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1.
Psychiatry Res ; 268: 508-513, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30165326

RESUMO

In a clinical setting, anxiety disorder is highly correlated with bipolar I disorder in humans. However, the comorbidity of anxiety behavior and bipolar disorder still remains unclear in an animal model. This study utilized an ouabain-induced animal mode to examine anxiety and mania in an open field test. In the present study, 5 µl of artificial cerebrospinal fluid (aCSF) or ouabain (10-5, 10-4, and 10-3 M) were administered into the left ventricle. The animals' motor functions and anxiety behaviors were measured for 15 min. The results showed that 10-3 M ouabain significantly increased the animal's total distance traveled, average speed, and maximum speed compared to the control group. The time spent inside (i.e., how much time rats spent in the center of the square) and the inside-outside times of the central square (i.e., how many times rats ran across the center square) of the higher-concentration groups (10-4 M and 10-3 M) were significantly decreased. Therefore, a high concentration of ouabain may induce hyperactivity. The 10-4 M and 10-3 M ouabain groups exhibited more anxiety behaviors. The study is the first model to examine comorbid anxiety behaviors and bipolar disorder in an animal model. The study provides some insights for comorbid anxiety and bipolar disorder in clinics.


Assuntos
Ansiedade/fisiopatologia , Transtorno Bipolar/fisiopatologia , Desempenho Psicomotor/efeitos dos fármacos , Acatisia Induzida por Medicamentos/fisiopatologia , Acatisia Induzida por Medicamentos/psicologia , Animais , Ansiedade/induzido quimicamente , Ansiedade/psicologia , Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/induzido quimicamente , Transtorno Bipolar/psicologia , Comorbidade , Modelos Animais de Doenças , Masculino , Ouabaína , Ratos , Ratos Wistar
2.
Artigo em Inglês | MEDLINE | ID: mdl-29971200

RESUMO

Background: Akathisia is an inner urge to move a body area with an objective motor component of restlessness. Tardive akathisia (TA) is usually bilateral with a predominant lower-body presentation. We report two patients with an asymmetrical predominantly upper-body involvement. Case Report: Two young men with history of psychiatric problems and neuroleptic use revealed atypical TA, characterized by asymmetrical and predominantly upper-body involvement. Their main manifestations were rubbing the face, mostly with one hand, accompanied by an inner sensation of restlessness. Discussion: Our patients are proof that TA can present with asymmetrical and upper-body involvement even with normal brain imaging.


Assuntos
Acatisia Induzida por Medicamentos/fisiopatologia , Agitação Psicomotora/fisiopatologia , Discinesia Tardia/induzido quimicamente , Discinesia Tardia/fisiopatologia , Extremidade Superior/fisiopatologia , Adulto , Antipsicóticos/efeitos adversos , Humanos , Masculino , Transtornos Mentais/tratamento farmacológico , Escalas de Graduação Psiquiátrica
3.
Artigo em Inglês | MEDLINE | ID: mdl-29417763

RESUMO

Activation of indirect pathway medium spiny neurons (MSNs) via promotion of cAMP production is the principal mechanism of action of current antipsychotics with dopamine D2 receptor antagonism. TAK-063 [1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one] is a novel phosphodiesterase 10A inhibitor that activates both direct and indirect pathway MSNs through increasing both cAMP and cGMP levels by inhibition of their degradation. The activation of indirect pathway MSNs through the distinct mechanism of action of these drugs raises the possibility of augmented pharmacological effects by combination therapy. In this study, we evaluated the potential of combination therapy with TAK-063 and current antipsychotics, such as haloperidol or olanzapine after oral administration. Combined treatment with TAK-063 and either haloperidol or olanzapine produced a significant increase in phosphorylation of glutamate receptor subunit 1 in the rat striatum. An electrophysiological study using rat corticostriatal slices showed that TAK-063 enhanced N-methyl-D -aspartic acid receptor-mediated synaptic responses in both direct and indirect pathway MSNs to a similar extent. Further evaluation using pathway-specific markers revealed that coadministration of TAK-063 with haloperidol or olanzapine additively activated the indirect pathway, but not the direct pathway. Combined treatment with TAK-063 and either haloperidol or olanzapine at subeffective doses produced significant effects on methamphetamine- or MK-801-induced hyperactivity in rats and MK-801-induced deficits in prepulse inhibition in mice. TAK-063 at 0.1 mg/kg did not affect plasma prolactin levels and cataleptic response from antipsychotics in rats. Thus, TAK-063 may produce augmented antipsychotic-like activities in combination with antipsychotics without effects on plasma prolactin levels and cataleptic responses in rodents.


