RESUMO
There is strong biochemical, pharmacological and genetic evidence for the involvement of the endocannabinoid system (ECS) in alcohol dependence. However, the majority of studies have been performed in animal models. The aim of the present study was to assess the state of the CB1 receptor, the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), and the extracellular signal-regulated kinase (ERK) and cyclic-AMP response element-binding protein (CREB) in the post-mortem prefrontal cortex of alcoholic subjects. Experiments were performed in samples from 44 subjects classified in four experimental groups: (1) non-suicidal alcoholic subjects (n = 11); (2) suicidal alcoholic subjects (n = 11); (3) non-alcoholic suicide victims (n = 11); and (4) control subjects (n = 11). We did not observe statistically significant differences in CB1 mRNA relative expression among the four experimental groups. Conversely, our results showed an increase in CB1 receptor protein expression in the prefrontal cortex of the suicidal alcoholic group (127.2 ± 7.3%), with no changes in functionality with regard to either G protein activation or the inhibition of adenylyl cyclase. In parallel, alcoholic subjects presented lower levels of MAGL activity, regardless of the cause of death. A significant decrease in the active form of ERK and CREB levels was also observed in both alcoholic groups. Taken together, our data are consistent with a role for the ECS in the neurobiological mechanisms underlying alcoholism. Moreover, the alterations reported here should be of great interest for the therapeutic treatment of this chronic psychiatric disease.
Assuntos
Alcoolismo/enzimologia , Endocanabinoides/fisiologia , Córtex Pré-Frontal/enzimologia , Amidoidrolases/metabolismo , Análise de Variância , Proteína de Ligação a CREB/metabolismo , Cadáver , Estudos de Casos e Controles , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monoacilglicerol Lipases/metabolismo , RNA Mensageiro/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Transdução de Sinais , SuicídioRESUMO
Differences among antipsychotics in effectiveness have turned out to be a topic of increasing research interest, although comparisons between the different second-generation antipsychotics are scarce. From October 2005 to March 2011, a prospective, randomized, open-label study comparing the effectiveness of aripiprazole, ziprasidone, and quetiapine in the short-term treatment of first-episode schizophrenia-spectrum disorders was undertaken. Two hundred two patients were randomly assigned to aripiprazole (n = 78), ziprasidone (n = 62), or quetiapine (n = 62) and followed up for 6 weeks. The primary effectiveness measure was all-cause of treatment discontinuation. In addition, an analysis based on per protocol populations was conducted in the analysis for clinical efficacy. The overall dropout rate at 6 weeks was small (6.4%). The treatment discontinuation rate differed significantly between treatment groups (aripiprazole, 15%; ziprasidone, 19%; and quetiapine, 35%; χ(2) = 8.529; P = 0.014). Insufficient efficacy in the group of quetiapine is the main reason for discontinuation rate differences (χ = 10.139; P = 0.006). The mean time to all-cause discontinuation was significantly different between the groups (log-rank, 12.783; P = 0.001). Quetiapine was associated with a greater depressive symptoms improvement than ziprasidone (P = 0.045). The rate of responders at 6 weeks differed between the groups (F = 6, 116; P = 0.047), with a higher rate of the responders with aripiprazole. The profile of adverse effects varies between the treatments. Patients on quetiapine were less likely to be prescribed concomitant medications. Treatment with quetiapine was associated with a higher risk of treatment discontinuation during treatment owing to insufficient efficacy. Differences in effectiveness between second-generation antipsychotics would determine their position in everyday clinical practice and could help physicians choose the more efficacious antipsychotics.
Assuntos
Antipsicóticos/uso terapêutico , Dibenzotiazepinas/uso terapêutico , Piperazinas/uso terapêutico , Quinolonas/uso terapêutico , Esquizofrenia/tratamento farmacológico , Tiazóis/uso terapêutico , Adulto , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Aripiprazol , Dibenzotiazepinas/administração & dosagem , Dibenzotiazepinas/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Estudos Prospectivos , Fumarato de Quetiapina , Quinolonas/administração & dosagem , Quinolonas/efeitos adversos , Esquizofrenia/fisiopatologia , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
It is widely accepted that changes underlying depression and antidepressant-like effects involve not only alterations in the levels of neurotransmitters as monoamines and their receptors in the brain, but also structural and functional changes far beyond. During the last two decades, emerging theories are providing new explanations about the neurobiology of depression and the mechanism of action of antidepressant strategies based on cellular changes at the CNS level. The neurotrophic/plasticity hypothesis of depression, proposed more than a decade ago, is now supported by multiple basic and clinical studies focused on the role of intracellular-signalling cascades that govern neural proliferation and plasticity. Herein, we review the state-of-the-art of the changes in these signalling pathways which appear to underlie both depressive disorders and antidepressant actions. We will especially focus on the hippocampal cellularity and plasticity modulation by serotonin, trophic factors as brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF) through intracellular signalling pathways-cAMP, Wnt/ ß -catenin, and mTOR. Connecting the classic monoaminergic hypothesis with proliferation/neuroplasticity-related evidence is an appealing and comprehensive attempt for improving our knowledge about the neurobiological events leading to depression and associated to antidepressant therapies.
