RESUMO
OBJECTIVES: The purpose of the present study was to investigate the safety and tolerability of the monoaminergic stabilizer (-)-OSU6162 in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In addition, a potential therapeutic effect of (-)-OSU6162 in ME/CFS was evaluated by means of observer-rated scales and self-assessment rating scales. MATERIALS AND METHODS: In the current study using an open-label single-arm design ME/CFS patient received treatment with (-)-OSU6162 during 12 weeks. The patients received the following doses of (-)-OSU6162: 15 mg b.i.d. during the first 4-week period, up to 30 mg b.i.d. during the second 4-week period and up to 45 mg b.i.d. during the third 4-week period, with follow-up visits after 16 and 20 weeks. RESULTS: Out of 33 included patients, 28 completed the 12 weeks treatment period. (-)-OSU6162 was well tolerated; only one patient discontinued due to an adverse event. Vital signs and physical examinations showed no abnormal changes. Blood analyses showed an increase in serum prolactin. Therapeutically, improvements were seen on the Clinical Global Impression of Change scale, the FibroFatigue scale, the Mental Fatigue Scale, the Fatigue Severity Scale, Beck Depression Inventory, and the Short Form 36 Health Survey Questionnaire. CONCLUSIONS: (-)-OSU6162 is well tolerated in ME/CFS patients and shows promise as a novel treatment to mitigate fatigue and improve mood and health-related quality of life in ME/CFS. Obviously, the present results need to be confirmed in future placebo-controlled double-blind trials.
Assuntos
Síndrome de Fadiga Crônica , Síndrome de Fadiga Crônica/tratamento farmacológico , Humanos , Piperidinas , Escalas de Graduação Psiquiátrica , Qualidade de VidaRESUMO
OBJECTIVES: The main objective of this study was to investigate the tolerability and safety of the monoaminergic stabilizer (-)-OSU6162 in patients with multiple sclerosis (MS). In addition, a potential therapeutic effect of (-)-OSU6162 with focus on MS-related fatigue was estimated by means of various self-assessment rating scales as well as a clinical investigator-rated scale. MATERIALS AND METHODS: In this open-label, single-arm study, 30 MS patients received treatment with the monoaminergic stabilizer (-)-OSU6162 during 12 weeks. The dose of (-)-OSU6162 was 15 mg twice daily during the first 4-week period, up to 30 mg twice daily during the second 4-week period and up to 45 mg twice daily during the third 4-week period, with follow-up visits after 16 and 20 weeks. MS-related fatigue was rated by the clinical investigator or by self-assessments, using mainly established rating scales. Twenty-five patients completed the study. RESULTS: (-)-OSU6162 was well tolerated by all patients, and no serious adverse events were observed. Therapeutically, improvements were observed with respect to fatigue and mood, as judged by ratings on the Mental Fatigue Scale (MFS), Short Form-36 (SF-36) scale and Beck Depression Inventory (BDI). Furthermore, the large majority of patients were rated as globally improved in the medical observers' rating scale Clinical Global Impression of Change (CGI-C). CONCLUSIONS: In view of its good tolerability, (-)-OSU6162 may offer a new treatment option for alleviating mental fatigue, as well as depression, in MS. Larger, randomized double-blind controlled trials are warranted to confirm the present preliminary observations.
