RESUMO
Higher cognitive functions require the integration and coordination of large populations of neurons in cortical and subcortical regions. Oscillations in the gamma band (30-45 Hz) of the electroencephalogram (EEG) have been involved in these cognitive functions. In previous studies, we analysed the extent of functional connectivity between cortical areas employing the 'mean squared coherence' analysis of the EEG gamma band. We demonstrated that gamma coherence is maximal during alert wakefulness and is almost absent during rapid eye movement (REM) sleep. The nucleus pontis oralis (NPO) is critical for REM sleep generation. The NPO is considered to exert executive control over the initiation and maintenance of REM sleep. In the cat, depending on the previous state of the animal, a single microinjection of carbachol (a cholinergic agonist) into the NPO can produce either REM sleep [REM sleep induced by carbachol (REMc)] or a waking state with muscle atonia, i.e. cataplexy [cataplexy induced by carbachol (CA)]. In the present study, in cats that were implanted with electrodes in different cortical areas to record polysomnographic activity, we compared the degree of gamma (30-45 Hz) coherence during REMc, CA and naturally-occurring behavioural states. Gamma coherence was maximal during CA and alert wakefulness. In contrast, gamma coherence was almost absent during REMc as in naturally-occurring REM sleep. We conclude that, in spite of the presence of somatic muscle paralysis, there are remarkable differences in cortical activity between REMc and CA, which confirm that EEG gamma (≈40 Hz) coherence is a trait that differentiates wakefulness from REM sleep.
Assuntos
Carbacol/farmacologia , Cataplexia/fisiopatologia , Agonistas Colinérgicos/farmacologia , Neurônios/efeitos dos fármacos , Sono REM/efeitos dos fármacos , Animais , Cataplexia/induzido quimicamente , Gatos , Eletroencefalografia/métodos , Neocórtex/efeitos dos fármacos , Neurônios/fisiologia , Ponte/efeitos dos fármacos , Ponte/fisiologia , Vigília/efeitos dos fármacosRESUMO
PURPOSE OF REVIEW: A number of European countries have reported a dramatic increase in the rates of childhood narcolepsy with cataplexy in children immunized with a split-virion adjuvanted swine flu vaccine. Here, we review the strengths and weaknesses of these epidemiological studies and possible neuroimmunological mechanisms. RECENT FINDINGS: Initial concerns of a 13-fold increased relative risk of narcolepsy were raised by the Scandinavian health protection agencies in 2010. Subsequent retrospective studies support these findings in Canada, France, Ireland, England and Denmark. The cases are predominantly young children who present with severe and rapid onset of cataplexy as well as narcolepsy often within a few weeks of vaccination. The proposed mechanism for postvaccination narcolepsy is one in which an environmental trigger causes or enhances an antibody-mediated autoimmune response in patients with a preexisting genetic susceptibility. However, there have not yet been any reports of specific autoimmunity, either antibody or T-cell-mediated. SUMMARY: There is a strong association between narcolepsy and H1N1 vaccination. However, whether this reflects a true increase in affected individuals or a hastening of disease onset in individuals who would otherwise have developed narcolepsy later will become clear in the coming years. The pathological explanation of this association and narcolepsy is likely to be autoimmune, although supportive evidence is lacking.Video abstract available: See the Video Supplementary Digital Content 1 (http://links.lww.com/COPM/A9).