Assuntos
Antidepressivos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Transtorno Depressivo/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Antidepressivos/farmacologia , Transtorno Depressivo/fisiopatologia , Hipocampo/fisiopatologia , Humanos , Plasticidade Neuronal/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
It has been recently suggested that activation of 5-HT4 receptors might exert antidepressant-like effects in rats after 3 d treatment, suggesting a new strategy for developing faster-acting antidepressants. We studied the effects of 3 d and 7 d treatment with the 5-HT4 receptor partial agonist RS67333 (1.5 mg/kg.d) in behavioural tests of chronic efficacy and on neuroplastic-associated changes, such as adult hippocampal neurogenesis, expression of CREB, BDNF, ß-catenin, AKT and 5-HT4 receptor functionality. RS67333 treatment up-regulated hippocampal cell proliferation, ß-catenin expression and pCREB/CREB ratio after 3 d treatment. This short-term treatment also reduced immobility time in the forced swim test (FST), together with a partial reversion of the anhedonic-like state (sucrose consumption after chronic corticosterone). Administration of RS67333 for 7 d resulted in a higher increase in the rate of hippocampal cell proliferation, a significant desensitization of 5-HT4 receptor-coupled adenylate cyclase activity and a more marked increase in the expression of neuroplasticity-related proteins (BDNF, CREB, AKT): these changes reached the same magnitude as those observed after 3 wk administration of classical antidepressants. Consistently, a positive behavioural response in the novelty suppressed feeding (NSF) test and a complete reversion of the anhedonic-like state (sucrose consumption) were also observed after 7 d treatment. These results support the antidepressant-like profile of RS67333 with a shorter onset of action and suggest that this time period of administration (3-7 d) could be a good approximation to experimentally predict the onset of action of this promising strategy.
Assuntos
Compostos de Anilina/farmacologia , Comportamento Animal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Proteínas do Tecido Nervoso/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Piperidinas/farmacologia , Compostos de Anilina/administração & dosagem , Animais , Antidepressivos/farmacologia , Masculino , Piperidinas/administração & dosagem , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: The main goal of this study was to assess the long-term effect of haloperidol, olanzapine, and risperidone on serum prolactin levels in a naturalistically treated first-episode psychosis population. METHODS: Patients included in this study were drawn from a prospective, randomized, open-label clinical trial. Prolactin levels were measured in 110 patients with medication-naive first-episode psychosis at baseline, 3 months, and 1 year. RESULTS: A repeated-measures analysis of variance revealed a significant difference between treatments (F = 17.28, P < 0.001). At 1-year follow-up, most patients in the haloperidol and olanzapine arms had prolactin values that fell within the reference range. Patients treated with risperidone experienced a significant increase at 3 months resulting in prolactin levels above the reference range in 90% of men and 87% of women. The levels showed a tendency to decrease at 1 year, although still more than 70% of the values remained above the normative range. Sexual adverse drug reactions at 1 year assessed by the Udvalg for Kliniske Undersogelser scale showed that a higher percentage (39.3%) of patients had symptoms in the risperidone group compared to the olanzapine group (24%) or haloperidol group (20%), but the difference did not reach statistical significance (P = 0.281). CONCLUSION: Olanzapine and haloperidol treatments do not significantly affect serum prolactin levels at long term. After 1 year, elevated prolactin levels persist in most patients treated with risperidone.
