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Ras-related C3 botulinum toxin substrate 1 (Rac1), of the Rho small GTPase family, is a key regulator of actin cytoskeleton rearrangement and plays an important role in dendritic morphogenesis. Cocaine produces neuronal alterations, including structural changes in dendritic number and morphology. Emerging data indicate sigma-1 receptors (σ-1Rs) as a promising candidate for the prevention of cocaine craving. Opipramol is a σ-1R agonist approved in some European countries for depression and anxiety. Here we report that opipramol, mediated by Rac1, attenuates cocaine-seeking behavior in a rat model of self-administration. The opipramol effect was shown in two phases. It decreased cocaine-seeking behavior throughout the withdrawal phase and, interestingly, showed a significant reduction of cocaine-primed reinstatement in 75% of the opipramol-treated group (termed 'responders'). All opipramol-treated rats showed a decrease in σ-1R mRNA expression levels in the nucleus accumbens (NAc) versus controls. Responders also exhibited significantly decreased NAc Rac1 mRNA expression levels, compared with non-responder rats. Hence, Rac1 differentiated responders from non-responders. Rac1 correlated positively with σ-1R mRNA levels in opipramol responders. In another experiment, Rac1 inhibitor injected directly into the NAc core decreased active lever presses on the first day of extinction, indicating the critical role of Rac1 in the opipramol effect on drug seeking. We postulate that chronic activation of σ-1R, through a dynamic interaction with Rac1, may suggest a new approach to treat substance use disorder (SUD). Rac1 inhibition is a prerequisite for decreasing drug seeking and rehabilitation, and this can be achieved by opipramol, a medication that can be given during detoxification.
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Antidepressivos Tricíclicos/uso terapêutico , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Fissura/efeitos dos fármacos , Opipramol/uso terapêutico , Proteínas rac1 de Ligação ao GTP/metabolismo , Animais , Cocaína/farmacologia , Sinais (Psicologia) , Modelos Animais de Doenças , Comportamento de Procura de Droga/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Masculino , Neurônios/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Autoadministração , Síndrome de Abstinência a Substâncias/tratamento farmacológicoRESUMO
A major problem in the treatment of addiction is predicting and preventing relapse following a rehabilitation program. Recently, in preclinical rodent studies dehydroepiandrosterone (DHEA) was found to markedly improve the resistance to drug reuse. In a double-blind, placebo-controlled study, we examined the effect of DHEA on relapse rates in adult polydrug users taking part in a detoxification program enriched with intensive psychosocial interventions and aftercare. During treatment, participants (79 percent males, mean age 28) consumed DHEA (100 mg/day) or placebo daily for at least 30 days. Of the 121 initial volunteers, 64 participated for at least 1 month. While in treatment, DHEA reduced negative affect on the Positive and Negative Affect Scale (F = 4.25, P = 0.04). Furthermore, in a 16-month follow-up, we found that reuse rates in the DHEA condition were about a third compared with placebo (12 versus 38 percent; χ(2) = 5.03, P = 0.02). DHEA treatment also resulted in an increase in DHEA sulfate (DHEA-S) 1 month following treatment, and the level of DHEA-S predicted relapse in the follow-up assessment.
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Afeto/efeitos dos fármacos , Tomada de Decisões/efeitos dos fármacos , Desidroepiandrosterona/uso terapêutico , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Adjuvantes Imunológicos/uso terapêutico , Adulto , Método Duplo-Cego , Feminino , Humanos , Israel , Masculino , Recidiva , Transtornos Relacionados ao Uso de Substâncias/psicologia , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVES: Individuals with polysubstance use disorder (pSUD) exhibit vulnerability to relapse even after prolonged abstinence, with rehabilitation efforts achieving limited success. Previous studies highlighted dehydroepiandrosterone (DHEA) as a putative therapeutic agent that may aid rehabilitation, potentially by impacting white matter (WM) properties. The current study tested, for the first time, the effect of DHEA administration during rehabilitation on WM integrity among pSUD individuals, while assessing its putative association with long-term relapse rates. METHODS: Immediately after admission to rehabilitation, 30 pSUD individuals were assigned to receive either placebo or DHEA (100 mg) daily for 3 months, via a randomized double-blind counterbalanced design. Participants also provided blood samples to assess circulating DHEA levels at treatment initiation and completed a diffusion tensor imaging (DTI) scan approximately 1 month after treatment initiation. Clinical status was evaluated 16 months after treatment initiation. Thirty matched healthy controls also underwent a DTI scan without any intervention. RESULTS: DHEA administration was not associated with reduced relapse rates compared with placebo. Nevertheless, exploratory analysis revealed that DHEA was associated with successful rehabilitation among pSUD individuals with low circulating DHEA levels at treatment initiation. White matter integrity in the splenium corpus callosum (CC) was reduced in pSUD individuals compared with healthy controls, yet pSUD individuals receiving DHEA exhibited recovery of splenium CC WM integrity. CONCLUSIONS: DHEA administration during rehabilitation may restore WM integrity in the CC among pSUD individuals. Although DHEA was not associated with reduced relapse rates in here, its therapeutic efficacy may depend on circulating DHEA levels at treatment initiation.
