RESUMO
The aim of the present work was to evaluate the distribution of the different clones of the parasite prevailing after treatment with benznidazole (BZ) and clomipramine (CLO), in mice infected with Trypanosoma cruzi, Casibla isolate which consists of a mixture of two discrete typing units (DTUs). Albino Swiss mice were infected and treated with high and low concentrations of BZ (100 or 6.25 mg/kg), CLO (5 or 1.25 mg/kg), or the combination of both low doses (BZ6.25 + CLO1.25), during the acute phase of experimental infection. Treatment efficacy was evaluated by comparing parasitaemia, survival and tissular parasite presence. For DTUs genotyping, blood, skeletal and cardiac muscle samples were analysed by multiplex quantitative polymerase chain reaction. The combined treatment had similar outcomes to BZ6.25; BZ100 was the most effective treatment, but it failed to reach parasite clearance and produced greater histological alterations. Non-treated mice and the ones treated with monotherapies showed both DTUs while BZ6.25 + CLO1.25 treated mice showed only TcVI parasites in all the tissues studied. These findings suggest that the treatment may modify the distribution of infecting DTUs in host tissues. Coinfection with T. cruzi clones belonging to different DTUs reveals a complex scenario for the treatment of Chagas disease and search for new therapies.
Assuntos
Doença de Chagas , Coinfecção , Trypanosoma cruzi , Animais , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Combinação de Medicamentos , Genótipo , Camundongos , Distribuição TecidualRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Calea zacatechichi is a plant with an extensive popular and ritual use in Mexico. In healthy volunteers, it induces well-being and tranquility senses, and facilitates superficial stages of sleep. However, anxiolytic, and antidepressant-like effects and changes on the sleep-waking stages have not been explored. AIM: To determine anxiolytic and antidepressant-like effects of an aqueous extract of C. zacatechichi (CZ) in rodents and to analyze their effects on hippocampal activity in the rat sleep-waking cycle. MATERIAL AND METHODS: CZ anxiolytic- and antidepressant-like effects were evaluated in several mice and rat behavioral paradigms. CZ effects on temporal distribution of sleep were described, and hippocampus EEG frequency patterns were analyzed during the sleep-waking cycle; absolute and relative powers were analyzed during Rapid Eye Movements (REM) and non-REM sleep stages. CZ chemical analysis was performed by UPLC-ESI-MS. RESULTS: CZ produced specific and robust anxiolytic- and antidepressant-like effects in mice and rats, similar to those of prototypical drugs, at doses ranging from 0.5 to 50 mg/kg. CZ at 100 mg/kg produced visible mild sedative effects in rats, associated with a significant increase in Slow Wave Sleep episodes during a 6 h recording, and enhanced fast frequencies of hippocampus (gamma-band:31-50 Hz) during REM sleep. CONCLUSION: Results could support the well-being and tranquility senses reported by healthy consumers, and to explain the oneiric content during dreams and some improvements in cognitive processes described by consumers. Anxiolytic- and antidepressant-like effects of this species, reported for first time in this study could improve some aspects of mental health.
Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Asteraceae/química , Extratos Vegetais/farmacologia , Animais , Ansiolíticos/administração & dosagem , Ansiolíticos/isolamento & purificação , Antidepressivos/administração & dosagem , Antidepressivos/isolamento & purificação , Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , México , Camundongos , Extratos Vegetais/administração & dosagem , Ratos , Ratos Wistar , Sono/efeitos dos fármacos , Sono REM/efeitos dos fármacosRESUMO
Background: Compulsive disorders are excessive and repetitive behaviors that jeopardize the quality of life of both animaland guardian. It generally affects dogs between 6 and 36 months of age and its etiology is associated to stress, anxiety andgenetic predisposition. Clinical manifestations are the usual behaviors of the dog, but overly and inappropriately done.Diagnosis is based on a history of repetitive behavior and on clinical and complementary exams to discard other diseases.The aim of this study is to report a case of compulsive disorder in a female Border Collie dog, including diagnostic andtherapeutic approaches.Case: A 5-month-old, female, Border Collie dog was presented to Uberabas Veterinary Hospital owing to a chasingshadows behavior that started as a playtime activity but intensified to the point of becoming a repetitive and excessive act,followed by self-trauma and excessive barking. Clinical examination showed lesions in nasal planum region. No alterationswere observed on neurological examination apart from the chasing of shadows that also happened in the consultation room.Therefore, since there were no other findings on clinical and neurological exams, and since the manifestation occurredas a response to environmental stimuli (presence of shadows), it was established a presumptive diagnosis of compulsivedisorder. Treatment with trazodone chlorhydrate was performed, and it was indicated ovariohysterectomy, a follow-upwith a professional behaviorist and trainer and environment modifications. After a fortnight, it was observed a discreetimprovement of the clinical signs, hence a second anxiolytic, clomipramine, was added to the treatment. Approximately3 months after the beggining of therapy, there was improvement of the animals clinical picture...(AU)
Assuntos
Animais , Feminino , Cães , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Comportamento Animal , Clomipramina/administração & dosagem , Trazodona/administração & dosagem , Quimioterapia Combinada/veterináriaRESUMO
Administering clomipramine during the early days of life induced several behavioral and neurochemical alterations in adult male rats, which resemble major depression disorder. The alterations included poor sexual performance, which is considered a reward-seeking behavior regulated by dopaminergic system. Given that estrogen receptors are expressed in different areas of the brain involved in regulating reproductive behavior, motivation and mood. The objective of this study was to analyze the effect of a non-selective dopamine agonist (apomorphine) on sexual incentive motivation in rats exposed to clomipramine (CMI) in the neonatal period. In addition, we evaluated the expression of mRNA ERα and ERß in nucleus accumbens (NAcc) and septum of CMI rats. We found that only a few rats subjected to neonatal CMI treatment performed mounts, intromissions and ejaculations. Also, those rats spent less time exploring the sexual incentive zone and had lower preference scores; this effect was reverted by administering 0.1â¯mg/kg of apomorphine. Finally, the CMI rats presented higher levels of mRNA ERα and ERß, only in septum area. These data indicate that neonatal treatment with CMI altered the expression of mRNA ERα and ERß in the septum, which participates in regulating the motivational component of sexual behavior.
Assuntos
Apomorfina/farmacologia , Clomipramina/farmacologia , Copulação/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Septo do Cérebro/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Apomorfina/administração & dosagem , Clomipramina/administração & dosagem , Agonistas de Dopamina/administração & dosagem , Feminino , Masculino , Motivação/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , RNA Mensageiro/genética , Ratos , Ratos Wistar , Recompensa , Septo do Cérebro/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Transdução de Sinais/efeitos dos fármacosRESUMO