Assuntos
Benzodiazepinas/administração & dosagem , Haloperidol/administração & dosagem , Prolactina/sangue , Transtornos Psicóticos/sangue , Transtornos Psicóticos/tratamento farmacológico , Risperidona/administração & dosagem , Adulto , Antipsicóticos/administração & dosagem , Biomarcadores/sangue , Feminino , Seguimentos , Humanos , Masculino , Olanzapina , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Increasing data indicate that brain endocannabinoid system plays a role in the effects of antidepressant medications. Here we examined the effect of in vivo exposure to the selective serotonin uptake inhibitor fluoxetine on cannabinoid type 1 (CB(1)) receptor density and functionality in the rat prefrontal cortex (PFC) and cerebellum. Long-term treatment with fluoxetine (10 mg/kg/day) enhanced CB(1) receptor inhibition of adenylyl cyclase (AC) in the PFC and reduced it in the cerebellum without altering receptor density and agonist stimulation of guanosine 5'-O-(3-[(35)S]thio) triphosphate ([(35)S]GTP gamma S) in either area. Analysis of [(35)S]GTP gamma S-labeled G alpha subunits allowed for the detection of up-regulated CB(1) receptor coupling to G alpha(i2), G alpha(i3) in the PFC, and reduced coupling to G alpha(i3) in the cerebellum of fluoxetine-treated rats. Concomitant administration of the 5-HT(1A) receptor antagonist N-[2-[4- (2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate (WAY100635; 0.1 mg/kg/day) reduced fluoxetine-induced modulation of CB(1) receptor coupling to G alpha subunits and AC in the PFC but not in the cerebellum. These results indicate that increased CB(1) receptor signaling at the G alpha(i)-AC transduction level is a long-term adaptation induced by fluoxetine in the PFC and point to a role for 5-HT(1A) receptors in this effect. Basal AC activity, protein kinase A (PKA) catalytic subunit expression, and phospho-cAMP response element-binding protein (pCREB)/CREB ratio were also up-regulated in the PFC of fluoxetine-treated animals, whereas no differences were detected in the cerebellum. It is interesting that long-term Delta(9)-tetrahydrocannabinol treatment did not elicit antidepressant-like effects or modulated behavioral responses of fluoxetine in an animal model of depression (olfactory bulbectomy). These data suggest that altered signal transduction through CB(1) receptors in the PFC may participate in the regulation of the AC-PKA-CREB cascade induced by fluoxetine in this brain area.
Assuntos
Inibidores de Adenilil Ciclases , Fluoxetina/administração & dosagem , Córtex Pré-Frontal/fisiologia , Receptor CB1 de Canabinoide/fisiologia , Receptor 5-HT1A de Serotonina/fisiologia , Adenilil Ciclases/metabolismo , Animais , Benzoxazinas/administração & dosagem , Canabinoides/administração & dosagem , Relação Dose-Resposta a Droga , Masculino , Morfolinas/administração & dosagem , Naftalenos/administração & dosagem , Córtex Pré-Frontal/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/agonistas , Fatores de TempoRESUMO
Lamotrigine (LTG) is metabolized by UGT1A4 but UGT2B7 also contributes to its glucuronidation. The aim of this study was to determine whether UGT2B7_- 161C>T and UGT2B7_372A>G polymorphisms contribute to the intersubject variability in LTG concentration-to-dose ratio (LTG-CDR) in epileptic patients. Fifty-three white epileptic patients attending the Neuropediatric and Neurology Services at the Marqués de Valdecilla University Hospital, in whom LTG serum concentration was to be measured for pharmacokinetic monitoring, were selected according to predefined criteria for LTG-CDR evaluation. All patients had at least one steady-state LTG serum concentration obtained before the first dose in the morning. Patients were classified in 3 groups of comedication: (1) LTG in combination with metabolism-inducer anticonvulsants (n = 22), (2) LTG in combination with valproate (n = 13), and (3) LTG as monotherapy (n = 16) or in combination with valproate and inducers (n = 2). Genotypes were determined by Applied Biosystems Genotyping Assays with TaqMan probes. A significant association was found between LTG-CDR and UGT2B7_-161C>T polymorphism (P = 0.021) when patient age and concomitant antiepileptic drugs were taken into account. Comedication explained 70% of the LTG-CDR variability, patient age 24%, and UGT2B7_-161C>T 12%. In contrast, a significant association between LTG-CDR and this polymorphism was not found in the bivariate study when age and comedication groups were not considered. A significant association between UGT2B7_372A>G and LTG-CDR was not found in the bivariate or the multivariate studies. UGT2B7_-161C>T polymorphism is significantly associated with LTG-CDR when comedication with other antiepileptic drugs and patient age are taken into account in a multivariate analysis.