Assuntos
Cataplexia/induzido quimicamente , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/efeitos adversos , Influenza Humana/prevenção & controle , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Narcolepsia/induzido quimicamente , Vacinação/efeitos adversos , Adolescente , Autoimunidade/efeitos dos fármacos , Autoimunidade/imunologia , Proteínas Quinases Dependentes de Cálcio-Calmodulina , Canadá/epidemiologia , Cataplexia/epidemiologia , Cataplexia/imunologia , Criança , Europa (Continente)/epidemiologia , Feminino , Humanos , Incidência , Vacinas contra Influenza/administração & dosagem , Masculino , Narcolepsia/epidemiologia , Narcolepsia/imunologia , RiscoRESUMO
Loss of orexin/hypocretin causes serious sleep disorder; narcolepsy. Cataplexy is the most striking symptom of narcolepsy, characterized by abrupt muscle paralysis induced by emotional stimuli, and has been considered pathological activation of REM sleep atonia system. Clinical treatments for cataplexy/narcolepsy and early pharmacological studies in narcoleptic dogs tell us about the involvement of monoaminergic and cholinergic systems in the control of cataplexy/narcolepsy. Muscle atonia may be induced by activation of REM sleep-atonia generating system in the brainstem. Emotional stimuli may be processed in the limbic systems including the amygdala, nucleus accumbens, and medial prefrontal cortex. It is now considered that orexin/hypocretin prevents cataplexy by modulating the activity of different points of cataplexy-inducing circuit, including monoaminergic/cholinergic systems, muscle atonia-generating systems, and emotion-related systems. This review will describe the recent advances in understanding the neural mechanisms controlling cataplexy, with a focus on the involvement of orexin/hypocretin system, and will discuss future experimental strategies that will lead to further understanding and treatment of this disease.
Assuntos
Cataplexia , Narcolepsia , Animais , Cães , Cataplexia/tratamento farmacológico , Cataplexia/induzido quimicamente , Cataplexia/diagnóstico , Orexinas , Narcolepsia/tratamento farmacológico , Narcolepsia/diagnóstico , Sono REM/fisiologia , Colinérgicos/efeitos adversosRESUMO
INTRODUCTION: Child and adolescent catatonia has been poorly investigated. Moreover, diagnosis criteria only exist for adult psychiatry, and there are no therapeutic guidelines. The aim of this paper is to describe the case of a 14-year-old girl presenting an overlap between psychogenic and neuroleptic induced catatonia, acute treatment and ten year's follow-up. CASE REPORT: A 14-year-old Caucasian French girl, Elsa, was admitted in February 1998 to a University adolescent mental health center with an acute psychotic disorder. She showed agitation, impulsivity (sudden engagement in inappropriate behaviour), paranoid delusions, visual and auditory hallucinations, diurnal and nocturnal urinary incontinence, lack of self-care, inadequate food intake because of fear of poisoning, and vomiting after meals leading to rapid weight loss of 5 kg. Clinical examination, laboratory tests, EEG and RMI were normal. Toxicological tests were negative. Her IQ, assessed six months before admission, was in the dull average range (70-75). Elsa was treated with loxapine 150 mg per day for one week without improvement and this was then replaced by haloperidol 30 mg per day. One week after the start of haloperidol her agitation, impulsivity, and hallucinatory symptoms decreased. Twenty four days after loxapine introduction and 17 days after the haloperidol, her condition deteriorated rapidly over less than 48 hours. She exhibited immobility, minimal response to stimuli, staring and catalepsy with waxy flexibility. The diagnosis of catatonia was established. Examination revealed tremulous extremities, tachychardia (110 pm) and apyrexia. Creatine phosphokinase levels were 106 UI/l (normal range 0-250). Human immunodeficiency virus, hepatitis, listeria and Lyme serology were negative. Cerebrospinal fluid analysis was normal. Haloperidol was stopped and intravenous clonazepam 5mg/kg was begun. It was not possible to obtain signed consent from the two parents for Electroconvulsive therapy. The patient was transferred to a pediatric intensive care unit. The treatment was standard parenteral nutrition, nursing, intravenous clonazepam 0.05 mg/kg, with regular attendance by a child psychiatrist. Elsa stayed three weeks in this condition. She then began to notice the child psychiatrist, and a few days later she was able to carry out simple requests. Elsa was transferred to an adolescent psychiatric unit. As soon as she could eat by herself again, carbamazepine 400mg per day was begun. Her agitation reduced at a carbamazepine level of 7 mg/l. One month later her condition was stable. However, language difficulties persisted for a further six months. One year