Assuntos
Esclerose Múltipla/tratamento farmacológico , Piperidinas/uso terapêutico , Adulto , Depressão/tratamento farmacológico , Depressão/etiologia , Fadiga/tratamento farmacológico , Fadiga/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Escalas de Graduação Psiquiátrica , Resultado do TratamentoRESUMO
OBJECTIVE: The monoaminergic stabiliser (-)-OSU6162 has in previous studies shown promising effects on mental fatigue after stroke and traumatic brain injury. This study investigated the safety and effectiveness of (-)-OSU6162 in patients with myalgic encephalomyelitis/chronic fatigue syndrome. METHODS: A total of 62 patients were randomly assigned to placebo or (-)-OSU6162. Primary outcomes were assessment on the mental fatigue scale (MFS) and the clinical global impression of change (CGI-C) scale. Secondary outcomes were results on the FibroFatigue scale (FF), the Beck Depression Inventory (BDI), the pain visual analogue scale and neuropsychological tests. Assessments were performed at baseline, after 1 and 2 weeks of treatment and at follow-up after 6 weeks. RESULTS: MFS and CGI-C showed significant improvements for both treatment groups after treatment but not at follow-up; a similar pattern was seen for FF and BDI. However, significant differences between groups could not be demonstrated. On the other hand, correlation analyses showed a significant correlation between (-)-OSU6162 concentration and change in MFS, FF, and BDI score within the concentration interval 0.1-0.7 µM. Exploratory subgroup analyses showed a larger treatment effect with (-)-OSU6162 in improving MFS and FF symptoms in patients on antidepressant therapy compared to those without antidepressant treatment. CONCLUSION: (-)-OSU6162 was found to be safe and well tolerated. When analysing the entire material (-)-OSU6162 was not found to differ significantly from placebo in alleviating fatigue in ME patients but was superior to placebo in counteracting fatigue in a subgroup of ME patients who received concomitant pharmacological treatment for depression.
Assuntos
Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Dopaminérgicos/farmacologia , Síndrome de Fadiga Crônica/tratamento farmacológico , Fadiga Mental/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde/métodos , Piperidinas/farmacologia , Adulto , Terapia Combinada , Depressão/fisiopatologia , Dopaminérgicos/administração & dosagem , Relação Dose-Resposta a Droga , Síndrome de Fadiga Crônica/fisiopatologia , Feminino , Seguimentos , Humanos , Masculino , Fadiga Mental/fisiopatologia , Pessoa de Meia-Idade , Piperidinas/administração & dosagemRESUMO
OBJECTIVE: Obsessive-compulsive disorder (OCD) is a chronic psychiatric disorder leading to considerable distress and disability. Therapies are effective in a majority of paediatric patients, however, many only get partial response. It is therefore important to study the underlying pathophysiology of the disorder. METHODS: 1H magnetic resonance spectroscopy (MRS) was used to study the concentration of brain metabolites in four different locations (cingulate gyrus and sulcus, occipital cortex, thalamus and right caudate nucleus). Treatment-naive children and adolescents with OCD (13 subjects) were compared with a group of healthy age- and gender-matched subjects (11 subjects). Multivariate analyses were performed on the concentration values. RESULTS: No separation between controls and patients was found. However, a correlation between metabolite concentrations and symptom severity as measured with the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) was found. Strongest was the correlation with the CY-BOCS obsession subscore and aspartate and choline in the caudate nucleus (positively correlated with obsessions), lipids at 2 and 0.9 ppm in thalamus, and occipital glutamate+glutamine, N-acetylaspartate and myo-inosytol (negatively correlated with obsessions). CONCLUSIONS: The observed correlations between 1H MRS and CY-BOCS in treatment-naive patients further supports an occipital involvement in OCD. The results are consistent with our previous study on adult OCD patients. The 1H MRS data were not supportive of a separation between the patient and control groups.
Assuntos
Encéfalo/diagnóstico por imagem , Transtorno Obsessivo-Compulsivo/diagnóstico por imagem , Transtorno Obsessivo-Compulsivo/metabolismo , Lobo Occipital/diagnóstico por imagem , Espectroscopia de Prótons por Ressonância Magnética/métodos , Adolescente , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Encéfalo/metabolismo , Criança , Colina/metabolismo , Feminino , Humanos , Inositol/metabolismo , Masculino , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Transtorno Obsessivo-Compulsivo/fisiopatologia , Lobo Occipital/metabolismo , Índice de Gravidade de DoençaRESUMO
Alcohol dependence is associated with a dysregulated dopamine system modulating reward, craving and cognition. The monoamine stabilizer (-)-OSU6162 (OSU6162) can counteract both hyper- and hypo-dopaminergic states and we recently demonstrated that it attenuates alcohol-mediated behaviors in long-term drinking rats. The present Phase II exploratory human laboratory study investigated to our knowledge for the first time the effects of OSU6162 on cue- and priming-induced craving in alcohol dependent individuals. Fifty-six alcohol dependent individuals were randomized to a 14-day-treatment period of OSU6162 or placebo after their baseline impulsivity levels had been determined using the Stop Signal Task. On Day 15, participants were subjected to a laboratory alcohol craving test comprised of craving sessions induced by: i) active - alcohol specific cues, ii) neutral stimuli and iii) priming - intake of an alcoholic beverage (0.20g ethanol/kg bodyweight). Subjective ratings of alcohol craving were assessed using the shortened version of the Desire for Alcohol Questionnaire and visual analog scales (VAS). OSU6162 treatment had no significant effect on cue-induced alcohol craving, but significantly attenuated priming-induced craving. Exploratory analysis revealed that this effect was driven by the individuals with high baseline impulsivity. In addition, OSU6162 significantly blunted the subjective liking of the consumed alcohol (VAS). Although the present 14-day-treatment period, showed that OSU6162 was safe and well tolerated, this exploratory human laboratory study was not designed to evaluate the efficacy of OSU6162 to affect alcohol consumption. Thus a larger placebo-controlled efficacyclinical trial is needed to further investigate the potential of OSU6162 as a novel medication for alcohol dependence.