Assuntos
Desidroepiandrosterona , Substância Branca , Humanos , Cognição , Desidroepiandrosterona/farmacologia , Imagem de Tensor de Difusão , Recidiva , Substância Branca/diagnóstico por imagemRESUMO
Cocaine addiction is an acquired behavioral state developed in vulnerable individuals after cocaine exposure. It is characterized by compulsive drug-seeking and high vulnerability to relapse even after prolonged abstinence, associated with decreased neurogenesis in the hippocampus. This addictive state is hypothesized to be a form of "memory disease" in which the drug exploits the physiological neuroplasticity mechanisms that mediate regular learning and memory processes. Therefore, a major focus of the field has been to identify the cocaine-induced neuroadaptations occurring in the usurped brain's reward circuit. The neurosteroid dehydroepiandrosterone (DHEA) affects brain cell morphology, differentiation, neurotransmission, and memory. It also reduces drug-seeking behavior in an animal model of cocaine self-administration. Here, we examined the long-lasting effects of DHEA treatment on the attenuation of cocaine-seeking behavior. We also examined its short- and long-term influence on hippocampal cells architecture (neurons and astrocytes). Using a behavioral examination, immunohistochemical staining, and diffusion tensor imaging, we found an immediate effect on tissue density and activation of astrocytes, which has a continuous beneficial effect on neurogenesis and tissue organization. This research emphasizes the requites concert between astrocytes and neurons in the rehabilitation from addiction behavior. Thus, DHEA may serve as a treatment that corrects brain damage following exposure to and abstinence from cocaine.
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Substance use disorders (SUDs) are associated with depression and anxiety, with the latter being one of the major factors in substance-seeking and relapse. Due to dose-dependent sedative side effects there is limited efficacy of baclofen treatment for SUDs. Here we suggest the use of a novel combination of opipramol and baclofen (O/B) which is known to attenuate anxiety and depression, for the facilitation of recovery from SUDs. Since both opipramol and baclofen have a common downstream signal transduction, their individual doses could be reduced while still maintaining the benefits of the combination. We tested the O/B combination in both animals and patients. Rats treated with O/B showed significant attenuation in craving behavior and in relapse rate during withdrawal from cocaine. In a double-blind, placebo-controlled pilot study, conducted in a residential detoxification center, 14 males and 3 females, aged 28-60 years were assigned to a study (n = 6) and a placebo (n = 11) group (placebo group: 40 ± 10.5 years; O/B group 40 ± 10.8 years). The participants completed scales measuring depression, anxiety and craving symptoms and provided saliva samples for stress hormone examination [cortisol and dehydroepiandrosterone-sulfate (DHEA-S)]. Participants with polysubstance use disorder (PsUD) treated with O/B showed a reduction in cravings and depression and an increase in DHEA-S and in the DHEA-S/cortisol ratio. Our findings indicate a beneficial effect of O/B treatment. This study suggests a novel candidate for pharmacological treatment of patients with SUD and comorbid mood/anxiety disorders that may facilitate their rehabilitation.