Nonsteroidal anti-inflammatory drugs (NSAIDs) possess as primary action mechanism the inhibition of cyclooxygenases (COX-1, COX-2, and COX-3), thus producing a decreasing prostaglandin synthesis. This study was designed to evaluate whether the antinociception induced by NSAIDs could be modulated by clomipramine or risperidone using a chemical model of inflammatory acute visceral pain, the abdominal acetic acid induced a writhing test in mice. Dose-response curves, intraperitoneal, or intrathecal for the antinociceptive activity displayed by ketoprofen, piroxicam, nimesulide, parecoxib, and paracetamol were analyzed in order to obtain the ED50 of each drug. Pretreatment of mice with either clomipramine or risperidone, increased antinociceptive potency of ketoprofen, piroxicam, nimesulide, parecoxib, and paracetamol, expressed by a decrease in the values of antinociceptive ED50. The results that were obtained are in line with those where the inhibition of COXs provides a justification for most of the pharmacological actions. Nevertheless, several findings suggest other molecular mechanisms, among which may be mentioned, L-selecting shedding; inhibition of i-NOS; inhibition of NF-Kappa B; suppression metaloproteinasas; inhibition of ß2 integrin activation; activation of α2 -adrenoceptor; increase of IL-1ß; upregulation IL-6. In conclusion, the data generated in this study demonstrated that risperidone and clomipramine, separately, increase antinociceptive potency of NSAIDs in a chemical model of inflammatory acute visceral tonic pain.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Clomipramina/uso terapêutico , Risperidona/uso terapêutico , Dor Visceral/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Clomipramina/administração & dosagem , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Injeções Intraperitoneais , Injeções Espinhais , Masculino , Camundongos Endogâmicos , Medição da Dor , Risperidona/administração & dosagemRESUMO
Background: Compulsive disorders are excessive and repetitive behaviors that jeopardize the quality of life of both animaland guardian. It generally affects dogs between 6 and 36 months of age and its etiology is associated to stress, anxiety andgenetic predisposition. Clinical manifestations are the usual behaviors of the dog, but overly and inappropriately done.Diagnosis is based on a history of repetitive behavior and on clinical and complementary exams to discard other diseases.The aim of this study is to report a case of compulsive disorder in a female Border Collie dog, including diagnostic andtherapeutic approaches.Case: A 5-month-old, female, Border Collie dog was presented to Uberabas Veterinary Hospital owing to a chasingshadows behavior that started as a playtime activity but intensified to the point of becoming a repetitive and excessive act,followed by self-trauma and excessive barking. Clinical examination showed lesions in nasal planum region. No alterationswere observed on neurological examination apart from the chasing of shadows that also happened in the consultation room.Therefore, since there were no other findings on clinical and neurological exams, and since the manifestation occurredas a response to environmental stimuli (presence of shadows), it was established a presumptive diagnosis of compulsivedisorder. Treatment with trazodone chlorhydrate was performed, and it was indicated ovariohysterectomy, a follow-upwith a professional behaviorist and trainer and environment modifications. After a fortnight, it was observed a discreetimprovement of the clinical signs, hence a second anxiolytic, clomipramine, was added to the treatment. Approximately3 months after the beggining of therapy, there was improvement of the animals clinical picture...
Assuntos
Feminino , Animais , Cães , Clomipramina/administração & dosagem , Comportamento Animal , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Trazodona/administração & dosagem , Quimioterapia Combinada/veterináriaRESUMO
Combination therapies based on the available drugs have been proposed as promising therapeutic alternatives for many diseases. Clomipramine (CLO) has been found to modify the evolution of the experimental infection. The objective of this study was to evaluate the combined effect of benznidazole (BZ) and clomipramine (CLO) against different life-stages of Trypanosoma cruzi in vitro and their efficacy in a murine model. Life-stages of T. cruzi, BZ-partially-resistant (Y) strain, were incubated with BZ and CLO and isobolograms and combination index (CI) were obtained. Swiss mice were infected with trypomastigotes and different treatment schedules were performed, each of which consisted of 30 consecutive daily doses. Treatment efficacy was evaluated by comparing parasitemia, qPCR, survival and histological analysis. These results were analyzed using multivariate analysis to determine the combined effect of the drugs in vivo. CLO + BZ showed synergistic activity in vitro against the clinically relevant life-stages of T. cruzi. The most susceptible forms were the intracellular amastigotes (CI: 0.20), followed by trypomastigotes (CI: 0.60), with no toxicity upon mammalian cells. The combination of both drugs CLO (1.25â¯mg/kg) and BZ (6.25â¯mg/kg), in vivo, significantly diminished the parasitic load in blood and the mortality rate. CLO + BZ presented a similar inflammatory response in cardiac and skeletal muscle (amount of inflammatory cells) to BZ (6.25 mg/kg). Finally, the results from the principal component analysis reaffirmed that both drugs administered in combination presented higher activity compared with the individual administration in the acute experimental model.