Assuntos
Alcoolismo/tratamento farmacológico , Alcoolismo/psicologia , Fissura/efeitos dos fármacos , Piperidinas/uso terapêutico , Adulto , Sinais (Psicologia) , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Comportamento Impulsivo/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Piperidinas/farmacologia , Escalas de Graduação Psiquiátrica , Estudos Retrospectivos , Estatísticas não Paramétricas , Fatores de TempoRESUMO
(-)-OSU6162 is a dopamine stabilizer that can counteract both hyperdopaminergic and hypodopaminergic states. In this study, D2/D3 receptor occupancy of (-)-OSU6162 in the human brain was investigated using positron emission tomography (PET). Twelve male healthy volunteers underwent [(11)C]raclopride PET scanning before and 1 h after a single oral dose of (-)-OSU6162 (15-90 mg). Blood samples for determination of (-)-OSU6162 and prolactin plasma levels were collected at Tmax. Parametric images of [(11)C]raclopride binding potential relative to nondisplaceable tissue (cerebellar grey matter) uptake (BPND) at baseline and after (-)-OSU6162 administration were generated using the simplified reference tissue model. MRI-based regions of interest were defined for the striatum, composed of caudate nucleus and putamen, and projected onto the co-registered parametric [(11)C]raclopride BPND image. Furthermore, three striatal subregions, ie, anterior dorsal caudate, anterior dorsal putamen, and ventral striatum, were defined manually and additionally analyzed. Plasma concentrations of (-)-OSU6162, ranging from 0.01 to 0.9 µM, showed a linear relationship with prolactin levels, reflecting blockade of pituitary D2 receptors. A concentration-dependent increase in striatal D2/D3 receptor occupancy was observed, reaching a value of about 20% at an (-)-OSU6162 plasma level of 0.2 µM, and which for higher concentrations leveled off to a maximal occupancy of about 40%. Findings were similar in the striatal subregions. The present data corroborate the notion that (-)-OSU6162 binds preferentially to a subpopulation of D2/D3 receptors, possibly predominantly extrasynaptic, and this may form the basis for the dopamine-stabilizing properties of (-)-OSU6162.
Assuntos
Corpo Estriado/metabolismo , Dopaminérgicos/farmacologia , Piperidinas/farmacologia , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Administração Oral , Radioisótopos de Carbono , Corpo Estriado/diagnóstico por imagem , Dopaminérgicos/sangue , Humanos , Processamento de Imagem Assistida por Computador , Modelos Lineares , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Piperidinas/sangue , Tomografia por Emissão de Pósitrons , Prolactina/sangue , Racloprida , Compostos RadiofarmacêuticosRESUMO
OBJECTIVE: To evaluate the safety (primary objective) and efficacy (secondary objective) of (-)-OSU6162 in Huntington's disease (HD). METHODS: In a double-blind, cross-over trial, patients with HD were randomly assigned to start treatment on either (-)-OSU6162 or placebo. After 4 weeks, those patients who initially received active drug were switched to placebo for another 4 weeks, and vice versa. During the first week the (-)-OSU6162 dose was 15 mg twice daily, during the second week 30 mg twice daily, and during the last 2 weeks 45 mg twice daily. Motor, cognitive, mental and social functions were rated by the clinical investigator or by self-assessment, using established rating scales. RESULTS: Fifteen patients fulfilling inclusion and exclusion criteria completed the study. (-)-OSU6162 was well tolerated by all patients and no adverse effects were observed. (-)-OSU6162 treatment significantly improved the Short Form 36 Vitality score, mainly due to an improvement of the individual item 'worn-out' (VT3). In addition, an improvement of depressive symptoms was found using Beck Depression Inventory. In contrast to a general trend of improvement in several non-motor variables only small and non-significant differences between (-)-OSU6162 and placebo were found regarding motor functions. CONCLUSIONS: (-)-OSU6162 offers promise for the treatment of HD, as a drug with good tolerability, capable of improving the patients' experienced non-motor functions such as energy and mood and thus alleviating symptoms of great importance for their quality of life.