Assuntos
Acatisia Induzida por Medicamentos/tratamento farmacológico , Antipsicóticos/farmacologia , Antagonistas de Dopamina/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Administração Oral , Acatisia Induzida por Medicamentos/sangue , Acatisia Induzida por Medicamentos/etiologia , Acatisia Induzida por Medicamentos/fisiopatologia , Animais , Antipsicóticos/uso terapêutico , Benzodiazepinas/farmacologia , Benzodiazepinas/uso terapêutico , Catalepsia/sangue , Catalepsia/induzido quimicamente , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/fisiopatologia , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/fisiologia , Modelos Animais de Doenças , Antagonistas de Dopamina/uso terapêutico , Sinergismo Farmacológico , Quimioterapia Combinada/métodos , Haloperidol/farmacologia , Haloperidol/uso terapêutico , Humanos , Masculino , Metanfetamina/toxicidade , Camundongos , Camundongos Endogâmicos ICR , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Olanzapina , Inibidores de Fosfodiesterase/uso terapêutico , Prolactina/sangue , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Piridazinas/farmacologia , Piridazinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Potenciais Sinápticos/efeitos dos fármacos , Resultado do Tratamento
4.
Artigo em Inglês | MEDLINE | ID: mdl-29358037

RESUMO

The tolerability of antidepressants is poorly characterized in children and adolescents with depressive and anxiety disorders. Among adverse events that affect the tolerability of antidepressants in youth is activation, a cluster of symptoms that represent a hyperarousal event characterized by impulsivity, restlessness, and/or insomnia. This cluster of symptoms was first identified as a side effect of selective serotonin and selective serotonin norepinephrine inhibitors (SSRIs and SSNRIs) in the early 1990s; however, activation remains poorly characterized in terms of prevalence, risk factors, and pathophysiology. This article describes the pathophysiology of antidepressant-related activation, predictors of activation and its clinical management in youth with depressive and anxiety disorders who are treated with antidepressant medications.


Assuntos
Acatisia Induzida por Medicamentos/fisiopatologia , Antidepressivos/efeitos adversos , Transtornos Disruptivos, de Controle do Impulso e da Conduta/induzido quimicamente , Transtornos Disruptivos, de Controle do Impulso e da Conduta/fisiopatologia , Inibidores de Captação de Serotonina/efeitos adversos , Inibidores da Recaptação de Serotonina e Norepinefrina/efeitos adversos , Adolescente , Antidepressivos/uso terapêutico , Transtornos de Ansiedade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/induzido quimicamente , Criança , Transtorno Depressivo/tratamento farmacológico , Humanos , Agitação Psicomotora , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Ideação Suicida
5.
Eur Arch Psychiatry Clin Neurosci ; 268(6): 603-609, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28577223

RESUMO

There has been a debate in the literature about the distinction between primary and secondary negative symptoms of schizophrenia. Our aim was to study the associations between negative symptoms and potential sources of secondary negative symptoms over time. A sample of 275 participants with at least mid-moderate negative symptoms was randomized into body psychotherapy or Pilates class in a previous study. No significant differences were found between groups over time and changes in the symptom domains were modest. The present investigation considers the longitudinal correlation between variables of interest at baseline, 3 and 9 months follow-up. Measures were the Clinical Assessment Interview for Negative Symptoms (CAINS), the Positive and Negative Symptom Scale (PANSS), the Calgary Depression Scale (CDSS) and the Simpson-Angus Extrapyramidal side-effects Scale (SAS). Mixed models were computed to test the longitudinal association between these variables. In a sensitivity analysis, the dosages of antipsychotic, illness duration and allocated intervention were taken into account. Overall, the course of extrapyramidal side-effects, depressive and positive symptoms was significantly related to the course of negative symptoms. Only extrapyramidal effects were longitudinally correlated to expressive negative symptoms. The sensitivity analyses showed unaltered results for positive symptoms and depression but a lack of association between extrapyramidal effects and the CAINS outcomes. In conclusion, the unambiguous interpretation between primary and secondary negative symptoms may lead to refined treatment approaches for schizophrenia and to increased effects of the interventions.


Assuntos
Acatisia Induzida por Medicamentos , Antipsicóticos/efeitos adversos , Depressão , Discinesia Induzida por Medicamentos , Técnicas de Exercício e de Movimento/métodos , Psicoterapia/métodos , Esquizofrenia/fisiopatologia , Esquizofrenia/terapia , Adulto , Idoso , Acatisia Induzida por Medicamentos/etiologia , Acatisia Induzida por Medicamentos/fisiopatologia , Acatisia Induzida por Medicamentos/terapia , Terapia Combinada , Depressão/fisiopatologia , Depressão/terapia , Discinesia Induzida por Medicamentos/etiologia , Discinesia Induzida por Medicamentos/fisiopatologia , Discinesia Induzida por Medicamentos/terapia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Esquizofrenia/tratamento farmacológico , Adulto Jovem
7.
Brain Nerve ; 69(12): 1417-1424, 2017 Dec.
Artigo em Japonês | MEDLINE | ID: mdl-29282345