Assuntos
Doença de Chagas/tratamento farmacológico , Clomipramina/farmacologia , Nitroimidazóis/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Clomipramina/uso terapêutico , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Concentração Inibidora 50 , Masculino , Camundongos , Análise Multivariada , Músculo Esquelético/parasitologia , Músculo Esquelético/patologia , Miocárdio/patologia , Nitroimidazóis/uso terapêutico , Parasitemia/tratamento farmacológico , Análise de Componente Principal , Reação em Cadeia da Polimerase em Tempo Real , Tripanossomicidas/uso terapêuticoRESUMO
Administration of clomipramine (CMI), a tricyclic antidepressant, in early stages of development in rats, is considered an animal model for the study of depression. This pharmacological manipulation has induced behavioral and physiological alterations, i.e., less pleasure-seeking behaviors, despair, hyperactivity, cognitive dysfunction, alterations in neurotransmitter systems and in HPA axis. These abnormalities in adult male rats are similar to the symptoms observed in major depressive disorders. One of the main pleasure-seeking behaviors affected in male rats treated with CMI is sexual behavior. However, to date, no effects of early postnatal CMI treatment have been reported on female reproductive cyclicity and sexual behavior. Therefore, we explored CMI administration in early life (8-21 PN) on the estrous cycle and sexual behavior of adult female rats. Compared to the rats in the early postnatal saline treatment (CTRL group), the CMI rats had fewer estrous cycles, fewer days in the estrous stage, and longer cycles during a 20-day period of vaginal cytology analysis. On the behavioral test, the CMI rats displayed fewer proceptive behaviors (hopping, darting) and had lower lordosis quotients. Also, they usually failed to display lordosis and only rarely manifested marginal or normal lordosis. In contrast, the CTRL rats tended to display normal lordosis. These results suggest that early postnatal CMI treatment caused long-term disruptions of the estrous cycle and female sexual behavior, perhaps by alteration in the hypothalamic-pituitary-gonadal (HPG) axes and in neuronal circuits involved in the regulation of the performance and motivational of sexual behavior as the noradrenergic and serotonergic systems.
Assuntos
Clomipramina/administração & dosagem , Ciclo Estral/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Comportamento Sexual Animal/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Clomipramina/toxicidade , Ciclo Estral/fisiologia , Feminino , Gravidez , Ratos , Ratos Wistar , Inibidores Seletivos de Recaptação de Serotonina/toxicidade , Comportamento Sexual Animal/fisiologiaRESUMO
Chronic administration of clomipramine (CMI) to neonatal rats produces behaviors that resemble a depressive state in adulthood. Dysfunctions in the activity of the central nervous system's serotonergic function are important in understanding the pathophysiology of depression. The serotonin system is implicated in major depression and suicide and is negatively regulated by somatodendritic 5-HT1A autoreceptors. Desensitization of 5-HT1A autoreceptors is implicated in the long latency of some antidepressant treatments. Alterations in 5-HT1A receptor levels are reported in depression and suicide. In this study, we analyzed the effect of neonatal administration of CMI on the activity of 5-HT1A receptors, both pre- and post-synaptically, by administering an agonist of 5-HT1A receptors, 8-OH-DPAT, and then subjecting the rats to the forced swimming test (FST) a common procedure used to detect signs of depression in rats. Also measured were levels of the mRNA expression of 5-HT1A receptors in the dorsal raphe (DR), the hypothalamus and the hippocampus. Wistar rats were injected twice daily with CMI at doses of 15mgkg(-1) or saline as vehicle (CON) via s.c. from postnatal day 8 for 14days. At 3-4months of age, one set of rats from each group (CON, CMI) was evaluated for the effect of a selective agonist to the 5-HT1A receptor subtype, 8-OH-DPAT, by testing in the FST. Also determined was the participation of the pre- or post-synaptic 5-HT1A receptor in the antidepressant-like action of 8-OH-DPAT. This involved administering an inhibitor of tryptophan hydroxylase, parachlorophenylalanine (PCPA), and pretreatment with 8-OH-DPAT before the FST test and to evaluate the rectal temperature and locomotor activity. The expression of the mRNA of the 5-HT1A receptors was examined in the dorsal raphe nucleus, the hypothalamus and the hippocampus using the semi-quantitative RT-PCR method. The results from this study corroborate that neonatal treatment with clomipramine induces a pronounced immobility in the FST when animals reach adulthood, manifested by a significant decrease in swimming behavior, though counts of climbing behavior were not modified. This effect was similar in magnitude when 8-OH-DPAT was administered to CON group. Furthermore, the administration of 8-OH-DPAT induces a significant and similar increase in rectal temperature and locomotor activity in both the CON as in the CMI group. Neonatal treatment with CMI resulted in a significant decrease in the expression of the mRNA of the 5-HT1A receptors in the DR (% more than vehicle) in adulthood. In the case of the postsynaptic receptors located in the hypothalamus and hippocampus, neonatal treatment with CMI induced a significant increase in the mRNA expression of the 5-HT1A receptors. These data suggest that neonatal treatment with CMI induces a downregulation of the mRNA of the 5-HT1A autoreceptors in the DR, and an increment in the expression of the postsynaptic 5-HT1A receptors. The results after the administration of PCPA and 8-OH-DPAT on FST, rectal temperature and locomotor activity for both groups suggest that the function of postsynaptic receptors remains unchanged. All together these data show that the depressive behavior observed in adulthood in this animal model may be associated with long-term alterations in the expression of the mRNA of the 5-HT1A receptors.