Assuntos
Doença de Huntington/tratamento farmacológico , Piperidinas/uso terapêutico , Adulto , Cognição/efeitos dos fármacos , Estudos Cross-Over , Método Duplo-Cego , Feminino , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Atividade Motora/efeitos dos fármacos , Inquéritos e Questionários , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: New medications for alcohol use disorder (AUD) are needed. Long-term alcohol consumption leads to a dysregulated dopamine system. A novel approach to normalize these dysregulations might be treatment with "monoamine stabilizers," a novel class of compounds characterized by the ability to either suppress, stimulate, or not influence dopamine activity depending on the prevailing dopaminergic tone. METHODS: The effects of the monoamine stabilizer (-)-OSU6162 (OSU6162) on voluntary ethanol intake and ethanol withdrawal symptoms were evaluated in rats voluntarily consuming ethanol for at least 3 months before testing. Furthermore, effects of OSU6162 on ethanol seeking behavior were evaluated with the progressive ratio and cue-induced reinstatement paradigms. Finally, the interaction of OSU6162 with ethanol on dopamine output and metabolism was studied with microdialysis. RESULTS: The OSU6162 attenuated several ethanol-mediated behaviors, including voluntary ethanol consumption, ethanol withdrawal symptoms, operant ethanol self-administration under progressive ratio schedule, and cue-induced reinstatement of ethanol seeking in rats that had voluntarily consumed ethanol for at least 3 months before treatment. In addition, OSU6162 blunted ethanol-induced dopamine output in nucleus accumbens of ethanol-naïve rats. CONCLUSIONS: These results highlight the ability of OSU6162 to stabilize dopamine activity depending on the prevailing dopaminergic tone and indicate that OSU6162 might decrease ethanol intake by attenuating the acute rewarding properties of ethanol. In addition, OSU6162 might have potential to prevent relapse triggered by alcohol craving, alcohol related cues, and or an urge to relieve abstinence symptoms. The present study is to our knowledge the first indicating that OSU6162 might serve as a novel medication for AUD.