RESUMO

Akathisia consists of subjective inner restlessness, such as awareness of the inability to remain seated, restless legs, fidgetiness, and the desire to move constantly, and of objective increased motor phenomena, such as body rocking, shifting from foot to foot, stamping in place, crossing and uncrossing legs, pacing around. Although the broad definition of akathisia includes the inner and motor restlessness observed in patients with idiopathic Parkinson's disease, post-encephalitic parkinsonism, and restless legs syndrome, here we exclusively focus on the narrow definition of antipsychotic-induced akathisia. The most reliable treatment for acute akathisia is the reduction or the withdrawal of antipsychotic medication. However, this is often not possible because it may worsen the patients' mental condition. Various pharmacological agents have been used for the treatment of this condition. These include anticholinergic agents (e.g., biperiden and trihexyphenidyl), benzodiazepines, beta-adrenoceptor blockers (e.g., propranolol), and serotonin 2A receptor antagonists (e.g., mianserin, cyproheptadine, and mirtazapine).


Assuntos
Acatisia Induzida por Medicamentos , Acatisia Induzida por Medicamentos/tratamento farmacológico , Acatisia Induzida por Medicamentos/epidemiologia , Acatisia Induzida por Medicamentos/fisiopatologia , Antipsicóticos/efeitos adversos , Progressão da Doença , Humanos , Guias de Prática Clínica como Assunto , Síndrome das Pernas Inquietas , Índice de Gravidade de Doença
8.
Neurol Sci ; 38(9): 1683-1689, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28681310

RESUMO

Akathisia is a sensori-motor phenomenon which is generally encountered as an adverse effect of antidopaminergic medications suggesting involvement of dopaminergic pathways. We recently showed nociceptive flexor reflex was altered in akathisia as compared to restless legs syndrome and therefore, these findings may indicate co-involvement of pathways other than dopaminergic ones. To examine functional status of different pathways, we investigated auditory startle reflex (ASR), startle response to somatosensory input (SSS), and trigemino-cervical reflex (TCR) in a group of patients with akathisia. Consecutive seven patients with drug-induced akathisia and age- and gender-matched healthy subjects were prospectively included in the study. The diagnosis was made by appropriate clinical criteria. Brainstem reflexes, ASR, SSS, and TCR were examined in all participants. The probability, onset latency, amplitude, and duration were measured and compared between groups. The probability and amplitudes of ASRs were significantly increased and durations of ASRs and TCRs were prolonged in the patient group. Latencies of all responses as well as patterns of startle responses were similar between groups. The results reveal hyperactivity of the ASR and TCR in drug-induced akathisia. Hyperactive ASRs and TCRs also confirm suprasegmental hypodopaminergic state in akathisia. Although we keep in mind the confounding effects due to concurrent antidopaminergic treatments and the small sample group, we speculate that hyperactive ASRs and TCRs might be related to deficient control by forebrain and limbic-mainly amygdala-network in patients with drug-induced akathisia.


Assuntos
Acatisia Induzida por Medicamentos/fisiopatologia , Tronco Encefálico/fisiopatologia , Reflexo , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vias Neurais/fisiopatologia , Estimulação Física , Estudos Prospectivos , Reflexo/fisiologia
9.
Toxicol Lett ; 277: 84-91, 2017 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-28579487

RESUMO

OBJECTIVE: To study the profile of European gamma-hydroxybutyrate (GHB) and gammabutyrolactone (GBL) intoxication and analyse the differences in the clinical manifestations produced by intoxication by GHB/GBL alone and in combination with other substances of abuse. METHOD: We prospectively collected data on all the patients attended in the Emergency Departments (ED) of the centres participating in the Euro-DEN network over 12 months (October 2013 to September 2014) with a primary presenting complaint of drug intoxication (excluding ethanol alone) and registered the epidemiological and clinical data and outcomes. RESULTS: We included 710 cases (83% males, mean age 31 years), representing 12.6% of the total cases attended for drug intoxication. Of these, 73.5% arrived at the ED by ambulance, predominantly during weekend, and 71.7% consumed GHB/GBL in combination with other substances of abuse, the most frequent additional agents being ethanol (50%), amphetamine derivatives (36%), cocaine (12%) and cannabis (8%). Among 15 clinical features pre-defined in the project database, the 3 most frequently identified were altered behaviour (39%), reduced consciousness (34%) and anxiety (14%). The severity ranged from mild cases requiring no treatment (308 cases, 43.4%) to severe cases requiring admission to intensive care (103 cases, 14.6%) and mechanical ventilation (49 cases, 6.9%). No deaths were reported. In comparison with only GHB/GBL consumption, patients consuming GHB/GBL with co-intoxicants presented more vomiting (15% vs. 3%, p<0.001) and cardiovascular symptoms (5.3% vs. 1.5%, p<0.05), a greater need for treatment (59.8% vs. 48.3%, p<0.01) and a longer ED stay (11.3% vs. 3.6% patients with ED stay >12h, p<0.01). CONCLUSIONS: The profile of the typical GHB/GBL-intoxicated European is a young male, requiring care for altered behaviour and reduced level of consciousness, mainly during the weekend. The clinical features are more severe when GHB is consumed in combination with other substances of abuse.


