and impaired sperm concentration and quality. Mn, under these experimental conditions, seems to exert reproductive toxicity by different testicular mechanisms, i.e. direct and indirect action on germ cells. On the other hand, exposure to Mn did not change the pattern of cognitive and emotional behaviors and the histological organization of kidneys of experimental rats. The liver showed a weight increasement and hidropic degeneration, probable due to the detoxification overload. In summary, for the first time it was demonstrated that adult male reproductive system was more sensitive to Mn toxicity than nervous, hepatic and renal systems, although nervous system is known as the main target tissue of this metal.

Investigation of depression, anxiety and quality of life in patients with knee osteoarthritis: a comparative study.

INTRODUCTION: Osteoarthritis (OA) affects the articular cartilage and subchondral bone, compromising the joint as a whole. The knee joint is characterized as one of the main sites of involvement of OA and the most significant risk factors for developing the disease are aging, overweight and female gender. OA is considered one of the most frequent causes of disability, which may affect the quality of life of the patients, favoring the onset of mental disorders. OBJECTIVE: To investigate whether anxiety and depression symptoms are more significant in women with OA, when compared with women without this diagnosis, and to what extent this rheumatic disease affects the quality of life of these patients. METHODS: The study included 75 women, mean age 67 years; 40 were diagnosed with knee OA and 35 without this diagnosis. The following instruments were used: State-Trait Anxiety Inventory (STAI), Beck Depression Inventory (BDI) and SF-36, a quality of life questionnaire. RESULTS: Women with knee OA have higher rates of depression and anxiety when compared to controls; in addition, they have a lower quality of life. CONCLUSION: We believe that the treatment of patients with OA should consider the combination of pharmacotherapy, psychotherapy, counseling and family support, in order to achieve a better quality of life.

Prenatal exposure of Long-Evans rats to 17alpha-ethinylestradiol modifies neither latent inhibition nor prepulse inhibition of the startle reflex but elicits minor deficits in exploratory behavior.

Prenatal administration of synthetic estrogens in humans as well as lower mammals was reported to alter behavior in adulthood. The alterations remain to be characterized according to specific pathophysiological hypotheses. In this study, three common behavioral models of schizophrenia were tested, i.e., latent inhibition (LI), prepulse inhibition of the startle response (PPI) and hyperlocomotion under amphetamine. Female Long-Evans rats were injected i.p. with a solution of 17alpha-ethinylestradiol (15 microg kg(-1)) everyday from day 9 to 14 of pregnancy, and behavioral characteristics of their offspring, raised by Wistar foster mothers, were compared to those of rats born from dams injected with the vehicle only, over the same gestation period. LI was tested in a conditioned taste aversion and a conditioned passive avoidance paradigm followed by a parametric study of PPI and an evaluation of locomotion in an open field under saline or amphetamine (1.5 mg kg(-1)). Histological brain measurements were also carried out in a subset of the same rats. Neither LI nor PPI was altered using methods that had proven sensitive in previous pharmacological studies. Treated rats' locomotion was impaired, but amphetamine did not elicit a differential enhancement. A thinner Amon's horn layer was observed in their hippocampus. This indicates that standard models of schizophrenia did not fit to the behavioral abnormalities found by others and confirmed in this study. They were not due to the abnormal maternal care to pups elicited by the treatment.

Investigation of stress, anxiety and depression in women with fibromyalgia: a comparative study.

INTRODUCTION: Depression has emerged as the most prevalent mental disorder in patients with fibromyalgia. Stress, whose stages are alarm, resistance, near-exhaustion and exhaustion, constitutes a physical reaction to a threatening situation. OBJECTIVE: To investigate the levels of stress, anxiety and depression in women with fibromyalgia, comparing them with those of healthy women. PATIENTS AND METHODS: Participants were 50 women, 25 with a diagnosis of fibromyalgia according to the criteria of the American College of Rheumatology, and 25 without this diagnosis, matched for age. Instruments used: Lipp Inventory of Stress Symptoms for Adults (LISS), State-Trait Anxiety Inventory (STAI) and Beck Depression Inventory (BDI). RESULTS: The mean age was 49.36 years for the group with fibromyalgia (FM) and 49.20 years for the group without fibromyalgia (non-FM). FM showed a higher incidence of stress (96%) compared with non-FM (5%). The resistance phase was predominant in both groups, FM (42%) and non-FM (100%). In FM there was distribution of the four stages (alarm, resistance, near-exhaustion and exhaustion). The differences between phases in the analyzed groups were significant (p < 0.001). FM showed predominance of psychological symptoms (54%); non-FM did show the same frequency of psychological and physical/psychological (40%) symptoms. Symptoms of state and trait anxiety and of depression in FM were significantly higher, when compared with non-FM (p < 0.01). CONCLUSION: Stress index (96%), trait anxiety (over 50) and clinically relevant depression (greater than 20) in FM were relevant. The understanding of the emotional variables involved in fibromyalgia is important to define the therapeutic strategy.