Assuntos
Consumo de Bebidas Alcoólicas , Modelos Animais de Doenças , Dopamina/metabolismo , Etanol/farmacologia , Núcleo Accumbens/metabolismo , Piperidinas/farmacologia , Síndrome de Abstinência a Substâncias , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Consumo de Bebidas Alcoólicas/metabolismo , Animais , Sintomas Comportamentais/tratamento farmacológico , Sintomas Comportamentais/etiologia , Sintomas Comportamentais/metabolismo , Sinais (Psicologia) , Descoberta de Drogas , Masculino , Microdiálise , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Ratos , Recompensa , Prevenção Secundária , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Síndrome de Abstinência a Substâncias/etiologia , Síndrome de Abstinência a Substâncias/metabolismoRESUMO
The locomotor effects of (-)- and (+)-OSU6162 were evaluated in 'low activity' animals (reserpinized mice and habituated rats) and 'high activity' animals (drug-naive mice and non-habituated rats). Both enantiomers of OSU6162 had dual effects on behavior, stimulating locomotor activity in 'low activity' animals and inhibiting locomotor activity in 'high activity' animals. There were also certain differences between the two enantiomers in their behavioral profiles. The stimulatory effects of both enantiomers in reserpinized mice were blocked by the 5-HT2A selective antagonist M100907, but not by the D2-selective antagonists haloperidol or raclopride, or by the D1-selective antagonists SCH23390 or SCH39166. The stimulatory effect in mice was more pronounced for (+)- than for (-)-OSU6162. In drug-naive mice, both enantiomers of OSU6162 produced head twitches, albeit to a much lesser extent than DOI, and both enantiomers inhibited DOI-induced head twitches, the (-)-form more effectively so than the (+)-form. These results suggest that (-)- and (+)-OSU6162 are partial agonists on 5-HT2A receptors and that the (+)-form has a higher intrinsic activity than the (-)-form. At high doses, both enantiomers inhibited locomotor activity in drug-naive mice, with (-)-OSU6162 being more potent than (+)-OSU6162. Similarly, in high-active rats, both enantiomers inhibited locomotor activity, with the (-)-enantiomer being more potent than the (+)-enantiomer. Conversely, in habituated rats, both enantiomers stimulated locomotor activity, and here, as opposed to the case in low-active mice, (-)-OSU6162 was more effective than (+)-OSU6162. The stimulatory effects in habituated rats of both enantiomers could be antagonized with either haloperidol or M100907. Overall, these results indicate that the dual effects on behavior of (-)- and (+)-OSU6162 are mediated through D2 and 5-HT2A receptors, consistent with their in vitro functional selectivity profiles (see Burstein et al., accompanying paper). Thus, both enantiomers of OSU6162 seem to act as stabilizers not only on dopaminergic, but also on serotonergic brain signaling. These discoveries have important implications for the potential clinical utility of both compounds, as well as for several of their congeners.
Assuntos
Química Encefálica/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Piperidinas/farmacologia , Receptor 5-HT2A de Serotonina/fisiologia , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Animais , Química Encefálica/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos , Atividade Motora/fisiologia , Piperidinas/química , Ratos , Ratos Sprague-Dawley , EstereoisomerismoRESUMO
(-)-OSU6162 has promise for treating Parkinson's disease, Huntington's disease and schizophrenia. Behavioral tests evaluating the locomotor effects of (-) and (+)-OSU6162 on 'low activity' animals (reserpinized mice and habituated rats) and 'high activity' animals (drug naive mice and non-habituated rats) revealed that both enantiomers of OSU6162 had dual effects on behavior, stimulating locomotor activity in 'low activity' animals and inhibiting locomotor activity in 'high activity' animals. To elucidate a plausible mechanism of action for their behavioral effects, we evaluated the intrinsic actions of (-)- and (+)-OSU6162, and a collection of other antipsychotic and antiparkinsonian agents at 5-HT2A and D2 receptors in functional assays with various degrees of receptor reserve, including cellular proliferation, phosphatidyl inositol hydrolysis, GTPγS and beta-arrestin recruitment assays. We also tested for possible allosteric actions of (-)-OSU6162 at D2 receptors. Both enantiomers of OSU6162 were medium intrinsic activity partial agonists at 5-HT2A receptors and low intrinsic activity partial agonists at D2 receptors. (+)-OSU6162 had higher efficacy at 5-HT2A receptors, which correlated with its greater stimulatory activity in vivo, but (-)-OSU6162 had higher potency at D2 receptors, which correlated with its greater inhibitory activity in vivo. (-)-OSU6162 did not display any convincing allosteric properties. Both (+)- and (-)-OSU6162 were significantly less active at 27 other monoaminergic receptors and reuptake transporters tested suggesting that D2 and 5-HT2A receptors play crucial roles in mediating their behavioral effects. Compounds with balanced effects on these two receptor systems may offer promise for treating neuropsychiatric diseases.