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To investigate the possible effect of fetal exposure to selective serotonin reuptake inhibitors (SSRIs) on somatic growth and on hormones of the hypothalamic-pituitary-adrenal (HPA) and insulin-like growth factor (IGF)-I axes, we compared the anthropometric parameters and hormonal profile of 21 SSRI-exposed infants and 20 matched controls. The SSRI group was characterized by lower crown-heel length (p < 0.01), smaller head circumference (p = 0.08), and higher percentage of infants with birth weight, birth length, and head circumference below the 10th percentile (p < 0.045, p = 0.08, p < 0.04, respectively), in addition to a significantly lower cord blood level of cortisol (p < 0.03) and higher level of thyroid-stimulating hormone (TSH) (p < 0.004). Infants exposed to citalopram had a lower cord blood IGF-I level than infants exposed to paroxetine (p < 0.001) and controls (p < 0.003). Placental IGF-I receptor (IGF-IR) expression was significantly higher in the SSRI group than in controls (p < 0.01). Urine 5-hydroxyindoleacetic acid (5-HIAA) level was negatively correlated with birth weight (r = -0.71, p < 0.025) and with dehydroepiandrosterone (DHEA) level (r = -0.71, p < 0.025). The Finnegan score was correlated with dehydroepiandrosterone sulfate (DHEAS) (r = 0.8, p < 0.005) and cortisol (r = 0.62, p = 0.05). Fetal exposure to SSRIs causes impaired intrauterine growth accompanied by alterations in the IGF-I and HPA axes. The findings may raise concern regarding maternal use of SSRIs during pregnancy.
Assuntos
Desenvolvimento Fetal/efeitos dos fármacos , Retardo do Crescimento Fetal/induzido quimicamente , Feto/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/metabolismo , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Adulto , Peso ao Nascer/efeitos dos fármacos , Estudos de Casos e Controles , Citalopram/efeitos adversos , Feminino , Sangue Fetal/metabolismo , Retardo do Crescimento Fetal/metabolismo , Feto/metabolismo , Fluoxetina/efeitos adversos , Hormônios/sangue , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Recém-Nascido , Masculino , Paroxetina/efeitos adversos , Sistema Hipófise-Suprarrenal/metabolismo , Placenta/metabolismo , GravidezRESUMO
We evaluated the effect of DHEA complementary treatment in opiate addicts undergoing detoxification. DHEA (100 mg/day) or placebo was added to the routine medication protocol in a randomized, double blind controlled study. Follow-up for 12 months was conducted. Two separate DHEA-treated subgroups were identified by the Fuzzy clustering method: one showed statistically significant improvement in the severity of withdrawal symptoms, depression and anxiety scores (n=34; p<0.001 for all) and the other subgroup deteriorated in all measures (n=15). DHEA at the end of the detoxification program showed a tendency towards correlation with the duration of abstinence (r=0.6843; p>0.05; n=6), while a negative correlation was obtained with the cortisol level (r=-0.900; p=0.005, n=8). The completion-rate of the DHEA-improved subgroup was greater than in the DHEA-deteriorated subgroup (64.7% vs. 33.3%, respectively). The influence of supplementary DHEA treatment was mostly effective in heroin addicts who had not previously used either cocaine or benzodiazepines and who had experienced only few withdrawal programs.
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Adjuvantes Imunológicos/uso terapêutico , Desidroepiandrosterona/uso terapêutico , Dependência de Heroína/tratamento farmacológico , Centros de Tratamento de Abuso de Substâncias , Análise de Variância , Transtorno Depressivo/etiologia , Método Duplo-Cego , Feminino , Seguimentos , Lógica Fuzzy , Dependência de Heroína/complicações , Humanos , Hidrocortisona/metabolismo , Masculino , Escalas de Graduação Psiquiátrica , Características de Residência , Índice de Gravidade de Doença , Síndrome de Abstinência a Substâncias/etiologiaRESUMO
Drug addiction has a great negative influence on society, both social and economic burden. It was widely thought that addicts could choose to stop using drugs if only they had some self-control and principles. Nowadays, science has changed this view, defining drug addiction as a complex brain disease that affects behavior in many ways, both biological and psychological. Currently there is no ground-breaking reliable treatment for drug addiction. For more than a decade we are researching an alternative approach for intervention with drug craving and relapse to its usage, using DHEA, a well-being and antiaging food supplement. In this chapter we navigate through the significant therapeutic effect of DHEA on the brain circuits that control addiction and on behavioral performance both in animal models and addicts. We suggest that an integrative program of add-on DHEA treatment may further enable to dynamically evaluate the progress of rehabilitation of an individual patient, in a comprehensive assessment. Such a program may boost and support the detoxification and rehabilitation process, and help patients regain a normal life in a shorter amount of time.