Assuntos
4-Butirolactona/envenenamento , Overdose de Drogas , Oxibato de Sódio/envenenamento , Transtornos Relacionados ao Uso de Substâncias , Adulto , Acatisia Induzida por Medicamentos/etiologia , Acatisia Induzida por Medicamentos/fisiopatologia , Acatisia Induzida por Medicamentos/psicologia , Estado de Consciência/efeitos dos fármacos , Interações de Medicamentos , Overdose de Drogas/diagnóstico , Overdose de Drogas/fisiopatologia , Overdose de Drogas/psicologia , Overdose de Drogas/terapia , Serviço Hospitalar de Emergência , Europa (Continente) , Feminino , Humanos , Intubação Intratraqueal , Masculino , Atividade Motora/efeitos dos fármacos , Estudos Prospectivos , Respiração Artificial , Índice de Gravidade de Doença , Oxibato de Sódio/análogos & derivados , Transtornos Relacionados ao Uso de Substâncias/diagnóstico , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/psicologia , Transtornos Relacionados ao Uso de Substâncias/terapia , Fatores de Tempo , Resultado do Tratamento
10.
J Med Toxicol ; 13(4): 343-346, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28547577

RESUMO

INTRODUCTION: Pramipexole is a dopamine D2 receptor agonist used to treat idiopathic Parkinson's disease and primary restless legs syndrome. There is limited information on pramipexole overdose. CASE REPORT: A 59-year-old male ingested 3 mg pramipexole, 2250 mg venlafaxine, 360 mg mirtazapine, with suicidal intent. He presented alert, had normal vital observations and normal pupillary reflexes. He was mildly agitated, reported visual hallucinations and was given 5 mg diazepam. He had a mildly elevated lactate of 1.7 mmol/L, but otherwise normal laboratory investigations. Overnight, he remained agitated with visual hallucinations and developed myoclonus while awake. He had increasing difficulty passing urine on a background of mild chronic urinary retention. On review, 14 h post-ingestion, he was hypervigilant, jittery and mildly agitated. He had pressured speech and difficulty focusing on questioning. He had a heart rate of 110 bpm, but had an otherwise normal examination, with no clonus or extrapyramidal effects. He was unable to mobilize due to dizziness and ataxia. Over the next few hours, he improved, the visual hallucinations and agitation resolved and he mobilized independently. Pramipexole was measured with liquid chromatography mass spectrometry. The initial plasma pramipexole concentration was 34.2 ng/mL (therapeutic range 0.2 to 7 ng/mL), 9 h post-overdose. Concentration time data fitted a one-compartment model with an estimated elimination half-life of 18 h. DISCUSSION: Pramipexole overdose with hallucination, agitation, and myoclonus is consistent with adverse effects reported with therapeutic toxicity, but mirtazapine and venlafaxine may have contributed. Pramipexole concentrations exceeded the therapeutic range for over 24 h. With the increasing use of pramipexole in restless legs syndrome, adult overdoses may become more common.


Assuntos
Acatisia Induzida por Medicamentos/etiologia , Benzotiazóis/envenenamento , Agonistas de Dopamina/envenenamento , Overdose de Drogas/genética , Alucinações/induzido quimicamente , Atividade Motora/efeitos dos fármacos , Mioclonia/induzido quimicamente , Tentativa de Suicídio , Percepção Visual/efeitos dos fármacos , Acatisia Induzida por Medicamentos/diagnóstico , Acatisia Induzida por Medicamentos/fisiopatologia , Benzotiazóis/sangue , Benzotiazóis/farmacocinética , Agonistas de Dopamina/sangue , Agonistas de Dopamina/farmacocinética , Overdose de Drogas/diagnóstico , Overdose de Drogas/fisiopatologia , Overdose de Drogas/psicologia , Alucinações/diagnóstico , Alucinações/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Mioclonia/diagnóstico , Mioclonia/fisiopatologia , Pramipexol
11.
Neurosci Lett ; 641: 40-44, 2017 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-28115240