Assuntos
Membrana Celular/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Piperidinas/farmacologia , Receptor 5-HT2A de Serotonina/fisiologia , Receptores de Dopamina D2/fisiologia , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Animais , Membrana Celular/metabolismo , Células HEK293 , Humanos , Camundongos , Células NIH 3T3 , Piperidinas/química , Frações SubcelularesRESUMO
Dopaminergic stabilizers may be conceptualized as drugs with normalizing effects on dopamine-mediated behaviours and neurochemical events. (S)-(-)-OSU6162 (OSU6162) and ACR16 are two structurally related compounds ascribed such properties, principally because of their stabilizing effects on motor activity in rodents. Reports in the literature indicate possible partial D2 receptor agonist effects using various in vitro systems. This study aimed to measure D2 receptor antagonist and agonist effects of OSU6162 and ACR16 in vivo. To address this, we have studied the effects of both compounds on prolactin secretion in drug-naive and dopamine-depleted rats; dopamine depletion was induced by pretreatment with reserpine plus α-methyl-DL: -p-tyrosine. We find that OSU6162 and ACR16 both stimulate prolactin secretion in drug-naive rats with OSU6162 being considerably more potent and efficacious. Both compounds show a non-significant trend towards reversal of the increased secretion caused by dopamine depletion, whereas the D2 receptor antagonist haloperidol further increased prolactin secretion. Thus, this study suggests that OSU6162 and ACR16 act as D2 receptor antagonists under normal conditions in vivo, possibly with minor agonist effects in a state of dopamine depletion.
Assuntos
Antagonistas dos Receptores de Dopamina D2 , Dopamina/deficiência , Lactotrofos/efeitos dos fármacos , Piperidinas/farmacologia , Prolactina/sangue , Receptores de Dopamina D2/agonistas , Animais , Aripiprazol , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/administração & dosagem , Antagonistas de Dopamina/farmacologia , Haloperidol/administração & dosagem , Haloperidol/farmacologia , Hiperprolactinemia/sangue , Hiperprolactinemia/induzido quimicamente , Lactotrofos/metabolismo , Masculino , Metiltirosinas/administração & dosagem , Metiltirosinas/farmacologia , Piperazinas/administração & dosagem , Piperazinas/farmacologia , Piperidinas/administração & dosagem , Prolactina/metabolismo , Quinolonas/administração & dosagem , Quinolonas/farmacologia , Ratos , Ratos Sprague-Dawley , Reserpina/administração & dosagem , Reserpina/farmacologiaRESUMO
Recent clinical trials have raised questions over the perceived advantages of second-generation 'atypical' antipsychotics over those from the first generation. An atypical antipsychotic in its original sense is one that lacks extrapyramidal side effects. However, the addition of other clinical features to the original concept of atypicality, such as efficacy against negative and cognitive symptoms, seems to have become a feature of searches for novel antipsychotics in the past two decades. Although this approach has led to some therapeutic advances, we propose that it has also hampered antipsychotic drug research and that reframing the concept of atypicality could have a key role in making genuine breakthroughs in schizophrenia therapy.
Assuntos
Antipsicóticos/uso terapêutico , Desenho de Fármacos , Esquizofrenia/tratamento farmacológico , Antipsicóticos/efeitos adversos , Antipsicóticos/farmacologia , Doenças dos Gânglios da Base/induzido quimicamente , Ensaios Clínicos como Assunto , Indústria Farmacêutica/organização & administração , HumanosRESUMO
1H magnetic resonance spectroscopy (1H MRS) studies exploring brain metabolites, especially glutamine + glutamate (Glx), in obsessive compulsive disorder (OCD) are of vital interest for trying to understand more about the pathophysiology of OCD. Therefore, we conducted the present 1H MRS study with the aims of (1) comparing MRS metabolites in a group of adult patients with OCD and a group of healthy controls, and (2) examining the relationship between MRS metabolite concentrations and symptom severity in the patient group. Three brain regions were studied, the right caudate nucleus, the anterior gyrus cinguli and the occipital cortex bilaterally. Since multivariate analysis is a highly useful tool for extraction of 1H MRS data, we applied principal component analysis (PCA) and partial least square projection to latent structures (PLS) to the MRS data. PLS disclosed a strong relationship between several of the metabolites and OCD symptom severity, as measured with Yale-Brown obsessive-compulsive scale (YBOCS): the YBOCS score was found to be positively correlated to caudate creatine, Glx, glutamate, and choline compounds as well as occipital cortex myoinositol, and negatively correlated to occipital cortex Glx. The negative correlation between occipital cortex Glx and YBOCS was the most impressive. PCA did not reveal any tendency for a separation between the patients with OCD and controls with respect to MRS metabolites. The results are discussed in relation to corticostriatothalamocortical feedback and previous observations of poor visuospatial ability in OCD.