Assuntos
Glucuronosiltransferase/genética , Polimorfismo de Nucleotídeo Único/genética , Triazinas/administração & dosagem , Triazinas/sangue , Adolescente , Adulto , Criança , Pré-Escolar , Citosina , Relação Dose-Resposta a Droga , Feminino , Humanos , Lamotrigina , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Timina , Adulto JovemRESUMO
The mode of action of antidepressant drugs may be related to mechanisms of monoamines receptor adaptation, including serotonin 5-HT(4) receptor subtypes. Here we investigated the effects of repeated treatment with the selective serotonin reuptake inhibitor fluoxetine for 21 days (5 and 10 mg/kg, p.o., once daily) on the sensitivity of 5-HT(4) receptors by using receptor autoradiography, adenylate cyclase assays and extracellular recording techniques in rat brain. Fluoxetine treatment decreased the density of 5-HT(4) receptor binding in the CA1 field of hippocampus as well as in several areas of the striatum over the doses of 5-10 mg/kg. In a similar way, we found a significant lower response to zacopride-stimulated adenylate cyclase activity in the fluoxetine 10 mg/kg/day treated group. Furthermore, post-synaptic 5-HT(4) receptor activity in hippocampus-measured as the excitatory action of zacopride in the pyramidal cells of CA1 evoked by Schaffer collateral stimulation was attenuated in rats treated with both doses of fluoxetine. Taken together, these results support the concept that a net decrease in the signalization pathway of 5-HT(4) receptors occurs after chronic selective serotonin reuptake inhibitor treatment: this effect may underlie the therapeutic efficacy of these drugs.
Assuntos
Encéfalo/fisiologia , Fluoxetina/administração & dosagem , Receptores 5-HT4 de Serotonina/fisiologia , Transdução de Sinais/fisiologia , Adenilil Ciclases/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Fatores de TempoRESUMO
Stress can cause damage and atrophy of neurons in the hippocampus by deregulating the expression of neurotrophic factors that promote neuronal plasticity. The endocannabinoid system represents a physiological substrate involved in neuroprotection at both cellular and emotional levels. The lack of CB1 receptor alters neuronal plasticity and originates an anxiety-like phenotype in mice. In the present study, CB1 knockout mice exhibited an augmented response to stress revealed by the increased despair behavior and corticosterone levels showed in the tail suspension test and decreased brain derived neurotrophic factor (BDNF) levels in the hippocampus. Interestingly, local administration of BDNF in the hippocampus reversed the increased despair behavior of CB1 knockout mice, confirming the crucial role played by BDNF on the emotional impairment of these mutants. The neurotrophic deficiency seems to be specific for BDNF as no differences were found in the levels of nerve growth factor and NT-3, two additional neurotrophic factors. Moreover, BDNF impairment is not related to the activity of its specific tyrosine kinase receptor or the activity of the transcription factor cAMP responsive element binding. These results suggest that the lack of CB1 receptor originates an enhanced response to stress and deficiency in neuronal plasticity by decreasing BDNF levels in the hippocampus that lead to impairment in the responses to emotional disturbances.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Reação de Congelamento Cataléptica/fisiologia , Hipocampo/patologia , Receptor CB1 de Canabinoide/deficiência , Estresse Fisiológico/patologia , Estresse Fisiológico/fisiopatologia , Análise de Variância , Animais , Comportamento Animal , Fator Neurotrófico Derivado do Encéfalo/administração & dosagem , Proteína de Ligação a CREB/metabolismo , Corticosterona/sangue , Elevação dos Membros Posteriores/métodos , Humanos , Camundongos , Camundongos Knockout , Radioimunoensaio/métodos , Receptor trkB/metabolismo , Estresse Fisiológico/tratamento farmacológico , Estresse Fisiológico/genéticaRESUMO
Increasing evidences have been accumulated during recent years suggesting a role for antidepressant drugs (ADs) as hippocampal neurogenesis enhancers, but the information about the transductional mechanisms involved in this response is very limited. We have studied in the adult rat hippocampus the effects of chronic treatment with the dual reuptake inhibitor (SNRI) venlafaxine on both cellular proliferation rate and expression of key effectors of several signaling pathways. Increased cell proliferation (BrdU incorporation) in subgranular zone (SGZ) was achieved after chronic treatment with a high dose (40 mg/kg/day) of venlafaxine. However, significant increases in the immunoreactivity of hippocampal beta-catenin in SGZ were already detected after administration of a lower dose of the drug (10 mg/kg/day). Western blot and immunoelectron microscopy studies demonstrated an increased presence of beta-catenin at the nuclear level. An increase in cytosolic AKT levels was also observed in venlafaxine-treated animals. These results suggest that the hippocampal proliferative effect of chronic venlafaxine, only evident when both serotonin (5-HT) and noradrenaline/norepinephrine (NE) reuptake systems are inhibited, requires a strong activation of intracellular signaling through Wnt (beta-catenin translocation) and AKT/PKB pathways. This activation would probably result in an increase of the expression of cell cycle regulator genes. Furthermore pERK2/ERK2 rate was also increased in the hippocampus of AD-treated animals, while no differences in the levels of CREB and p-CREB were observed. These results illustrate the complexity of the intracellular events underlying the neurogenetic responses of ADs. They also support the relevance of such effects for the therapeutic effects of these drugs.