Assuntos
Desidroepiandrosterona/uso terapêutico , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Animais , Comportamento Aditivo , Humanos , Transtornos Mentais/tratamento farmacológico , Estresse Fisiológico , Síndrome de Abstinência a Substâncias/tratamento farmacológicoRESUMO
Previous studies in animal models of cocaine craving have delineated broad changes in DNA methylation profiles in the nucleus accumbens. A crucial factor for progress in behavioral and mental health epigenetics is the discovery of epigenetic markers in peripheral tissues. Several studies in primates and humans have associated differences in behavioral phenotypes with changes in DNA methylation in T cells and brain. Herein, we present a pilot study (n = 27) showing that the T cell DNA methylation profile differentiates persons with a substance use disorder from controls. Intervention with dehydroepiandrosterone (DHEA), previously shown to have a long-term therapeutic effect on human addicts herein resulted in reversal of DNA methylation changes in genes related to pathways associated with the addictive state.
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Several studies have demonstrated the effective use of dehydroepiandrosterone (DHEA) in the management of mood, however studies of its use in psychosis remain limited. The aim of this study was to investigate for the first time efficacy of DHEA augmentation with standardized antipsychotic medication (olanzapine) and to explore effects of DHEA augmentation on side-effect profiles including weight gain, glucose tolerance, aggression, quality of life and neurocognitive function. Finally, we aimed to analyze any relationship between plasma levels and clinical response to DHEA administration. Forty patients with chronic schizophrenia stabilized on olanzapine were randomized in double-blind fashion to receive either DHEA (titrated up to 150mg) or placebo augmentation for a period of 12-weeks. Blood samples were collected at baseline, mid-study and study completion. Results indicated improvement of negative symptoms (SANS scale) even when baseline scores were controlled as a covariate. Some improvement in Parkinsonism and akathisia compared to baseline was seen in patients receiving DHEA. No change in psychosis as reflected by the PANSS was noted. Patients receiving DHEA appeared to demonstrate relatively stable glucose levels compared to controls at the end of the study. An improvement in cognitive performance (most notably memory), which did not reach significance due to low sample number, was observed following DHEA administration. Results further suggest preliminary evidence of involvement of the neurosteroid system in schizophrenia pathophysiology, and confirm initial "cautious" findings identifying an agent capable of improving negative symptoms and certain features of extrapyramidal side effects.
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Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Desidroepiandrosterona/uso terapêutico , Discinesia Induzida por Medicamentos/fisiopatologia , Esquizofrenia/tratamento farmacológico , Psicologia do Esquizofrênico , Adolescente , Adulto , Idoso , Benzodiazepinas/efeitos adversos , Benzodiazepinas/uso terapêutico , Glicemia/metabolismo , Cognição/fisiologia , Desidroepiandrosterona/sangue , Método Duplo-Cego , Feminino , Teste de Tolerância a Glucose , Hormônios/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Olanzapina , Escalas de Graduação Psiquiátrica , Qualidade de Vida , Aumento de PesoRESUMO
RATIONALE: Search for safe and effective strategies to diminish weight gain associated with second generation antipsychotics (SGAs) is imperative. In the present study, we sought to replicate our preliminary findings, which indicated that coadministration of the selective norepinephrine reuptake inhibitor reboxetine attenuates olanzapine-induced weight gain. MATERIALS AND METHOD: Fifty-nine patients hospitalized for first-episode DSM-IV schizophrenic disorder participated in this randomized double-blind study. Reboxetine (4 mg/day; 31 patients) or placebo (29 patients) was coadministered with olanzapine (10 mg/day) for 6 weeks. Analysis was by intention-to-treat. RESULTS: Nine patients in each group prematurely discontinued the trial. Olanzapine/reboxetine-treated patients showed a significantly lower increase in body weight (mean = 3.31 kg, SD = 2.73) than their olanzapine/placebo-treated counterparts (mean = 4.91 kg, SD = 2.45). Significantly fewer olanzapine/reboxetine-treated patients gained at least 7% of their initial weight, the cutoff for clinically significant weight gain (6 [19.4%] of 31 patients vs 13 [46.4%] of 28 patients). Seven (22.6%) olanzapine/reboxetine-treated patients compared to only one patient (3.6%) in the olanzapine/placebo group revealed no weight change or even modest weight loss. Appetite increase was significantly lower in the olanzapine/reboxetine than olanzapine/placebo group and was correlated with attenuation of weight gain. Reboxetine addition was safe and well tolerated. CONCLUSIONS: The results confirm that coadministration of reboxetine promotes a clinically meaningful attenuation of olanzapine-induced weight gain in schizophrenia patients. If substantiated in long-term studies, along with behavioral management and diet counseling, reboxetine may have a clinical utility in controlling SGA-induced weight gain.