Assuntos
Envelhecimento/metabolismo , Clomipramina/farmacologia , Atividade Motora/efeitos dos fármacos , Receptor 5-HT1A de Serotonina/biossíntese , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Animais Recém-Nascidos , Temperatura Corporal/efeitos dos fármacos , Depressão/induzido quimicamente , Depressão/metabolismo , Regulação para Baixo/efeitos dos fármacos , Fenclonina/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Resposta de Imobilidade Tônica/efeitos dos fármacos , Masculino , Núcleos da Rafe/efeitos dos fármacos , Núcleos da Rafe/metabolismo , Ratos , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Triptofano HidroxilaseRESUMO
CONTEXT: Tricyclic antidepressive agents are widely used in suicide attempts and present a variety of deleterious effects. Rhabdomyolysis is a rare complication of such poisoning. CASE REPORT: A 55-year-old woman ingested 120 pills of 25 mg clomipramine in a suicide attempt two days before admission. After gastric lavage in another emergency department on the day of intake, 80 pills were removed. On admission to our department, she was disoriented, complaining of a dry mouth and tremors at the extremities. An electrocardiogram showed a sinus rhythm with narrow QRS complexes. Laboratory results showed high creatine phosphokinase (CK = 15,094 U/l on admission; normal range = 26 to 140 U/l), hypocalcemia, slightly increased serum transaminases and mild metabolic acidosis. The patient's medical history included depression with previous suicide attempts, obsessive-compulsive disorder, hypothyroidism and osteoporosis. She presented cardiac arrest with pulseless electric activity for seven minutes and afterwards, without sedation, showed continuous side-to-side eye movement. She developed refractory hypotension, with need for vasopressors. Ceftriaxone and clindamycin administration was started because of a hypothesis of bronchoaspiration. The patient remained unresponsive even without sedation, with continuous side-to-side eye movement and a decerebrate posture. She died two months later. Rhabdomyolysis is a very rare complication of poisoning due to tricyclic drugs. It had only previously been described after an overdose of cyclobenzaprine, which has a toxicity profile similar to tricyclic drugs. CONCLUSIONS: Although arrhythmia is the most important complication, rhabdomyolysis should be investigated in cases of clomipramine poisoning. .
CONTEXTO: Antidepressivos tricíclicos são amplamente utilizados em tentativas de suicídio e apresentam diversos efeitos deletérios, sendo a rabdomiólise uma complicação rara dessa intoxicação. RELATO DO CASO: Uma mulher de 55 anos ingeriu 120 comprimidos de clomipramina de 25 mg numa tentativa de suicídio dois dias antes da admissão. Após lavagem gástrica em outro serviço de urgência no dia da ingestão, 80 comprimidos foram retirados. Na admissão em nosso serviço, a paciente estava desorientada, queixando-se de boca seca e tremores de extremidades. O eletrocardiograma mostrou ritmo sinusal com complexos QRS estreitos. Exames laboratoriais evidenciaram aumento de creatinofosfoquinase (CK = 15.094 U/L na admissão; intervalo da normalidade = 26 a 140 U/L), hipocalcemia, discreto aumento das transaminases e leve acidose metabólica. Antecedentes pessoais incluíam depressão com tentativas de suicídio prévias, transtorno obsessivo compulsivo, hipotireoidismo e osteoporose. A paciente apresentou parada cardiorrespiratória com atividade elétrica sem pulso por sete minutos e, posteriormente, sem sedação, foi observado olhar em varredura. A paciente evoluiu com hipotensão refratária, necessitando de vasopressores. Ceftriaxone e clindamicina foram iniciados pela hipótese de broncoaspiração. A paciente permaneceu irresponsiva mesmo sem sedação, com olhar em varredura contínuo e postura descerebrada. A paciente evoluiu para óbito dois meses após. Rabdomiólise é uma complicação rara da intoxicação por tricíclicos, e só foi descrita em overdose de ciclobenzaprina, a qual tem um perfil de toxicidade semelhante aos tricíclicos. CONCLUSÕES: Apesar de as arritmias serem as complicações mais temidas, ...