after the episode she scored 66 on a repeat IQ test and her RMI was normal. She exhibited no significant residual symptoms except some cognitive impairment. She integrated into a special education facility. These attempts to stop the carbamazepine were followed by depressed mood, aggressiveness and impulsivity; carbamazepine was finally stopped successfully after seven years. Ten years later, Elsa is the mother of two young children and is able to take care of them. She has never had a relapse of her psychotic disorder or catatonic state. DISCUSSION: The etiopathogenic diagnosis is problematic. Some indices in the familial history may suggest a traumatic event. But one to the total residual amnesia it was never confirmed, and traumatic catatonia are extremely rare. Normal CPK levels, with autonomic disturbance limited to tachycardia and the lack of resolution after discontinuance of medication, argues against a diagnosis of neuroleptic malignant syndrome (NMS). But CPK levels are non specific, and NMS without pyrexia has been described. The occurrence of the catatonic syndrome 21 days after the first dose of a neuroleptic could be diagnostic. This case involved a non organic catatonic psychosis followed by neuroleptic induced catatonia. Catatonia is described as a risk factor for the development of NMS and some consider NMS to be a variant of malignant catatonia. The interest of this report is (1) it reinforces the need to be cautious before prescribing neuroleptics in adolescents presenting with symptoms of catatonia; (2) the complete recovery from catatonia after treatment with intensive care and more than three weeks of intravenous clonazepam without the use of ECT and (3) the effectiveness of carbamazepine over a long period of follow-up. Although trials on carbamazepine in catatonia are published, there are no data available for the control of residual symptoms or the long term prognosis, especially in child and adolescent psychiatry.
Assuntos
Antipsicóticos/efeitos adversos , Cataplexia/induzido quimicamente , Catatonia/induzido quimicamente , Haloperidol/efeitos adversos , Loxapina/efeitos adversos , Transtornos Psicóticos/tratamento farmacológico , Doença Aguda , Adolescente , Adulto , Anticonvulsivantes/uso terapêutico , Antipsicóticos/uso terapêutico , Carbamazepina/uso terapêutico , Cataplexia/diagnóstico , Cataplexia/tratamento farmacológico , Cataplexia/psicologia , Catatonia/diagnóstico , Catatonia/tratamento farmacológico , Catatonia/psicologia , Clonazepam/uso terapêutico , Terapia Combinada , Cuidados Críticos , Quimioterapia Combinada , Feminino , Seguimentos , Haloperidol/uso terapêutico , Humanos , Infusões Intravenosas , Loxapina/uso terapêutico , Síndrome Maligna Neuroléptica/diagnóstico , Síndrome Maligna Neuroléptica/tratamento farmacológico , Síndrome Maligna Neuroléptica/psicologia , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/psicologia , Ajustamento Social , Adulto JovemRESUMO
OBJECTIVES: To evaluate the human abuse potential of pitolisant, a selective histamine 3 (H3)-receptor antagonist/inverse agonist recently approved by the US Food and Drug Administration for the treatment of excessive daytime sleepiness in adult patients with narcolepsy. METHODS: Nondependent, recreational stimulant users able to distinguish phentermine HCl 60 mg from placebo in a drug discrimination test were randomized in a four-period, double-blind, crossover design to receive single doses of pitolisant 35.6 mg (therapeutic dose), pitolisant 213.6 mg (supratherapeutic dose), phentermine HCl 60 mg, and placebo. The primary endpoint was maximum effect (Emax) on the 100-point Drug Liking ("at this moment") visual analog scale. RESULTS: In 38 study completers (73.7% male; 65.8% white; mean age, 33.3 years), mean Drug Liking Emax was significantly greater for phentermine versus pitolisant 35.6 mg (mean difference, 21.4; p < 0.0001) and pitolisant 213.6 mg (mean difference, 19.7; p < 0.0001). Drug Liking Emax was similar for pitolisant (both doses) and placebo. Similarly, for key secondary measures of Overall Drug Liking and willingness to Take Drug Again, mean Emax scores were significantly greater for phentermine versus pitolisant (both doses) and similar for pitolisant (both doses) versus placebo. The incidence of adverse events was 82.1% after phentermine HCl 60 mg, 72.5% after pitolisant 213.6 mg, 47.5% after pitolisant 35.6 mg, and 48.8% after placebo administration. CONCLUSIONS: In this study, pitolisant demonstrated significantly lower potential for abuse compared with phentermine and an overall profile similar to placebo; this suggests a low risk of abuse for pitolisant. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03152123. Determination of the abuse potential of pitolisant in healthy, nondependent recreational stimulant users. https://clinicaltrials.gov/ct2/show/NCT03152123.