Assuntos
Antidepressivos/farmacologia , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Cicloexanóis/farmacologia , Hipocampo/citologia , Neurônios/efeitos dos fármacos , beta Catenina/metabolismo , Animais , Bromodesoxiuridina/metabolismo , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/ultraestrutura , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Microscopia Eletrônica/métodos , Modelos Biológicos , Neurônios/ultraestrutura , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Frações Subcelulares/efeitos dos fármacos , Cloridrato de VenlafaxinaRESUMO
Sustained administration of opioids leads to antinociceptive tolerance, while prolonged association of L-type Ca2+ channel blockers (e.g. nimodipine) with opioids results in increased antinociceptive response. Herein, we investigated the changes in mu-opioid receptor signalling underlying this shift from analgesic tolerance to supersensitivity. Thus, the interaction of mu-opioid receptors with G proteins and adenylyl cyclase was examined in lumbar spinal cord segments of rats. In control animals, the mu-opioid selective agonists, sufentanil and DAMGO, stimulated [35S]5'-(gamma-thio)-triphosphate ([35S]GTP gamma S) binding and inhibited forskolin-stimulated adenylyl cyclase activity, through a mechanism involving pertussis toxin (PTX) sensitive G alpha(i/o) subunits. Seven days of chronic sufentanil treatment developed antinociceptive tolerance associated with a reduction in mu-agonist-induced [35S]GTP gamma S binding, mu-agonist-induced adenylyl cyclase inhibition, and co-precipitation of G alpha o, G alpha i2 G alpha z and G alpha q11 subunits with mu-opioid receptors. In contrast, combined nimodipine treatment with sufentanil over the same period increased the sufentanil analgesic response. This antinociceptive supersensitivity was accompanied by a significant increase of mu-agonist-induced inhibition of adenylyl cyclase that was resistant to the antagonism by PTX. In good agreement, co-precipitation of the PTX-resistant, G alpha z and G alpha q/11 subunits with mu-opioid receptors was not lowered. On the other hand, the PTX-sensitive subunits, G alpha i2 and G alpha o, as well as agonist-stimulated [35S]GTP gamma S binding were still reduced. Our results demonstrate that mu-opioid analgesic tolerance follows uncoupling of spinal mu-opioid receptors from their G proteins and linked effector pathways. Conversely, the enhanced analgesic response following combined nimodipine treatment with sufentanil is associated with adenylyl cyclase supersensitivity to the opioid inhibitory effect through a mechanism involving PTX-resistant G protein subunits.
Assuntos
Inibidores de Adenilil Ciclases , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Toxina Pertussis/farmacologia , Receptores Opioides mu/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacologia , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , AMP Cíclico/metabolismo , Interpretação Estatística de Dados , Tolerância a Medicamentos , Guanosina 5'-O-(3-Tiotrifosfato)/farmacologia , Imunoprecipitação , Infusões Intravenosas , Masculino , Nimodipina/farmacologia , Medição da Dor/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Receptores Opioides mu/agonistas , Sufentanil/administração & dosagem , Sufentanil/farmacologiaRESUMO
Brain endocannabinoid system is proposed to play a role in the pathogenesis of affective disorders. In the present study, we analyzed the functionality of the cannabinoid receptor type 1 (CB1 receptor) at different transduction levels in prefrontal cortex (PFC) of depressed suicide victims. We examined stimulation of [35S]GTPγS binding, activation of Gα protein subunits and inhibition of adenylyl cyclase by the cannabinoid agonist WIN55,212-2, as well as [3H]CP55,940 binding, in PFC homogenates from suicide victims with major depression (MD) and matched control subjects. CB1 receptor-stimulated [35S]GTPγS binding was significantly greater in the PFC of MD compared with matched controls (23%, pâ¯<â¯0.05). This increase was most evident in the PFC from MD subgroup with negative blood test for antidepressants (AD) at the time of death (AD-free) (38%, pâ¯<â¯0.05), being absent when comparing the AD-treated MD cases with their controls. The density of CB1 receptors and their coupling to adenylyl cyclase were similar between MD and control cases, regardless of the existence of AD intake. Analysis of [35S]GTPγS-labelled Gα subunits allowed for the detection of upregulated CB1 receptor coupling to Gαo, but not to Gαi1, Gαi2, Gαi3, Gαz subunits, in the PFC from AD-free MD suicides. These results suggest that increased CB1 receptor functionality at the Gαi/o protein level in the PFC of MD subjects is due to enhanced coupling to Gαo proteins and might be modulated by AD intake. These data provide new insights into the role of endocannabinoid neurotransmission in the pathobiology of MD and suggest its regulation by ADs.