Assuntos
Encéfalo/metabolismo , Encéfalo/patologia , Espectroscopia de Ressonância Magnética , Transtorno Obsessivo-Compulsivo/diagnóstico , Transtorno Obsessivo-Compulsivo/metabolismo , Adulto , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Mapeamento Encefálico , Estudos de Casos e Controles , Colina/metabolismo , Creatina/metabolismo , Feminino , Ácido Glutâmico/metabolismo , Glutamina/metabolismo , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Análise de Componente Principal , Prótons , Índice de Gravidade de Doença , Inquéritos e QuestionáriosRESUMO
In this review, we focus on the marked adaptability of dopamine D(2) receptors to varying agonist levels and we discuss the extent to which this phenomenon can account for the heterogeneity of these receptors in regard to function and pharmacological responsiveness. We emphasize the significance of a distinction between synaptic and extrasynaptic receptors in this context. For example, the application of this dichotomy appears to shed new light on the various subgroups of antipsychotic drugs and the mechanisms underlying their different profiles.
Assuntos
Adaptação Fisiológica/efeitos dos fármacos , Dopaminérgicos/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Receptores de Dopamina D2/fisiologia , Adaptação Fisiológica/fisiologia , Animais , HumanosRESUMO
Dopaminergic stabilizers can be defined as drugs that stimulate or inhibit dopaminergic signalling depending on the dopaminergic tone. (-)-OSU6162 and ACR16 appear to possess such a profile. They have been proposed to act as partial dopamine receptor agonists or as antagonists with preferential action on dopaminergic autoreceptors. Previous studies have shown either stimulation or inhibition of behaviour in response to (-)-OSU6162 and ACR16, which has been suggested to reflect their dual effects on dopaminergic signalling. The aims of the present work are to (1) examine the relation between behavioural response to these drugs and activity baseline, and (2) test the suggested mechanisms of action by means of close comparisons with the known partial D2-receptor agonists (-)-3-PPP and aripiprazole, and the D2 autoreceptor preferring antagonist amisulpride with respect to effects on behaviour. From the results of these experiments it can be concluded that: (1) The direction of the response to (-)-OSU6162 and ACR16 is dependent on activity baseline, which in turn, under physiological conditions, is determined primarily by test arena size of and degree of habituation to the environment. (2) The effects of (-)-OSU6162 and ACR16 cannot be explained on the basis of either partial dopamine receptor agonism or preferential dopamine autoreceptor antagonism. Nevertheless, the current data suggest at least two different D2-receptor-associated targets which mediate opposite effects on activity. This result fits in with a mechanism proposed from a recent in vitro study, according to which (-)-OSU6162 has a dual action on dopamine D2 receptors, (a) an allosteric effect causing an enhanced response to dopamine, and (b) the previously proposed orthosteric effect antagonizing the action of dopamine.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Dopamina/metabolismo , Atividade Motora/efeitos dos fármacos , Piperidinas/farmacologia , Receptores de Dopamina D2/efeitos dos fármacos , Animais , Dopaminérgicos/farmacologia , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Relação Dose-Resposta a Droga , Interações Medicamentosas/fisiologia , Habituação Psicofisiológica/efeitos dos fármacos , Habituação Psicofisiológica/fisiologia , Masculino , Atividade Motora/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologiaRESUMO
In contrast to the conventional view of dopamine involvement in schizophrenia, which posits hyperactive dopaminergic transmission, we propose that for unknown developmental and/or biochemical reasons, a primary defect occurs in efficient, tight dopaminergic synaptic transmission, triggering feedback activation and receptor upregulation, and resulting in the well-characterized increase in dopaminergic tone. This hypothesis is driven by suggestive evidence for subpopulations of dopamine D2 receptors delivering contrasting forms of dopaminergic transmission: synaptic receptors, responsible for basic dopaminergic function and subject to effective feedback control, and poorly controlled extrasynaptic receptors partly responsible for the positive symptoms of psychosis. Since the primary defect is dopamine deficiency, we term this theory the dopaminergic deficit hypothesis of schizophrenia. It is currently informing clinical studies with novel partial dopamine antagonists (dopamine stabilizers) such as ACR16, which preferentially target extrasynaptic receptors while leaving synaptic transmission and basic dopamine function intact.