Assuntos
Cataplexia , Narcolepsia , Adulto , Cataplexia/induzido quimicamente , Cataplexia/tratamento farmacológico , Estudos Cross-Over , Método Duplo-Cego , Feminino , Agonistas dos Receptores Histamínicos/efeitos adversos , Humanos , Masculino , Narcolepsia/tratamento farmacológico , Piperidinas/efeitos adversosRESUMO
Happiness is key for both mental and physical well-being. To further understand the brain mechanisms involved, we utilized the cataplexy that occurs in narcoleptic animal models as a quantitative behavioral measure because it is triggered by actions associated with happiness, such as laughter in humans and palatable foods in mice. Here we report that the rostral part of the nucleus accumbens (NAc) shell is strongly activated during the beginning of chocolate-induced cataplexy in orexin neuron-ablated mice. We made a local lesion in the NAc using ibotenic acid and observed the animals' behavior. The number of cataplexy bouts was negatively correlated to the lesion size. We also examined the hedonic response to palatable food by measuring the number of tongue protrusions in response to presentation of honey, which was also found to be negatively correlated to the lesion size. Next, we used clozapine N-oxide to either activate or inactivate the NAc through viral DREADD expression. As expected, the number of cataplexy bouts increased with activation and decreased with inactivation, and saline control injections showed no changes. Hedonic response in the DREADD experiment varied and showed both increases and decreases across mice. These results demonstrated that the rostral part of the NAc plays a crucial role in triggering cataplexy and hedonic orofacial movements. Since the NAc is also implicated in motivated behavior, we propose that the NAc is one of the key brain structures involved in happiness and is a driving force for positive emotion-related behaviors.
Assuntos
Comportamento Animal , Cataplexia/patologia , Chocolate/toxicidade , Narcolepsia/patologia , Neurônios/patologia , Núcleo Accumbens/patologia , Orexinas/fisiologia , Animais , Cataplexia/induzido quimicamente , Masculino , Camundongos , Camundongos Knockout , Neurônios/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacosRESUMO
BACKGROUND: A double-blind, placebo-controlled sodium oxybate trial provided a unique opportunity to compare changes in cataplexy following gradual withdrawal from antidepressants in narcolepsy patients. METHODS: Of 228 enrolled patients, 71 discontinued antidepressant therapy. Data from 57 patients were available for analysis: 37 patients discontinued tricyclic antidepressants (TCAs) and 20 discontinued selective serotonin reuptake inhibitors (SSRIs). The trial included a 21-day withdrawal phase followed by 18-day washout and 14-day single-blind treatment phases. Two additional weeks were permitted for withdrawal from fluoxetine due to its long half-life. Weekly cataplexy attacks were recorded throughout the trial. No historical data on the frequency of cataplexy prior to treatment with antidepressants was available. RESULTS: Among the patients who were and were not withdrawn from antidepressants treatment, the median frequency of baseline weekly cataplexy was similar (17.5 vs. 14.0, respectively). As expected, significant between-group differences emerged by the end of the washout period (52.04 vs. 15.25, respectively; p<0.05); however, the frequency of cataplexy events became similar again by the end of the trial (16.5 vs. 17.5, respectively). CONCLUSIONS: Patients gradually withdrawn from antidepressants experienced a significant increase in cataplexy, but eventually returned to their baseline frequency, comparable to previously untreated control patients. Compared to SSRIs, discontinuation from TCAs was associated with a greater increase in cataplexy attacks.