Assuntos
Transtorno Depressivo Maior/metabolismo , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Suicídio , Adenilil Ciclases/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtorno Depressivo Maior/enzimologia , Feminino , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Córtex Pré-Frontal/metabolismo , Regulação para CimaRESUMO
RATIONALE: Hyperprolactinemia is considered a troubling adverse effect of antipsychotics. Direct comparisons among second generation antipsychotics are scant in clinical practice. We hypothesize prolactin-sparing second-generation antipsychotics may have differential effects on prolactin levels and that they may be influenced by sex. OBJECTIVES: To explore the differential effect of three widely used prolactin-sparing antipsychotics, aripiprazole, quetiapine and ziprasidone, on prolactin plasma levels in first episode non-affective psychosis during a 1year of treatment. METHOD: From October 2005 to January 2011 a prospective, randomized, open-label study was undertaken. 141 patients who were randomly allocated to aripiprazole (N=56), quetiapine (N=36) or ziprasidone (N=49) were analyzed. The main outcome was differences in prolactin plasma levels over 1year follow-up among the three antipsychotics. Prolactin levels had a skewed distribution and therefore they were log-transformed before statistical analyses. RESULTS: Male patients on aripiprazole had a lower risk of suffering an increase on prolactin plasma levels (N=71; F=12.645; p<0.001). There was a gender effect with smaller changes in mean prolactin values only in males. Aripiprazole had a reduced risk of hyperprolactinemia (aripiprazole 19.6%) compared to quetiapine (44.4%) and ziprasidone (32.7%) (p=0.038); and quite similar findings were found when investigating males (p=0.040). No significant differences were found in females. The percentages of mild prolactin excess were: 14.3% on aripiprazole, 36.1% on quetiapine and 18.4% on ziprasidone (χ2=6.611 p=0.037). CONCLUSIONS: Our findings provide additional evidence of differential effects of three sparing-prolactin antipsychotics on prolactin release and may help clinicians to decide among therapeutic options.
Assuntos
Antipsicóticos/uso terapêutico , Prolactina/sangue , Transtornos Psicóticos/sangue , Transtornos Psicóticos/tratamento farmacológico , Adulto , Aripiprazol/uso terapêutico , Escalas de Graduação Psiquiátrica Breve , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Piperazinas/uso terapêutico , Prolactina/efeitos dos fármacos , Fumarato de Quetiapina/uso terapêutico , Caracteres Sexuais , Tiazóis/uso terapêutico , Fatores de Tempo , Adulto JovemRESUMO
Deep brain stimulation (DBS) is a treatment that has shown some efficacy in treatment-resistant depression. In particular, DBS of the subcallosal cingulate gyrus (Brodmann's area 25, Cg25) has been successfully applied to treat refractory depression. In the rat, we have demonstrated that DBS applied to infralimbic (IL) cortex elevates the levels of glutamate and monoamines in the prefrontal cortex, and requires the stimulation of cortical α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors for its antidepressant-like effects. However, the molecular targets of IL DBS are not fully known. To gain insight into these pathways, we have investigated whether IL DBS is able to reverse the behavioral, biochemical and molecular changes exhibited by the olfactory bulbectomized (OBX) rat. Our results revealed that 1 h IL DBS diminished hyperlocomotion, hyperemotionality and anhedonia, and increased social interaction shown by the OBX rats. Further, IL DBS increased prefrontal efflux of glutamate and serotonin in both sham-operated and OBX rats. With regard to molecular targets, IL DBS increases the synthesis of brain-derived neurotrophic factor (BDNF) and the GluA1 AMPA receptor subunit, and stimulates the Akt/mammalian target of rapamycin (mTOR) as well as the AMPA receptor/c-AMP response element binding (CREB) pathways. Temsirolimus, a known in vivo mTOR blocker, suppressed the antidepressant-like effect of IL DBS in naïve rats in the forced swim test, thus demonstrating for the first time that mTOR signaling is required for the antidepressant-like effects of IL DBS, which is in line with the antidepressant response of other rapid-acting antidepressant drugs.