RESUMO

BACKGROUND AND OBJECTIVE: Akathisia is characterized by restlessness and crawling sensations similar to restless legs syndrome (RLS). Long latency flexor reflex (LLFR) which has helped to advance RLS pathophysiology has never been investigated in akathisia. Due to the clinical commonalities of akathisia and RLS, we investigated the behavior of LLFR in patients with akathisia aiming to understand pathophysiology of akathisia. PATIENTS AND METHODS: Seven patients with neuroleptic-induced akathisia, 12 drug-naïve patients with primary RLS and 17 healthy subjects were prospectively enrolled in the study. LLFR was recorded from unilateral tibialis anterior (TA) and long head of biceps femoris (BF) muscles after stimulating the sole by trains of electrical stimuli. We measured amplitude, latency, duration, presence of response and compared between three groups. RESULTS: One-way ANOVA showed mean durations of early and late responses recorded over TA were the longest in akathisia group compared to both RLS group and healthy subjects (p=0.012). The spatial spread of LLFR in akathisia patients was comparable to those of healthy subjects whereas presence of response on BF was significantly less in akathisia than RLS group. CONCLUSIONS: Our findings indicate increased excitability of LLFR pathway in akathisia group. These findings are probably due to lack of inhibition originated in regions other than those known to downregulate in RLS.


Assuntos
Acatisia Induzida por Medicamentos/fisiopatologia , Extremidade Inferior/fisiopatologia , Reflexo , Síndrome das Pernas Inquietas/fisiopatologia , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Extremidade Inferior/inervação , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/fisiopatologia
12.
Toxicol Sci ; 156(1): 109-122, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28013217

RESUMO

The nitrile 3,3'-iminodipropionitrile (IDPN) causes a loss of hair cells in the vestibular epithelium of the inner ear in several species of both mammals and nonmammals. It is of interest as a model compound in ototoxicity and vestibular regeneration research, but its effects on the mouse, including the potential relevance of strain and sex differences for susceptibility, have not yet been thoroughly characterized. In this study, we compared the vestibular toxicity of IDPN in dose-response studies (0, 8, 12, 16, and 24 mmol/kg IDPN p.o.) in males and females of 2 different mouse strains (RjOrl:Swiss/CD-1 and 129S1/SvImJ). 3,3'-Iminodipropionitrile caused a dose-dependent loss of vestibular function in all sex and strain groups, as assessed by a specific battery of behavioral tests. However, large differences in systemic toxicity were recorded, with high systemic toxicity in 129S1 mice of both sexes compared to limited effects on the Swiss mice. Both male and female Swiss mice showed a marked increase of hindlimb stride width after exposure. The Swiss, but not the 129S1, mice treated with IDPN showed hyperactivity in the open field. The dose-response relationships in the behavioral effects were matched by the extent of hair cell loss assessed by scanning electron microscopy. Altogether, the data demonstrated prominent strain-dependent differences in the systemic toxicity of IDPN between 129S1 and Swiss mice, in contrast to no differences between the strains and small differences between the sexes in its vestibular toxicity. These results support the use of Swiss mice exposed to IDPN as a mouse lesion model for research in vestibular therapy and regeneration.


Assuntos
Acatisia Induzida por Medicamentos/patologia , Vestibulopatia Bilateral/induzido quimicamente , Resistência a Medicamentos , Células Ciliadas Vestibulares/efeitos dos fármacos , Nitrilos/toxicidade , Xenobióticos/toxicidade , Administração Oral , Acatisia Induzida por Medicamentos/fisiopatologia , Animais , Animais não Endogâmicos , Comportamento Animal/efeitos dos fármacos , Vestibulopatia Bilateral/patologia , Vestibulopatia Bilateral/fisiopatologia , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Feminino , Marcha/efeitos dos fármacos , Células Ciliadas Vestibulares/patologia , Células Ciliadas Vestibulares/ultraestrutura , Masculino , Camundongos , Camundongos da Linhagem 129 , Microscopia Eletrônica de Varredura , Nitrilos/administração & dosagem , Caracteres Sexuais , Especificidade da Espécie , Testes de Toxicidade Aguda , Perda de Peso/efeitos dos fármacos , Xenobióticos/administração & dosagem
14.
Bull Exp Biol Med ; 162(1): 56-59, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27878720

RESUMO

The effect of non-benzodiazepine anxiolytics on the ethanol-induced hyperlocomotion and behavioral sensitization was assessed in male DBA/2 mice. Selank that enhances activity of the endogenous opioid system (0.3 mg/kg, intraperitoneally), similar to the nonselective opiate receptor blocker naloxone (1.0 mg/kg, intraperitoneally), prevented the development of ethanol-induced (2.0 g/kg intraperitoneally) hyperlocomotion, in contrast to σ1-receptors agonist Afobazole (1.0 mg/kg, intraperitoneally) that did not inhibit ethanol-induced behavioral stimulation. Single dose of Selank significantly blocked manifestation of motor sensitization without affecting its formation. These findings suggest that Selank can modulate the motivational effects of ethanol.