Assuntos
Antidepressivos Tricíclicos/efeitos adversos , Cataplexia/induzido quimicamente , Cataplexia/epidemiologia , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Síndrome de Abstinência a Substâncias/epidemiologia , Adulto , Antidepressivos Tricíclicos/administração & dosagem , Cataplexia/diagnóstico , Estudos de Coortes , Relação Dose-Resposta a Droga , Humanos , Narcolepsia/tratamento farmacológico , Estudos Retrospectivos , Fatores de Risco , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Oxibato de Sódio/uso terapêutico , Síndrome de Abstinência a Substâncias/diagnósticoAssuntos
Cataplexia/induzido quimicamente , Vacinas contra Influenza/efeitos adversos , Narcolepsia/induzido quimicamente , Adolescente , Sistemas de Notificação de Reações Adversas a Medicamentos , Distribuição por Idade , Cataplexia/epidemiologia , Criança , Feminino , Humanos , Incidência , Lactente , Influenza Humana/prevenção & controle , Masculino , Narcolepsia/epidemiologia , Suécia/epidemiologia , Vacinação/estatística & dados numéricos , Adulto JovemRESUMO
INTRODUCTION: Narcolepsy type 1 is an organic sleep disorder caused by the destruction of hypocretin producing neurons in hypothalamus. In addition to daytime sleepiness, the spectrum and severity of symptoms are very variable. Psychiatric comorbidity and phenomena resembling psychotic symptoms are also common. Current treatment options for narcolepsy are symptomatic but there are few case reports of positive effect of immunotherapy. We report a very severely affected young boy treated with rituximab (RXB). CASE REPORT: A 12-year-old boy developed narcolepsy after Pandemrix H1N1 vaccination in 2010. He started to express severe psychiatric symptoms shortly after the onset. Cataplexy and sleepiness were devastatingly disabling. Conventional treatments did not have any effect on symptoms so we decided to try RXB, chimeric human monoclonal antibody against CD20 expressed in B lymphocytes. After the first treatment his condition ameliorated dramatically. Unfortunately, the effect lasted only for 2 months. Following attempts did not show any effect. CONCLUSIONS: Effect of RXB on narcolepsy has not been reported before. Remarkable but short-lasting effect of RXB in narcolepsy is intriguing as it could imply that there is still ongoing B cell-mediated autoimmune response possible contributing to symptoms in narcolepsy.
Assuntos
Cataplexia/tratamento farmacológico , Delusões/tratamento farmacológico , Alucinações/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Narcolepsia/tratamento farmacológico , Rituximab/uso terapêutico , Agressão/psicologia , Cataplexia/induzido quimicamente , Criança , Delusões/induzido quimicamente , Delusões/psicologia , Alucinações/induzido quimicamente , Alucinações/psicologia , Humanos , Vírus da Influenza A Subtipo H1N1 , Vacinas contra Influenza/efeitos adversos , Influenza Humana/prevenção & controle , Masculino , Narcolepsia/induzido quimicamenteRESUMO
Since H3 receptor (H3R) antagonists/inverse agonists can improve cognitive function in animal models, they may have the potential to be used as add-on therapy in the treatment of schizophrenia, a disease with significant cognitive deficits. However, a recent study showed potentiation of haloperidol-induced catalepsy by ciproxifan, an imidazole-containing H3R antagonist/inverse agonist, suggesting there is a potential risk of exacerbating extrapyramidal symptoms (EPS) if H3R antagonists were used as adjunctive treatment [Pillot, C., Ortiz, J., Heron, A., Ridray, S., Schwartz, J.C. and Arrang, J.M., Ciproxifan, a histamine H3-receptor antagonist/inverse agonist, potentiates neurochemical and behavioral effects of haloperidol in the rat, J Neurosci, 22 (2002) 7272-80]. In order to clarify the basis of this finding, we replicated this result and extended the work with another imidazole and two non-imidazole H3R antagonists. The results indicate that ciproxifan significantly augmented the effects of haloperidol and risperidone on catalepsy. Another imidazole H3R antagonist, thioperamide, also potentiated the effect of risperidone on catalepsy. In contrast, no catalepsy-enhancing effects were observed when selective non-imidazole H3R antagonists, ABT-239 and A-431404, were coadministered with haloperidol and/or risperidone. As ciproxifan and thioperamide are inhibitors of cytochrome P450 enzymes, responsible for metabolizing risperidone and haloperidol, the possibility that the augmentation of antipsychotics by imidazoles resulted from drug-drug interactions was tested. A drug metabolism study revealed that an imidazole, but not a non-imidazole, potently inhibited the metabolism of haloperidol and risperidone. Furthermore, ketoconazole, an imidazole-based CYP 3A4 inhibitor, significantly augmented risperidone-induced catalepsy. Together, these data suggest the potentiation of antipsychotic-induced catalepsy may result from pharmacokinetic drug-drug interactions and support the potential utility of non-imidazole H3R antagonists in treatment of cognitive impairment in schizophrenia without increased risk of increased EPS in patients.