Assuntos
Estimulação Encefálica Profunda/métodos , Depressão/metabolismo , Relações Interpessoais , Córtex Pré-Frontal/química , Córtex Pré-Frontal/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Depressão/cirurgia , Masculino , Bulbo Olfatório/química , Bulbo Olfatório/metabolismo , Bulbo Olfatório/cirurgia , Córtex Pré-Frontal/cirurgia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos WistarRESUMO
OBJECTIVE: The timing of antipsychotic discontinuation in patients who have fully recovered from their initial episode of psychosis is still open to discussion. We aimed to evaluate the risk of symptom recurrence during the 3 years after antipsychotic discontinuation in a sample of functionally recovered first-episode nonaffective psychosis (FEP) patients (DSM-IV criteria) with schizophrenia spectrum disorder. METHOD: Participants in this open-label, nonrandomized, prospective study were drawn from an ongoing longitudinal intervention program of FEP from a university hospital setting in Spain. From July 2004 to February 2011, functionally recovered FEP individuals were eligible if they met the inclusion criteria of (1) a minimum of 18 months on antipsychotic treatment, (2) clinical remission for at least 12 months, (3) functional recovery for at least 6 months, and (4) stabilization at the lowest effective doses for at least 3 months. Forty-six individuals who were willing to discontinue medication were included in the discontinuation group (target group). Twenty-two individuals opted to stay on the prescribed antipsychotic medication and therefore were included in the maintenance group (control group). Primary outcome measures were relapse rate at 18 and 36 months and time to relapse. RESULTS: The rates of relapse over the 3-year period were 67.4% (31 of 46) in the discontinuation group and 31.8% (7 of 22) in the maintenance group. The mean time to relapse was 209 (median = 122) days and 608 (median = 607) days, respectively (log rank = 10.106, P = .001). The resumption of antipsychotic medication after the relapse occurred was associated with clinical stability and lack of further relapses. When the overall group of relapsed individuals from the 2 conditions (N = 38) was compared to those who remained asymptomatic after 3 years (N = 30), there were significant differences (P < .05) in total scores on the Scale for the Assessment of Negative Symptoms, the Clinical Global Impressions scale, and the Disability Assessment Schedule. CONCLUSIONS: Antipsychotic treatment discontinuation in individuals who had accomplished a functional recovery after a single psychotic episode was associated with a high risk of symptom recurrence. Relapsed individuals had a greater severity of symptoms and lower functional status after 3 years. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02220504.
Assuntos
Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Transtornos Psicóticos/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Síndrome de Abstinência a Substâncias/diagnóstico , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Síndrome de Abstinência a Substâncias/psicologia , Adulto , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Escalas de Graduação Psiquiátrica , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/psicologia , Recidiva , Medição de Risco , Esquizofrenia/diagnóstico , Psicologia do EsquizofrênicoRESUMO
The number of large collaborative research networks in mental health is increasing. Training programs are an essential part of them. We critically review the specific implementation of a research training program in a translational Centre for Biomedical Research in Mental Health in order to inform the strategic integration of basic research into clinical practice to have a positive impact in the mental health system and society. Description of training activities, specific educational programs developed by the research network, and challenges on its implementation are examined. The Centre for Biomedical Research in Mental Health has focused on training through different activities which have led to the development of an interuniversity master's degree postgraduate program in mental health research, certified by the National Spanish Agency for Quality Evaluation and Accreditation. Consolidation of training programs within the Centre for Biomedical Research in Mental Health has considerably advanced the training of researchers to meet competency standards on research. The master's degree constitutes a unique opportunity to accomplish neuroscience and mental health research career-building within the official framework of university programs in Spain.
Assuntos
Pesquisa Biomédica/educação , Educação de Pós-Graduação/métodos , Saúde Mental/educação , Neurociências/educação , Pesquisadores/educação , Pesquisa Translacional Biomédica/educação , Pesquisa Biomédica/organização & administração , Educação de Pós-Graduação/normas , Humanos , Espanha , Pesquisa Translacional Biomédica/organização & administraçãoRESUMO
Nearly 50% of human malignancies exhibit unregulated RAS-ERK signaling; inhibiting it is a valid strategy for antineoplastic intervention. Upon activation, ERK dimerize, which is essential for ERK extranuclear, but not for nuclear, signaling. Here, we describe a small molecule inhibitor for ERK dimerization that, without affecting ERK phosphorylation, forestalls tumorigenesis driven by RAS-ERK pathway oncogenes. This compound is unaffected by resistance mechanisms that hamper classical RAS-ERK pathway inhibitors. Thus, ERK dimerization inhibitors provide the proof of principle for two understudied concepts in cancer therapy: (1) the blockade of sub-localization-specific sub-signals, rather than total signals, as a means of impeding oncogenic RAS-ERK signaling and (2) targeting regulatory protein-protein interactions, rather than catalytic activities, as an approach for producing effective antitumor agents.
