RESUMO
Perturbations in the levels of serotonin expression have a significant impact on behavior and have been implicated in the pathogenesis of several neuropsychiatric disorders including anxiety, mood and appetite. Fetal programming is a risk factor for the development of metabolic diseases during adulthood. Moreover, previous studies have shown that serotonin (5HT), dopamine and leptin are important in energy balance. In the present study, the impact of maternal malnutritioninduced prenatal undernutrition (UN) was investigated in mice and the expression of 5HT1A, dopamine (D)1, D2 and ObRb receptors was analyzed in the hypothalamus during adulthood. The UN group showed a low birth weight compared with the control group. With regard to receptor expression, 5HT1A in the UN group was increased in the hypothalamus and D1 was reduced, whereas D2 showed an increase from postnatal day (P)14 in the arcuate nucleus. ObRb receptor expression was increased in the hypothalamus at P14 and P90. These observations indicated that maternal caloric restriction programs a postnatal body weight gain in offspring with an increased food intake in early postnatal life which continues into adulthood. In addition, UN in mice was found to be affected by ObRb, 5HT1A and D1/2 receptor expression, indicating that these observations may be associated with hyperphagia and obesity.
Assuntos
Metabolismo Energético , Desenvolvimento Fetal , Receptores Dopaminérgicos/biossíntese , Receptores para Leptina/biossíntese , Receptores de Serotonina/biossíntese , Animais , Peso ao Nascer , Restrição Calórica , Dopamina/metabolismo , Ingestão de Alimentos , Feminino , Transtornos da Nutrição Fetal , Humanos , Hipotálamo/metabolismo , Leptina/metabolismo , Camundongos , Gravidez , Fatores de Risco , Serotonina/metabolismoRESUMO
The aim of the present study was to evaluate the behavioral patterns associated with autism and the prevalence of these behaviors in males and females, to verify whether our model of lipopolysaccharide (LPS) administration represents an experimental model of autism. For this, we prenatally exposed Wistar rats to LPS (100 µg/kg, intraperitoneally, on gestational day 9.5), which mimics infection by gram-negative bacteria. Furthermore, because the exact mechanisms by which autism develops are still unknown, we investigated the neurological mechanisms that might underlie the behavioral alterations that were observed. Because we previously had demonstrated that prenatal LPS decreases striatal dopamine (DA) and metabolite levels, the striatal dopaminergic system (tyrosine hydroxylase [TH] and DA receptors D1a and D2) and glial cells (astrocytes and microglia) were analyzed by using immunohistochemistry, immunoblotting, and real-time PCR. Our results show that prenatal LPS exposure impaired communication (ultrasonic vocalizations) in male pups and learning and memory (T-maze spontaneous alternation) in male adults, as well as inducing repetitive/restricted behavior, but did not change social interactions in either infancy (play behavior) or adulthood in females. Moreover, although the expression of DA receptors was unchanged, the experimental animals exhibited reduced striatal TH levels, indicating that reduced DA synthesis impaired the striatal dopaminergic system. The expression of glial cell markers was not increased, which suggests that prenatal LPS did not induce permanent neuroinflammation in the striatum. Together with our previous finding of social impairments in males, the present findings demonstrate that prenatal LPS induced autism-like effects and also a hypoactivation of the dopaminergic system.
Assuntos
Transtorno Autístico/induzido quimicamente , Transtorno Autístico/psicologia , Comportamento Animal/efeitos dos fármacos , Dopamina/fisiologia , Lipopolissacarídeos/toxicidade , Efeitos Tardios da Exposição Pré-Natal/psicologia , Animais , Feminino , Imuno-Histoquímica , Relações Interpessoais , Deficiências da Aprendizagem/induzido quimicamente , Deficiências da Aprendizagem/psicologia , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/psicologia , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Jogos e Brinquedos , Gravidez , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Receptores Dopaminérgicos/biossíntese , Tirosina 3-Mono-Oxigenase/biossíntese , Vocalização AnimalRESUMO
INTRODUCTION: It has been reported in some series that gsp+ somatotropinomas are more sensitive to somatostatin analogues (SA) and dopamine's actions which may be related to their somatostatin receptor (SSTR) and dopamine receptor (DR) profile. No previous studies have been undertaken to evaluate the SSTR and DR profile related with the gsp status in somatotropinomas. OBJECTIVES: To determine if (1) gsp status is correlated with response to octreotide LAR (LAR) and tumor expression patterns of SSTR1-5 and DR1-5 and (2) cAMP level can directly modulate SSTR and DR mRNA levels. METHODS: Response to SA was evaluated by GH and IGF-I percent reduction after 3 and 6 months of treatment with LAR. Conventional PCR and sequencing were used to identify gsp+ tumors. Quantitative real-time PCR was used to determine SSTR and DR tumor expression. Primary pituitary cell cultures of primates were used to study whether SSTR and DR expression is regulated by forskolin. RESULTS: The response to LAR did not significantly differ between patients with gsp+ and gsp- tumors; however, gsp+ tumors expressed higher levels of SSTR1, SSTR2, DR2 and a lower level of SSTR3. Forskolin increased SSTR1, SSTR2, DR1 and DR2 expression in cell cultures. CONCLUSION: Elevated SSTR1, SSTR2, and DR2 tumor expression may help improve responsiveness to SA and DA therapy; however, this study may not have been appropriately powered to observe significant effects in the clinical response. Elevated cAMP levels could be directly responsible for the upregulation in SSTR1, SSTR2 and DR2 mRNA levels observed in gsp+ patients.