Assuntos
Antipsicóticos/farmacocinética , Química Encefálica/efeitos dos fármacos , Cataplexia/induzido quimicamente , Antagonistas dos Receptores Histamínicos/farmacocinética , Histamina/metabolismo , Receptores Histamínicos H3/efeitos dos fármacos , Animais , Antipsicóticos/efeitos adversos , Benzofuranos/química , Benzofuranos/farmacocinética , Química Encefálica/fisiologia , Cataplexia/fisiopatologia , Cataplexia/prevenção & controle , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/metabolismo , Combinação de Medicamentos , Sinergismo Farmacológico , Haloperidol/farmacocinética , Antagonistas dos Receptores Histamínicos/química , Imidazóis/química , Imidazóis/farmacocinética , Cetoconazol/farmacocinética , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacos , Taxa de Depuração Metabólica/fisiologia , Piperidinas/química , Piperidinas/farmacocinética , Pirrolidinas/química , Pirrolidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptores Histamínicos H3/metabolismo , Risperidona/farmacocinética , Esquizofrenia/tratamento farmacológicoRESUMO
The nucleus pontis oralis (NPO) exerts an executive control over REM sleep. Cholinergic input to the NPO is critical for REM sleep generation. In the cat, a single microinjection of carbachol (a cholinergic agonist) into the NPO produces either REM sleep (REMc) or wakefulness with muscle atonia (cataplexy, CA). In order to study the central control of the heart rate variability (HRV) during sleep, we conducted polysomnographic and electrocardiogram recordings from chronically prepared cats during REMc, CA as well as during sleep and wakefulness. Subsequently, we performed statistical and spectral analyses of the HRV. The heart rate was greater during CA compared to REMc, NREM or REM sleep. Spectral analysis revealed that the low frequency band (LF) power was significantly higher during REM sleep in comparison to REMc and CA. Furthermore, we found that during CA there was a decrease in coupling between the RR intervals plot (tachogram) and respiratory activity. In contrast, compared to natural behavioral states, during REMc and CA there were no significant differences in the HRV based upon the standard deviation of normal RR intervals (SDNN) and the mean squared difference of successive intervals (rMSSD). In conclusion, there were differences in the HRV during naturally-occurring REM sleep compared to REMc. In addition, in spite of the same muscle atonia, the HRV was different during REMc and CA. Therefore, the neuronal network that controls the HRV during REM sleep can be dissociated from the one that generates the muscle atonia during this state.