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Inibidores da Captação Adrenérgica/uso terapêutico , Antipsicóticos/efeitos adversos , Morfolinas/uso terapêutico , Esquizofrenia/tratamento farmacológico , Inibidores da Captação Adrenérgica/efeitos adversos , Inibidores da Captação Adrenérgica/farmacologia , Adulto , Antipsicóticos/uso terapêutico , Apetite/efeitos dos fármacos , Benzodiazepinas/efeitos adversos , Benzodiazepinas/uso terapêutico , Índice de Massa Corporal , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Morfolinas/farmacologia , Olanzapina , Reboxetina , Aumento de Peso/efeitos dos fármacosRESUMO
BACKGROUND AND OBJECTIVE: Contradictory and confusing reports on serum dehydroepiandrosterone (DHEA) levels in schizophrenia led us to compare the serum concentration of its precursor, pregnenolone (PREG), between medicated schizophrenia patients and healthy subjects. The neurosteroid levels were monitored for two months and the relationship of these neurosteroids with schizophrenic symptomatology, emotional distress, and anxiety was examined. METHOD: We determined blood levels of PREG, and DHEA in 15 schizophrenia patients and 12 healthy controls at four time points: at the start of the study, after 2, 4 and 8 weeks. Analysis of covariance and canonical correlations across four time points were applied. RESULTS: Controlling for age, serum concentrations of PREG were lower, while the DHEA level and the molar ratio values of DHEA/PREG were higher in schizophrenia patients compared to healthy controls. Both levels of PREG and DHEA and their molar ratio did not change significantly during the study's period either among schizophrenia patients or healthy controls. The blood levels of PREG appear to be associated with trait-anxiety scores in the schizophrenia patients, while associations of clinical symptoms with two neurosteroids did not reach a significant level when the confounding effect of emotional distress, and anxiety scores was controlled. CONCLUSION: Low serum pregnenolone concentrations in schizophrenia appear to be associated with trait-anxiety scores independent of symptoms. Further research into the role of pregnenolone in schizophrenia is warranted.
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Desidroepiandrosterona/sangue , Pregnenolona/sangue , Esquizofrenia/sangue , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Radioimunoensaio/métodos , Estatística como Assunto , Fatores de TempoRESUMO
Neurosteroids play a significant role in neurodevelopment and are involved in a wide variety of psychopathological processes. There is accumulating evidence on their role in adult psychopathology, including Alzheimer disease, schizophrenia, mood disorder, anxiety disorders and post-traumatic stress disorder. Little is known, however, about the possible role of neurosteroids in child and adolescent psychopathology although there is increasing evidence for their critical role from the early stages of brain development until adolescence. In this review we focus on the involvement of neurosteroids in neurodevelopment and mental disorders in children and adolescents. Adequate physiological levels protect the developing neural system from insult and contribute to the regulation of brain organization and function. Neurosteroids may be involved in the pathophysiology and pharmacotherapy of a variety of disorders in children and adolescents, including schizophrenia, depression, eating disorders, aggressive behavior and attention deficit. The complex interaction between neurosteroids, neurodevelopment, life-events, genetics and mental disorders in children and adolescents merits further investigation.