Assuntos
Acatisia Induzida por Medicamentos/tratamento farmacológico , Ansiolíticos/farmacologia , Etanol/farmacologia , Oligopeptídeos/farmacologia , Agitação Psicomotora/tratamento farmacológico , Receptores Opioides/metabolismo , Acatisia Induzida por Medicamentos/fisiopatologia , Animais , Comportamento Animal , Benzimidazóis/farmacologia , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos DBA , Morfolinas/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Agitação Psicomotora/fisiopatologia , Receptores Opioides/agonistas
15.
Ann Pharmacother ; 49(10): 1136-52, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26185277

RESUMO

OBJECTIVE: Extrapyramidal reactions (EPRs) associated with serotonergic antidepressant treatments have been reported since 1958. These reactions can be distressing for patients and complicate treatment. Our objective was to complete a follow-up review of published EPR cases reported for serotonergic antidepressants. DATA SOURCES: Published cases between January 1998 and May 2015 were collected through a medical literature search. Citation reference lists were also searched manually. STUDY SELECTION AND DATA EXTRACTION: Identified cases were reviewed for patient age, gender, psychiatric diagnosis, dosage, time to reaction onset, concurrent medications, and EPR description. Cases were excluded when there was not a clear description, if descriptions were not consistent with accepted definitions, or if the written English was poor. We included cases of akathisia, dystonia, dyskinesia, parkinsonism, or mixed EPRs. Authors scored each case using the Naranjo adverse drug reaction probability scale. DATA SYNTHESIS: We identified 86 published reports involving 91 patients; selective serotonin reuptake inhibitors were implicated in 80.2% of cases. All EPR types were reported: 17 akathisia cases, 18 dyskinesia cases, 27 dystonia cases, 19 parkinsonism cases, and 10 mixed EPR cases. EPRs typically occurred within 30 days of either treatment initiation or dose increase. Age, gender, antidepressant dosing, or concurrent antipsychotic treatment did not appear to broadly contribute to EPR risk. Naranjo scores ranged from 2 to 8. CONCLUSIONS: Case reports associating serotonergic antidepressants with EPRs continue to be published. Practitioners are advised that monitoring for such is important. Rigorous research efforts are needed to better understand the clinical risk factors for these adverse drug reactions.


Assuntos
Antidepressivos/efeitos adversos , Tratos Extrapiramidais/efeitos dos fármacos , Inibidores de Captação de Serotonina/efeitos adversos , Inibidores da Captação Adrenérgica/efeitos adversos , Fatores Etários , Acatisia Induzida por Medicamentos/etiologia , Acatisia Induzida por Medicamentos/fisiopatologia , Antipsicóticos/efeitos adversos , Discinesia Induzida por Medicamentos/etiologia , Discinesia Induzida por Medicamentos/fisiopatologia , Tratos Extrapiramidais/fisiopatologia , Feminino , Humanos , Masculino , Doença de Parkinson Secundária/etiologia , Doença de Parkinson Secundária/fisiopatologia , Agitação Psicomotora/tratamento farmacológico , Fatores de Risco , Fatores Sexuais
16.
Int J Neuropsychopharmacol ; 18(11): pyv063, 2015 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-26037489

RESUMO

BACKGROUND: Ketamine produces schizophrenia-like behavioral phenotypes in healthy people. Prolonged ketamine effects and exacerbation of symptoms after the administration of ketamine have been observed in patients with schizophrenia. More recently, ketamine has been used as a potent antidepressant to treat patients with major depression. The genes and neurons that regulate behavioral responses to ketamine, however, remain poorly understood. Sp4 is a transcription factor for which gene expression is restricted to neuronal cells in the brain. Our previous studies demonstrated that Sp4 hypomorphic mice display several behavioral phenotypes relevant to psychiatric disorders, consistent with human SP4 gene associations with schizophrenia, bipolar disorder, and major depression. Among those behavioral phenotypes, hypersensitivity to ketamine-induced hyperlocomotion has been observed in Sp4 hypomorphic mice. METHODS: In the present study, we used the Cre-LoxP system to restore Sp4 gene expression, specifically in either forebrain excitatory or GABAergic inhibitory neurons in Sp4 hypomorphic mice. Mouse behavioral phenotypes related to psychiatric disorders were examined in these distinct rescue mice. RESULTS: Restoration of Sp4 in forebrain excitatory neurons did not rescue deficient sensorimotor gating nor ketamine-induced hyperlocomotion. Restoration of Sp4 in forebrain GABAergic neurons, however, rescued ketamine-induced hyperlocomotion, but did not rescue deficient sensorimotor gating. CONCLUSIONS: Our studies suggest that the Sp4 gene in forebrain GABAergic neurons regulates ketamine-induced hyperlocomotion.