Assuntos
Cataplexia/fisiopatologia , Frequência Cardíaca/fisiologia , Tegmento Pontino/fisiopatologia , Sono REM/fisiologia , Animais , Carbacol/farmacologia , Fármacos Cardiovasculares/farmacologia , Cataplexia/induzido quimicamente , Gatos , Agonistas Colinérgicos/farmacologia , Eletrocardiografia , Frequência Cardíaca/efeitos dos fármacos , Polissonografia , Tegmento Pontino/efeitos dos fármacos , Respiração/efeitos dos fármacos , Sono REM/efeitos dos fármacos , Vigília/efeitos dos fármacos , Vigília/fisiologiaRESUMO
A middle-aged woman with narcolepsy developed a pronounced exacerbation of cataplexy within 3 days of beginning treatment for hypertension with prazosin, an alpha 1-adrenoceptor antagonist. At times, episodes of cataplexy were virtually continuous (status cataplecticus), and there was only partial amelioration with tricyclic antidepressants. Cataplexy improved when prazosin was discontinued. These findings are similar to the reported effects of prazosin on cataplexy in narcoleptic dogs; they support a role for altered alpha 1-adrenoceptor function in narcolepsy.
Assuntos
Cataplexia/induzido quimicamente , Hipertensão/tratamento farmacológico , Prazosina/efeitos adversos , Feminino , Alucinações/induzido quimicamente , Humanos , Pessoa de Meia-Idade , Prazosina/uso terapêutico , Fases do Sono/efeitos dos fármacosRESUMO
Thalidomide is a sedative hypnotic that was widely used in the 1950s but was withdrawn due to its teratogenic properties. The compound has recently been reintroduced as an immune modulating agent. Thalidomide significantly aggravates canine cataplexy, a pathological manifestation of rapid eye movement (RFM) sleep atonia seen in narcolepsy. This compound also increases REM sleep and slow wave sleep in these animals. In vitro receptor binding and enzyme assays demonstrate that thalidomide does not bind to or enzymatically modulate the neurotransmitter systems reported to be involved in the regulation of cataplexy. Thalidomide may therefore affect cataplexy through its immune modulation properties. Further studies on the mechanisms of action of thalidomide should increase our understanding of the pathophysiology of this disabling disorder.
Assuntos
Cataplexia/induzido quimicamente , Córtex Cerebral/efeitos dos fármacos , Narcolepsia/induzido quimicamente , Sono/efeitos dos fármacos , Talidomida/farmacologia , Animais , Ligação Competitiva , Cataplexia/metabolismo , Córtex Cerebral/metabolismo , Cães , Relação Dose-Resposta a Droga , Narcolepsia/metabolismoRESUMO
We have recently demonstrated that local perfusion of dopaminergic D2/D3 agonists into the ventral tegmental area (VTA) significantly aggravates cataplexy and increases sleep in narcoleptic Dobermans. We further assessed the roles of the mesostriatal dopaminergic system and found that local perfusion of quinpirole and 7-OH-DPAT into the substantia nigra (SN) significantly aggravated cataplexy, while perfusion of a D2/D3 antagonist significantly reduced cataplexy. Neither a D1 agonist nor a D1 antagonist modified cataplexy. SN perfusion of quinpirole did not significantly modify sleep, while VTA perfusion significantly increased the drowsy state. Although autoregulation of the VTA and SN dopaminergic neurons are involved in the regulation of cataplexy, both structures have distinct roles for the regulation of sleep.
Assuntos
Cataplexia/induzido quimicamente , Agonistas de Dopamina/farmacologia , Receptores de Dopamina D2/agonistas , Sono/efeitos dos fármacos , Substância Negra/fisiologia , Animais , Nível de Alerta/efeitos dos fármacos , Azepinas/farmacologia , Cataplexia/fisiopatologia , Cães , Agonistas de Dopamina/administração & dosagem , Eletroencefalografia/efeitos dos fármacos , Eletromiografia/efeitos dos fármacos , Eletroculografia/efeitos dos fármacos , Microinjeções , Narcolepsia/fisiopatologia , Receptores de Dopamina D3 , Substância Negra/anatomia & histologia , Tetra-Hidronaftalenos/farmacologiaRESUMO
We have recently demonstrated that local perfusion of dopaminergic D2/D3 agonists into the ventral tegmental area (VTA) significantly aggravates cataplexy and increases sleep in narcoleptic Dobermans. We further assessed the roles of the mesostriatal dopaminergic system and found that local perfusion of quinpirole and 7-OH-DPAT into the substantia nigra (SN) significantly aggravated cataplexy, while perfusion of a D2/D3 antagonist significantly reduced cataplexy. Neither a D1 agonist nor a D1 antagonist modified cataplexy. SN perfusion of quinpirole did not significantly modify sleep, while VTA perfusion significantly increased the drowsy state. Although autoregulation of the VTA and SN dopaminergic neurons are involved in the regulation of cataplexy, both structures have distinct roles for the regulation of sleep.