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Transtornos Mentais/fisiopatologia , Transtornos Mentais/psicologia , Neurotransmissores/fisiologia , Esteroides/fisiologia , Adolescente , Agressão/fisiologia , Anorexia Nervosa/fisiopatologia , Anorexia Nervosa/psicologia , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Transtorno Autístico/fisiopatologia , Transtorno Autístico/psicologia , Criança , Transtorno Depressivo/fisiopatologia , Transtorno Depressivo/psicologia , Humanos , Esquizofrenia/fisiopatologiaRESUMO
INTRODUCTION: Schizophrenia patients display an extremely high rate of smoking. Neurosteroids appear to play a possible role in the pathophysiology and management of schizophrenia and have been proposed to be involved in the pathophysiology of nicotine addiction. Although many studies have evaluated blood levels of neurosteroids in schizophrenia patients, only a few studies have taken into consideration the effect of smoking on levels of neurosteroids in the illness. METHODS: Forty-five DSM-IV-TR chronic schizophrenia patients were sampled for plasma levels of three steroids: cortisol, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulphate (DHEA-S). Patients were rated with the Positive and Negative Syndrome Scale (PANSS) and provided data on their smoking behavior. RESULTS: The mean level of plasma cortisol in our sample (N=45) was 197.9 nmol/L (S.D.=81.5), and the levels of DHEA and DHEA-S were 23 nmol/L (S.D.=5.5) and 4276.6 nmol/L (S.D.=2665.58), respectively. Despite a trend for lower levels of cortisol, DHEA and DHEA-S among the smokers, only DHEA, but not DHEA-S and cortisol, was significantly lower among the smokers (33% decrease, p=0.012). Smoking predicted the positive and negative scores of the PANSS, whereas cortisol was correlated with the PANSS-negative subscale. CONCLUSIONS: Smoking in chronic schizophrenia patients appears to be associated with lower DHEA levels. The role of this decrease in the pathophysiology of nicotine addiction and schizophrenia merits further investigation.
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Neurotransmissores/sangue , Esquizofrenia/sangue , Fumar/sangue , Esteroides/sangue , Adulto , Antipsicóticos/uso terapêutico , Doença Crônica , Desidroepiandrosterona/sangue , Sulfato de Desidroepiandrosterona/sangue , Feminino , Humanos , Hidrocortisona/sangue , Masculino , Escalas de Graduação Psiquiátrica , Psicologia do EsquizofrênicoRESUMO
OBJECTIVE: In previous studies we have demonstrated high serum molar ratios of cortisol to dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) [together abbreviated DHEA(S)], and the value of both cortisol/DHEA(S) molar ratios for prediction of responsivity to antipsychotic treatment in schizophrenia patients. The present study aimed to examine the contribution of anxiety, and severity of symptoms to the prediction of serum cortisol, DHEA(S) levels and two molar ratios across three examinations. METHOD: Serum concentrations of cortisol and DHEA(S)were examined in 43 schizophrenia inpatients and in 20 age matched healthy controls at baseline, and after 2 and 4 weeks. The Positive and Negative Symptom Scale and the State-Trait Anxiety Inventory scores were used as independent variables for multiple regression analysis. RESULTS: Despite clinical improvement during the study period cortisol/DHEA(S) molar ratios were found persistently elevated as compared to healthy controls. Multiple regression analysis revealed that across three examinations cortisol/DHEA(S) molar ratios negatively associated with trait-anxiety (partial R(2)=7-14%) rather than with negative symptoms (partial R(2)=3-6%). Age and age of onset account for 12.7% for variability of cortisol/DHEAS ratio. Serum cortisol concentrations are predicted by trait and state-anxiety, activation symptoms and daily doses of antipsychotics. A small portion of variability in serum DHEA levels (R(2)=9%) is associated with symptom severity, while DHEAS levels were predicted by age at examination and age of onset. CONCLUSION: Elevated serum cortisol/DHEA(S) molar ratios were attributed to trait-anxiety and age rather than to clinical symptoms. The findings may indicate persistent dysfunction of the hypothalamic-pituitary-adrenal axis that is independent of the patients' clinical state.