Assuntos
Carcinogênese/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Multimerização Proteica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Proteínas ras/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Embrião de Galinha , Feminino , Células HEK293 , Humanos , Immunoblotting , Indóis/química , Indóis/metabolismo , Indóis/farmacologia , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Proteína Quinase 1 Ativada por Mitógeno/química , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Modelos Moleculares , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Estrutura Terciária de Proteína , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Peixe-ZebraRESUMO
BACKGROUND: Biochemical research on the etiopathogenesis of affective disorders has focused on transduction mechanisms beyond receptors, such as adenylate cyclase activity. METHODS: Adenylate cyclase activity (AC) was measured in postmortem frontal cortex samples from 11 suicide victims with a firm antemortem diagnosis of major depressive disorder and 11 matched control cases. We analyzed the basal activity of the enzyme and that following stimulation with forskolin, guanine nucleotides, and the beta(1)-adrenoceptor agonist xamoterol. RESULTS: A significant negative correlation between the period of tissue storage and the response of AC to the different stimuli assayed was observed. No difference was found in the levels of basal, forskolin-, and GTPgammaS-stimulated activity between control and major depressive disorder cases, both in the drug-free and the drug-treated subgroups. In contrast, we found a significant lower response to beta(1)-adrenoceptors agonist-stimulated AC activity in the major depressive disorder group (p <.01). This pattern of reduced response was also found in the subgroup of patients with negative toxicology for antidepressants. CONCLUSIONS: These results, directly obtained from the brain of depressed patients, reinforce the involvement of noradrenergic neurotransmission in depressive illness. They also support the relevance of cyclic adenosine monophosphate signaling pathways in the etiopathogenesis of affective disorders.
Assuntos
Adenilil Ciclases/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Lobo Frontal/enzimologia , Suicídio , Xamoterol/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Estudos de Casos e Controles , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Colforsina/farmacologia , Transtorno Depressivo Maior/metabolismo , Relação Dose-Resposta a Droga , Feminino , Lobo Frontal/citologia , Lobo Frontal/efeitos dos fármacos , Nucleotídeos de Guanina/farmacologia , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Mudanças Depois da Morte , Ensaio Radioligante/métodosRESUMO
The effects of cannabinoid drugs on cAMP production were examined in mammalian brain. The cannabinoid receptor agonist (R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3,-d,e-1,4-benzoxazin-6-yl]-(1-naphthalenyl) methanone (WIN55,212-2) decreased forskolin-induced cAMP accumulation in a concentration-dependent manner (10(-8)-10(-5) M) in membranes from several rat and human brain regions, this effect being antagonized by 10(-5) M N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A). Furthermore, high micromolar concentrations of SR141716A evoked a dose-dependent increase in basal cAMP in rat cerebellum and cortex, as well as in human frontal cortex. This effect was antagonized by WIN55,212-2 and abolished by N-ethylmaleimide, consistent with the involvement of cannabinoid CB(1) receptors through the activation of G(i/o) proteins. These results suggest a ligand-independent activity for cannabinoid CB(1) receptor signaling cascade in mammalian brain.
Assuntos
Encéfalo/efeitos dos fármacos , Canabinoides/metabolismo , AMP Cíclico/biossíntese , Antagonistas de Entorpecentes/farmacologia , Piperidinas/farmacologia , Pirazóis/farmacologia , Receptores de Droga/antagonistas & inibidores , Animais , Benzoxazinas , Encéfalo/anatomia & histologia , Encéfalo/metabolismo , Humanos , Ligantes , Masculino , Morfolinas/farmacologia , Naftalenos/farmacologia , Ratos , Ratos Wistar , Receptores de Canabinoides , RimonabantoRESUMO
We compared the effects of adding a non-protective dose of valproate to increasing doses of lamotrigine with those of monotherapy and vice versa in CD1 mice. Anticonvulsant effects were evaluated against seizures induced by both 4-aminopyridine and pentylenetetrazole, and neurotoxic effects were evaluated by the rotarod test. Changes in anticonvulsants, gamma-aminobutyric acid (GABA) and glutamate concentrations in the whole brain were also assessed. Lamotrigine increased the potency ratio of valproate against 4-aminopyridine and pentylenetetrazole but not on rotarod, the protective index being increased from 1.1 to 2.4 against 4-aminopyridine and from 1.9 to 3.8 against pentylenetetrazole, without changes in brain valproate, and with a significant increase in brain GABA. Valproate increased the potency ratio of lamotrigine against 4-aminopyridine but not on rotarod, the protective index being increased from 4.4 to 7.3; valproate also increased brain lamotrigine (but only at low doses), brain GABA and brain glutamate. In conclusion, non-protective doses of lamotrigine increased the therapeutic index of valproate and vice versa, and these effects appeared to be pharmacodynamic.