Atypical antipsychotic olanzapine reversed deficit on prepulse inhibition of the acoustic startle reflex produced by microinjection of dizocilpine (MK-801) into the inferior colliculus in rats.

Patients with schizophrenia exhibit deficits in an operational measure of sensorimotor gating: prepulse inhibition (PPI) of startle. PPI is the normal reduction in the startle response caused by a low intensity non-startling stimulus (prepulse) which is presented shortly before the startle stimulus (pulse). MK-801 is an NMDA receptor-antagonist known to produce hyperactivity, deficits in prepulse inhibition and social withdrawal, behaviors which correlate well with some of the positive, cognitive and negative symptoms of schizophrenia. The inferior colliculus (IC) is a critical part of the auditory pathway mediating acoustic PPI. The activation of the IC by the acoustic prepulse reduces startle magnitude. Thus, the purpose of the present study was to elucidate the role of glutamatergic transmission in the IC on the expression of acoustic PPI. For that we investigated whether NMDA receptor stimulation or blockade would affect this response. Unilateral microinjections of NMDA (30 nmol/0.5 µL) into the IC did not alter PPI while microinjections of MK-801 (30 nmol/0.5 µL) into this structure disrupted PPI. We also examined the ability of the atypical antipsychotic olanzapine (5.0mg/kg; i.p.) to reverse the disruption of pre-pulse inhibition produced by unilateral microinjections of MK-801 into the IC of rats. Pretreatment with olanzapine blocked MK-801-induced disruption of PPI. Altogether, these results suggest that glutamate-mediated mechanisms of the IC are involved in the expression of PPI in rodents and that this response is sensitive to atypical antipsychotic olanzapine.

Investigação da ansiedade, depressão e qualidade de vida em pacientes portadores de osteoartrite no joelho: um estudo comparativo / Investigation of depression, anxiety and quality of life in patients with knee osteoarthritis: a comparative study

RESUMOIntrodução:A osteoartrite (OA), artrose ou osteoartrose acomete a cartilagem hialina e o osso subcondral e compromete a articulação como um todo. A articulação do joelho caracteriza-se como um dos principais sítios de acometimento da OA. O envelhecimento, o sobrepeso e o gênero (prevalência em mulheres) são os fatores de risco mais significativos para o desenvolvimento da doença. A OA é considerada uma das mais frequentes causas de incapacidade laborativa e pode afetar a qualidade de vida de seus portadores e favorecer a emergência de transtornos mentais.Objetivo:Avaliar se os sintomas de ansiedade e depressão são mais expressivos em mulheres com OA quando comparados com mulheres sem tal diagnóstico e o quanto essa doença reumática compromete a qualidade de vida desses pacientes.Métodos:Participaram deste estudo 75 mulheres, com média de 67 anos, 40 com diagnóstico de OA no joelho e 35 sem. Foram usados os seguintes instrumentos: Inventário de Ansiedade Traço e Estado, Inventário de Depressão de Beck e SF-36, questionário de qualidade de vida.Resultados:Mulheres portadoras de OA no joelho têm níveis maiores de depressão e ansiedade, além de apresentar qualidade de vida inferior em comparação com o grupo sem a doença.Conclusão:Acreditamos que o tratamento aos portadores de OA deveria considerar a combinação de farmacoterapia, psicoterapia, orientação e apoio por parte dos parentes e/ou pessoas próximas para que o paciente possa atingir melhor qualidade de vida.

ABSTRACTIntroduction:Osteoarthritis (OA) affects the articular cartilage and subchondral bone, compromising the joint as a whole. The knee joint is characterized as one of the main sites of involvement of OA and the most significant risk factors for developing the disease are aging, overweight and female gender. OA is considered one of the most frequent causes of disability, which may affect the quality of life of the patients, favoring the onset of mental disorders.Objective:To investigate whether anxiety and depression symptoms are more significant in women with OA, when compared with women without this diagnosis, and to what extent this rheumatic disease affects the quality of life of these patients.Methods:The study included 75 women, mean age 67 years; 40 were diagnosed with knee OA and 35 without this diagnosis. The following instruments were used: State-Trait Anxiety Inventory (STAI), Beck Depression Inventory (BDI) and SF-36, a quality of life questionnaire.Results:Women with knee OA have higher rates of depression and anxiety when compared to controls; in addition, they have a lower quality of life.Conclusion:We believe that the treatment of patients with OA should consider the combination of pharmacotherapy, psychotherapy, counseling and family support, in order to achieve a better quality of life.