Assuntos
Acatisia Induzida por Medicamentos/fisiopatologia , Antagonistas de Aminoácidos Excitatórios/toxicidade , Neurônios GABAérgicos/fisiologia , Ketamina/toxicidade , Prosencéfalo/fisiopatologia , Fator de Transcrição Sp4/metabolismo , Animais , Estudos de Coortes , Feminino , Neurônios GABAérgicos/efeitos dos fármacos , Masculino , Camundongos da Linhagem 129 , Camundongos Transgênicos , Prosencéfalo/efeitos dos fármacos , Filtro Sensorial/fisiologia , Fator de Transcrição Sp4/genética
17.
Int J Neuropsychopharmacol ; 18(8)2015 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-25733538

RESUMO

BACKGROUND: Major depression has multiple comorbidities, in particular drug use disorders, which often lead to more severe and difficult-to-treat illnesses. However, the mechanisms linking these comorbidities remain largely unknown. METHODS: We investigated how a depressive-like phenotype modulates cocaine-related behaviors using a genetic model of depression: the Helpless H/Rouen (H) mouse. We selected the H mouse line for its long immobility duration in the tail suspension test when compared to non-helpless (NH) and intermediate (I) mice. Since numerous studies revealed important sex differences in drug addiction and depression, we conducted behavioral experiments in both sexes. RESULTS: All mice, regardless of phenotype or sex, developed a similar behavioral sensitization after 5 daily cocaine injections (10 mg/kg). Male H and NH mice exhibited similar cocaine-induced conditioned place preference scores that were only slightly higher than in I mice, whereas female H mice strikingly accrued much higher preferences for the cocaine-associated context than those of I and NH mice. Moreover, female H mice acquired cocaine-associated context learning much faster than I and NH mice, a facilitating effect that was associated to a rapid increase in striatal and accumbal brain-derived neurotrophic factor levels (BDNF; up to 35% 24 h after cocaine conditioning). Finally, when re-exposed to the previously cocaine-associated context, female H mice displayed greater Fos activation in the cingulate cortex, nucleus accumbens, and basolateral amygdala. CONCLUSIONS: Our data indicate that neurobiological mechanisms such as alterations in associative learning, striato-accumbal BDNF expression, and limbic-cortico-striatal circuit reactivity could mediate enhanced cocaine vulnerability in female depressive-like mice.


Assuntos
Encéfalo/fisiopatologia , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Transtorno Depressivo/fisiopatologia , Caracteres Sexuais , Acatisia Induzida por Medicamentos/fisiopatologia , Animais , Encéfalo/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cocaína/farmacologia , Modelos Animais de Doenças , Inibidores da Captação de Dopamina/farmacologia , Feminino , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Camundongos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Comportamento Espacial/efeitos dos fármacos , Comportamento Espacial/fisiologia , Fatores de Tempo
18.
Behav Brain Res ; 284: 218-24, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25712697

RESUMO

Posttraumatic stress disorder (PTSD) is often comorbid with substance use disorders (SUD). Single prolonged stress (SPS) is a well-validated rat model of PTSD that provides a framework to investigate drug-induced behaviors as a preclinical model of the comorbidity. We hypothesized that cocaine sensitization and self-administration would be increased following exposure to SPS. Male Sprague-Dawley rats were exposed to SPS or control treatment. After SPS, cocaine (0, 10 or 20 mg/kg, i.p.) was administered for 5 consecutive days and locomotor activity was measured. Another cohort was assessed for cocaine self-administration (0.1 or 0.32 mg/kg/i.v.) after SPS. Rats were tested for acquisition, extinction and cue-induced reinstatement behaviors. Control animals showed a dose-dependent increase in cocaine-induced locomotor activity after acute cocaine whereas SPS rats did not. Using a sub-threshold sensitization paradigm, control rats did not exhibit enhanced locomotor activity at Day 5 and therefore did not develop behavioral sensitization, as expected. However, compared to control rats on Day 5 the locomotor response to 20mg/kg repeated cocaine was greatly enhanced in SPS-treated rats, which exhibited enhanced cocaine locomotor sensitization. The effect of SPS on locomotor activity was unique in that SPS did not modify cocaine self-administration behaviors under a simple schedule of reinforcement. These data show that SPS differentially affects cocaine-mediated behaviors causing no effect to cocaine self-administration, under a simple schedule of reinforcement, but significantly augmenting cocaine locomotor sensitization. These results suggest that SPS shares common neurocircuitry with stimulant-induced plasticity, but dissociable from that underlying psychostimulant-induced reinforcement.