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Sulfato de Desidroepiandrosterona/sangue , Desidroepiandrosterona/sangue , Hidrocortisona/sangue , Esquizofrenia/sangue , Adulto , Análise de Variância , Ansiedade/sangue , Ansiedade/etiologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Valor Preditivo dos Testes , Esquizofrenia/complicaçõesRESUMO
BACKGROUND: In an attempt to model childhood depression, we examined whether existing genetic animal models of depression in adult rats are also valid in prepubertal rats. METHODS: Two different "depressed" rat lines were studied: the Flinders Sensitive Line (FSL) and their controls, Sprague-Dawley (SD); and the Wistar Kyoto (WKY) line and their controls, Wistar. We hypothesized that male prepubertal FSL and WKY rats would show increased swim test immobility and different patterns of social play and of basal plasma levels of corticosterone and adrenocorticotropic hormone (ACTH) compared with control rats. RESULTS: Prepubertal FSL and WKY rats exhibited significantly longer duration of immobility than control rats in the swim test. The FSL rats demonstrated significantly higher levels of social play behaviors and lower levels of corticosterone and ACTH compared with SD control rats, whereas WKY rats demonstrated significantly lower levels of social play behaviors and higher plasma levels of corticosterone and ACTH compared with Wistar control rats. CONCLUSIONS: The results might suggest that prepubertal FSL and WKY rats are both putative genetic animal models of childhood depression, exhibiting separate patterns and symptoms of childhood depression.
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Animais Recém-Nascidos/fisiologia , Depressão/genética , Depressão/fisiopatologia , Modelos Animais de Doenças , Hormônio Adrenocorticotrópico/sangue , Análise de Variância , Animais , Comportamento Animal , Corticosterona/sangue , Depressão/sangue , Feminino , Reação de Congelamento Cataléptica/fisiologia , Masculino , Atividade Motora/fisiologia , Ratos , Ratos Endogâmicos WKY , Ratos Sprague-Dawley , Ratos Wistar , Comportamento Social , Especificidade da Espécie , Natação/fisiologiaRESUMO
Dehydroepiandrosterone (DHEA), which can act as a potential antidepressant in both animals and humans, appears to lower distress involved with cocaine withdrawal. In fact, a role for neurosteroids in modulation of substance-seeking behavior is becoming increasingly clear. Therefore, we tested the effects of DHEA on the self-administration of cocaine (1 mg/kg/infusion) by rats. At maintenance, a relatively low dose of exogenous DHEA (2 mg/kg; i.p.) attenuated cocaine self-administration after several days of chronic treatment. More than 2 weeks (19 days) of daily DHEA injections were required to decrease the cocaine-seeking behavior of rats to less than 20% of their maintenance levels. DHEA does not seem to decrease cocaine self-administration by increasing the reinforcing properties of the drug, as indicated by a cocaine dose-response determination. After being subjected to extinction conditions in the presence of DHEA, rats demonstrated a minimal response to acute exposure to cocaine (10 mg/kg), which indicated a protective effect of DHEA on relapse to cocaine usage. Our results suggest a potential role for the neurosteroid DHEA in controlling cocaine-seeking behavior, by reducing both the desire for cocaine usage and the incidence of relapse.
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Adjuvantes Imunológicos/uso terapêutico , Anestésicos Locais/administração & dosagem , Comportamento Aditivo/tratamento farmacológico , Cocaína/administração & dosagem , Desidroepiandrosterona/uso terapêutico , Análise de Variância , Animais , Comportamento Aditivo/etiologia , Comportamento Animal/efeitos dos fármacos , Transtornos Relacionados ao Uso de Cocaína/complicações , Condicionamento Operante/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Sprague-Dawley , Autoadministração , Sacarose/administração & dosagemRESUMO
BACKGROUND: Several endocrine abnormalities are reported in obesity. In an earlier study, we found that the changes in BMI following laparoscopic adjustable gastric banding (LAGB) were associated with changes in hormone profiles such as insulin and proinsulin. In the current study, we explored the changes in plasma adiponectin levels in morbidly obese subjects who lost abundant weight following LAGB. METHODS: 23 adult morbidly obese patients (15 females), aged 21-56 years, were studied. Blood samples were collected before, and 6 and 14 months after LAGB. The plasma adiponectin levels were determined by commercial kit (B-Bridge International, Inc). Statistical analysis was based on one-way repeated measures ANOVA, followed by Student-Newman-Keuls post-hoc test. Regression model was used to look for predictors of adiponectin change after LAGB. RESULTS: Mean BMI before surgery was 46.04+/-4.44 kg/m2, and decreased significantly by 18% 6 months after surgery to 37.67+/-4.47 kg/m2. BMI further decreased by 32% 14 months after surgery to a mean of 31.30+/-4.65 kg/m2 (P=.000). The mean adiponectin level before surgery was 3997+/-1766 microg/ml, and increased significantly by 16% to 4763+/-1776 microg/ml 6 months after surgery, and to 6336+/-3292 microg/ml (37%) 14 months after surgery. Although BMI persistently decreased, while adiponectin persistently increased, BMI did not correlate with adiponectin. CONCLUSION: In morbidly obese patients who underwent LAGB, adiponectin levels persistently increased, probably due to the reduction of visceral fat mass. Adiponectin plasma increase was correlated with proinsulin levels prior to the surgery. The interaction between adiponectin, proinsulin and BMI change in morbid obesity merits further investigation.