Investigacao do estresse, ansiedade e depressao em mulheres com fibromialgia: um estudo comparativo / Investigation of stress, anxiety and depression in women with fibromyalgia: a comparative study

Introdução: A depressão tem se apresentado como o transtorno mental mais prevalente em pacientes com fibromialgia. O estresse, cujas fases são alarme, resistência, quase-exaustão e exaustão, constitui importante reação do organismo frente a uma situação ameaçadora. Objetivo: Investigar os índices de estresse, ansiedade e depressão em mulheres com fibromialgia, comparando-os com os de mulheres saudáveis. Pacientes e métodos: Participaram 50 mulheres, 25 com o diagnóstico de fibromialgia, segundo os critérios do American College of Rheumatology, e 25 sem o diagnóstico, pareadas por idade. Instrumentos utilizados: Inventário de Sintomas de Stress para Adultos de Lipp (ISSL), Inventário de Ansiedade Traço-Estado (IDATE) e Inventário de Depressão Beck (BDI). Resultados: Idade média de 49,36 anos para o grupo com fibromialgia (FM) e 49,20 anos para o grupo sem fibromialgia (não FM). O FM apresentou maior incidência de estresse (96%) quando comparado com o não FM (5%). A fase de resistência foi predominante nos dois grupos, FM (42%) e não FM (100%). No FM verificou-se distribuição nas quatro fases (alerta, resistência, quase-exaustão e exaustão). As diferenças entre as fases nos grupos analisados foram significativas (p<0,001). O FM apresentou predominância de sintomas psicológicos (54%), o não FM apresentou a mesma frequência de sintomas psicológico e físico/psicológico (40%). Os sintomas de ansiedade estado e traço e depressão do FM foram significativamente superiores, quando comparados com o não FM (p<0,01). Conclusão: Constatou-se índice de estresse (96%), traço de ansiedade (superior a 50) e depressão clinicamente (superior a 20) relevantes no FM. O entendimento das variáveis ...

Introduction: Depression has emerged as the most prevalent mental disorder in patients with fibromyalgia. Stress, whose stages are alarm, resistance, near-exhaustion and exhaustion, constitutes a physical reaction to a threatening situation. Objective: To investigate the levels of stress, anxiety and depression in women with fibromyalgia, comparing them with those of healthy women. Patients and methods: Participants were 50 women, 25 with a diagnosis of fibromyalgia according to the criteria of the American College of Rheumatology, and 25 without this diagnosis, matched for age. Instruments used: Lipp Inventory of Stress Symptoms for Adults (LISS), State-Trait Anxiety Inventory (STAI) and Beck Depression Inventory (BDI). Results: The mean age was 49.36 years for the group with fibromyalgia (FM) and 49.20 years for the group without fibromyalgia (non-FM). FM showed a higher incidence of stress (96%) compared with non-FM (5%). The resistance phase was predominant in both groups, FM (42%) and non-FM (100%). In FM there was distribution of the four stages (alarm, resistance, near-exhaustion and exhaustion). The differences between phases in the analyzed groups were significant (p < 0.001). FM showed predominance of psychological symptoms (54%); non-FM did show the same frequency of psychological and physical/psychological (40%) symptoms. Symptoms of state and trait anxiety and of depression in FM were significantly higher, when compared with non-FM (p < 0.01). Conclusion: Stress index (96%), trait anxiety (over 50) and clinically relevant depression (greater than 20) in FM were relevant. The understanding of the emotional variables involved in fibromyalgia is important to define the therapeutic strategy. .

Esquizofrenia: uma revisão / Schizophrenia: a review

A definição atual de esquizofrenia indica uma psicose crônica idiopática, aparentando ser um conjunto de diferentes doenças com sintomas que se assemelham e se sobrepõem. A esquizofrenia é de origem multifatorial onde os fatores genéticos e ambientais parecem estar associados a um aumento no risco de desenvolver a doença. Esse artigo tem como objetivo fazer uma revisão de alguns aspectos englobando: história, sintomatologia, tratamentos e modelos experimentais da esquizofrenia