Assuntos
Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Estresse Psicológico/fisiopatologia , Acatisia Induzida por Medicamentos/fisiopatologia , Animais , Cateteres de Demora , Estudos de Coortes , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Masculino , Ratos Sprague-Dawley , Autoadministração
19.
Neurobiol Dis ; 75: 159-76, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25595128

RESUMO

Repeated exposure to cocaine was previously found to cause sensitized behavioral responses and structural remodeling on medium spiny neurons of the nucleus accumbens (NAc) and caudate putamen (CPu). Rac1 has emerged as a key integrator of environmental cues that regulates dendritic cytoskeletons. In this study, we investigated the role of Rac1 in cocaine-induced dendritic and behavioral plasticity in the CPu. We found that Rac1 activation was reduced in the NAc but increased in the CPu following repeated cocaine treatment. Inhibition of Rac1 activity by a Rac1-specific inhibitor NSC23766, overexpression of a dominant negative mutant of Rac1 (T17N-Rac1) or local knockout of Rac1 attenuated the cocaine-induced increase in dendrites and spine density in the CPu, whereas overexpression of a constitutively active Rac1 exert the opposite effect. Moreover, NSC23766 reversed the increased number of asymmetric spine synapses in the CPu following chronic cocaine exposure. Downregulation of Rac1 activity likewise attenuates behavioral reward responses to cocaine exposure, with activation of Rac1 producing the opposite effect. Thus, Rac1 signaling is differentially regulated in the NAc and CPu after repeated cocaine treatment, and induction of Rac1 activation in the CPu is important for cocaine exposure-induced dendritic remodeling and behavioral plasticity.


Assuntos
Núcleo Caudado/efeitos dos fármacos , Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Neuropeptídeos/metabolismo , Putamen/efeitos dos fármacos , Proteínas rac1 de Ligação ao GTP/metabolismo , Acatisia Induzida por Medicamentos/fisiopatologia , Aminoquinolinas/farmacologia , Animais , Núcleo Caudado/patologia , Núcleo Caudado/fisiopatologia , Fármacos do Sistema Nervoso Central/farmacologia , /fisiologia , Dendritos/efeitos dos fármacos , Dendritos/patologia , Dendritos/fisiologia , Técnicas de Silenciamento de Genes , Masculino , Camundongos Transgênicos , Plasticidade Neuronal/fisiologia , Neuropeptídeos/antagonistas & inibidores , Neuropeptídeos/genética , Putamen/patologia , Putamen/fisiopatologia , Pirimidinas/farmacologia , Percepção Espacial/efeitos dos fármacos , Percepção Espacial/fisiologia , Sinapses/efeitos dos fármacos , Sinapses/patologia , Sinapses/fisiologia , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidores , Proteínas rac1 de Ligação ao GTP/genética
20.
Physiol Behav ; 139: 344-50, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25433314

RESUMO

In recent decades, the increased consumption of processed foods, which are rich in hydrogenated vegetable fat (HVF), has led to a decreased consumption of fish and oilseed, rich in omega-3 fatty acids. This eating habit provides an increased intake of trans fatty acids (TFA), which may be related to neuropsychiatric conditions, including inattention and hyperactivity. In this study, we evaluated the potential connection between prolonged trans fat consumption and development of hyperactivity-like symptoms in rats using different behavioral paradigms. Trans fat intake for 10 months (Experiment 1), as well as during pregnancy and lactation across two sequential generations of rats, (Experiment 4) induced active coping in the forced swimming task (FST). In addition, HVF supplementation was associated with increased locomotion before and after amphetamine (AMPH) administration (Experiment 2). Similarly, HVF supplementation during pregnancy and lactation were associated with increased locomotion in both young and adult rats (Experiment 3). Furthermore, trans fat intake across two sequential generations increased locomotor and exploratory activities following stressors (Experiment 4). From these results, we suggest that chronic consumption of trans fat is able to enhance impulsiveness and reactivity to novelty, facilitating hyperactive behaviors.


Assuntos
Gorduras na Dieta/toxicidade , Agitação Psicomotora/fisiopatologia , Ácidos Graxos Trans/toxicidade , Adaptação Psicológica/fisiologia , Acatisia Induzida por Medicamentos/fisiopatologia , Anfetamina/farmacologia , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Comportamento Exploratório/fisiologia , Feminino , Comportamento Impulsivo/fisiologia , Lactação , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Óleos Vegetais/toxicidade , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Agitação Psicomotora/etiologia , Distribuição Aleatória , Ratos Wistar , Estresse Psicológico/fisiopatologia
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