Assuntos
Adiponectina/sangue , Gastroplastia , Obesidade Mórbida/sangue , Adulto , Índice de Massa Corporal , Feminino , Humanos , Laparoscopia , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/cirurgia , Redução de PesoRESUMO
Neurosteroids are important neuroactive molecules with suggested central involvement in several neurophysiological and psychiatric disease processes. The discovery of neurosteroids followed the revelation that the brain exhibited the capacity to synthesize its own steroids in situ and thus be a potential site of steroidogenesis. In contrast to some steroids that exhibit traditional genomic steroid actions, most neurosteroids appear to regulate neuronal function by means of "non-genomic" mechanisms influencing neuronal excitability. Neurosteroids are synthesized either from CNS cholesterol or from peripheral steroid precursors and exhibit a wide range of modulatory effects on neurotransmitter receptor activity, most notably at the gamma-aminobutyric acid A (GABA(A)) receptor. Neurosteroids play an important role in neurodevelopment and neuroprotective effects, many aspects of which may have particular applicability to psychiatric disorders including various gender differences. Neurosteroids appear to be relevant to the pathophysiology and pharmacological treatment of many psychiatric disorders including the most notable mood and anxiety disorders, but also psychotic, childhood, eating, dementia, stress and postpartum disorders. It has been suggested that neurosteroids may become potential targets for pharmacological intervention in the future with further neurosteroid investigation contributing to a more comprehensive understanding of human behavior and psychopathology.
Assuntos
Transtornos Mentais/diagnóstico , Transtornos Mentais/fisiopatologia , Neurotransmissores/fisiologia , Esteroides/fisiologia , Envelhecimento/fisiologia , Humanos , Sistema Nervoso/crescimento & desenvolvimento , Neurotransmissores/sangueRESUMO
OBJECTIVE: The goals of this study were to determine whether alterations in serum dehydroepiandrosterone (DHEA), its sulfated conjugate (DHEAS), androstenedione, testosterone, and progesterone concentrations occur in schizophrenia patients compared with healthy controls over two months, and their associations with psychopathology, emotional distress, and antipsychotic treatment. METHOD: Serum hormones were repeatedly determined for 21 antipsychotic-treated male DSM-IV schizophrenia patients and 14 healthy controls. Observations were at four time points: upon entry into the study, and after 2, 4 and 8 weeks. RESULTS: In schizophrenia patients compared with healthy controls serum concentration of DHEA and androstenedione found increased, but that of DHEAS decreased, while progesterone and testosterone showed normal levels. Schizophrenia patients were also characterized by elevated androstenedione/DHEAS molar ratios, and reduced DHEAS/DHEA and testosterone/androstenedione molar ratios compared with healthy controls. Concentrations and molar ratios of serum hormones did not significantly change during the study either among schizophrenia patients, or healthy controls. Among patients alterations in DHEA, DHEAS and androstenedione were associated with emotional distress, anxiety, dysphoric mood, positive and activation symptoms, serum prolactin levels, but were not related to age, antipsychotic agents, and extrapyramidal side effects. CONCLUSIONS: Alterations in DHEA metabolism in schizophrenia are attributed to the distress, anxiety, severity of symptoms, prolactin levels, and may represent a marker for impaired hormonal responses to stress. These findings should be considered when evaluating the discrepancies in DHEA studies in schizophrenia.