Assuntos
Cataplexia/induzido quimicamente , Agonistas de Dopamina/farmacologia , Receptores de Dopamina D2/agonistas , Sono/efeitos dos fármacos , Substância Negra/efeitos dos fármacos , Animais , Cães , Relação Dose-Resposta a Droga , Eletroencefalografia , Quimpirol/farmacologia , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3 , Fases do Sono/efeitos dos fármacos , Substância Negra/metabolismo , Tetra-Hidronaftalenos/farmacologia , Fatores de Tempo , Área Tegmentar Ventral/efeitos dos fármacosRESUMO
Narcolepsy is a chronic sleep disorder marked by excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations. Since the discovery of sleep onset REM periods (SOREMPs) in narcoleptic patients, narcolepsy has often been regarded as a disorder of REM sleep generation: REM sleep intrudes in active wake or at sleep onset, resulting in cataplexy, sleep paralysis, or hypnagogic hallucinations. However, this hypothesis has not been experimentally verified. In the current study, we characterized the sleep abnormalities of genetically narcoleptic-cataplectic Dobermans, a naturally occurring animal model of narcolepsy, in order to verify this concept. Multiple sleep latency tests during the daytime revealed that narcoleptic Dobermans exhibit a shorter sleep latency and a higher frequency of SOREMPs, compared to control Dobermans. The total amount of time spent in wake and sleep during the daytime is not altered in narcoleptic dogs, but their wake and sleep patterns are fragmented, and state transitions into and from wake and other sleep stages are altered. A clear 30 min REM sleep cyclicity exists in both narcoleptic and control dogs, suggesting that generation of the ultradian rhythm of REM sleep is not altered in narcoleptics. In contrast, cataplexy displays no cyclicity and can be elicited in narcoleptic animals anytime with emotional stimulation and displays no cyclicity. Stimulation of a cholinoceptive site in the basal forebrain induces a long-lasting attack of cataplexy in narcoleptic dogs; however, bursts of rapid eye movements during this state still occur with a 30 min cyclicity. Sites and mechanisms for triggering cataplexy may therefore be different from those for REM sleep. Cataplexy and a dysfunction in the maintenance of vigilance states, but not abnormal REM sleep generation, may therefore be central to narcolepsy.
Assuntos
Encéfalo/fisiopatologia , Cães/fisiologia , Narcolepsia/fisiopatologia , Sono REM/fisiologia , Animais , Núcleo Basal de Meynert/efeitos dos fármacos , Núcleo Basal de Meynert/fisiologia , Carbacol/farmacologia , Cataplexia/induzido quimicamente , Cataplexia/fisiopatologia , Agonistas Colinérgicos/farmacologia , Ritmo Circadiano/fisiologiaRESUMO
The aim of the study was to examine the influence of the blockade of group I metabotropic glutamate receptors (mGluRs) on the haloperidol-induced catalepsy and proenkephalin mRNA expression in the rat striatum. Bilateral, intrastriatal injection of AIDA ((RS)-1-aminoindan-1,5-dicarboxylic acid, 3-15 microg/0.5 microl), a selective antagonist of group I mGluRs, inhibited catalepsy induced by haloperidol (0.5 mg/kg i.p.). Repeated intrastriatal AIDA administrations (3 x 15 microg/0.5 microl, 3 h apart) counteracted the haloperidol-induced (3 x 1.5 mg/kg s.c., 3 h apart) increase in the proenkephalin mRNA expression in that structure. The present study indicates that the blockade of the striatal group I mGluRs may inhibit parkinsonian akinesia by normalizing the function of the striopallidal pathway.