Assuntos
Dopamina/deficiência , Modelos Neurológicos , Esquizofrenia/metabolismo , Animais , Antipsicóticos/uso terapêutico , Dopamina/metabolismo , Agonistas de Dopamina/uso terapêutico , Antagonistas de Dopamina/farmacologia , Humanos , Receptores de Dopamina D2/fisiologia , Esquizofrenia/tratamento farmacológicoRESUMO
Dopaminergic agonists and NMDA-receptor antagonists form the basis for the dopamine and glutamate models of schizophrenia, respectively. In human subjects dopaminergic agonists evoke a psychosis resembling positive symptoms of schizophrenia, while NMDA-receptor antagonists produce both positive and negative symptoms. Consequently, the glutamate model may be considered the most complete of the two models. Alterations in animal behaviour, in response to amphetamine or NMDA-receptor antagonists, are widely used to model schizophrenia. NMDA-receptor antagonist induced social withdrawal in rat is an established model for negative symptoms of schizophrenia. In this study we have set up an automated method, based on video tracking, to assess social behaviour, motor activity and movement pattern in rats. This method was then used to evaluate the effects of amphetamine and the NMDA-receptor antagonist (+)-MK-801, administered as single intraperitoneal injections, on rat behaviour. Amphetamine caused significantly increased motor activity and a tendency towards stimulation of social interactions. (+)-MK-801 also stimulated motor activity, but induced a significant inhibition of social interactions. These results indicate that a single injection of (+)-MK-801 to rats models both positive and negative symptoms of schizophrenia. Amphetamine, in contrast, reflects only the positive symptoms of schizophrenia in this model.
Assuntos
Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Psicologia do Esquizofrênico , Comportamento Social , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Dextroanfetamina/farmacologia , Relação Dose-Resposta a Droga , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
Schizophrenia is manifested by positive and negative symptoms, as well as cognitive deficits. Most existing antipsychotic agents have poor effects on the negative symptoms of schizophrenia, thus emphasizing the necessity for developing new antipsychotic treatments. Dopaminergic stabilizers constitute one of the latest novelties in the quest for new antipsychotic drugs. Social withdrawal in rats, in response to treatment with NMDA-receptor antagonists such as (+)-MK-801, may be used to model negative symptoms. In this study we aimed to evaluate the dopaminergic stabilizers (-)-OSU6162 and ACR16, compared to haloperidol and clozapine, in a rat model for schizophrenia, focusing on (+)-MK-801 induced social withdrawal. Social behaviour and motor activity were assessed using a videotracking system, allowing automated analysis of the behaviour. Both (-)-OSU6162 and ACR16 were capable of restoring social behaviour, measured as proximity, to control level. These results indicate that these drugs may be effective in the treatments of negative symptoms.
Assuntos
Maleato de Dizocilpina/antagonistas & inibidores , Maleato de Dizocilpina/farmacologia , Dopamina/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Piperidinas/farmacologia , Comportamento Social , Animais , Antipsicóticos/farmacologia , Clozapina/farmacologia , Antagonistas de Dopamina/farmacologia , Haloperidol/farmacologia , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Psicologia do EsquizofrênicoRESUMO
Following initial observations of marked effects of nicotine self-medication in a patient with obsessive-compulsive disorder (OCD), another four OCD patients were treated with nicotine for eight weeks in an open label fashion. Patients fulfilling DSM-IV criteria for OCD and with initial Yale-Brown Obsessive-Compulsive Scale (YBOCS) score>15 were included in the study. The patients were scored with YBOCS, Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), NIMH Global Obsessive-Compulsive Scale (NIMH) and Global Assessment of Functioning (GAF). Four of five patients receiving nicotine treatment displayed a favourable response with reductions in YBOCS scores. For these four patients, the nicotine chewing gum enabled a more adequate behaviour in stressful, OCD-eliciting, situations. We feel that these results are encouraging enough to warrant a larger, controlled study on nicotine treatment of OCD.