Assuntos
Feminino , Humanos , Pessoa de Meia-Idade , Antidepressivos Tricíclicos/intoxicação , Clomipramina/intoxicação , Rabdomiólise/induzido quimicamente , Creatina Quinase/sangue , Evolução Fatal , Tentativa de SuicídioRESUMO
Many times in science, the discovery of a treatment that has certain effect happens accidentally while the scientists are investigating another phenomenon. This is the case of the discovery of a possible animal model of depression by the administration of clomipramine (CLI) during neonatal days. Adult animals exposed to CLI in neonatal days showed alterations in REM sleep (for example, the decrease of REM latency); lower weight, disruptions in locomotor activity (the increase in activity depend on the dark / light phase in which the test starts, when the animals were tested in the light phase they found increase in activity, but no changes were observed when the animals were tested in the dark phase); less intracraneal self-stimulation, lower saccharin and sucrose consumption, less suppression of the consummatory behavior, sexual alterations in males (for example, expressed as a lower number of mounts and ejaculations; no alterations were found in the activity of the Hypothalamic - Pituitary - Gonadal axis and the level of testosterone was normal), higher alcohol consumption, disruptions in the agonistic response (CLI - treated animals were significantly less aggressive than control groups) and in learning (in the passive avoidance task and 8 radial arm maze) compared to untreated animals (rats that received vehicle during neonatal days). Several of these abnormalities could be reversed with those treatments that are effective for treating depression in humans (antidepressive drugs, nicotine and REM sleep deprivation treatment). These results were obtained in male rats of different strains and in hamsters, and at different months, the majority of them at 3-4 months, and some of them after the sixth, this could be because some changes were caused with the decrement in the age of the animals, although further research is needed to elucidate this issue. Neuroendocrinal alterations analogous to those found in human depression were also discovered in CLI - treated rats, although the data is contradictory. These include Hypothalamic - Pituitary - Adrenal axis alterations; while it is true that some experimental results found that CLI - treated rats have a higher basal level of corticosterone than controls, others found that not only do they differ in basal level, also during the stress situation; circulating corticosterone increases less and returns more rapidly to basal levels than control groups. For this reason, we can conclude that if alterations in the HPA axis indeed exist in CLI - treated animals, it is still unclear in which way the deregulation is manifested. Other results support the hypothesis that alterations found in CLI - treated animals are due to alterations in serotoninergic transmission during a critical period of development, such as the neonatal stage; more specifically, a reduction in the hypothalamic concentration of serotonin, like a decrease in the neuronal firing in the dorsal raphe nucleus. An increase in cholinergic activity was also found, although the data in this field is not as vast as that found in relation to the neurotransmission of serotonin. All of these results suggest that rats treated with CLI during neonatal days present alterations in adulthood analogous to human depression, however other findings indicate that is not yet a valid model. Further research is needed, and we have to be cautious with the conclusions because there is some evidence suggesting that this is a promising model but other does not support its validity. If a model like the neonatal administration of CLI achieves the reproduction of some symptoms, neurophysiological and behavioral alterations of depression, the advantages are invaluable. In this sense, neonatal treatment with CLI is a very promising animal model for the study of depression.
El presente trabajo describe los principales resultados acerca de un nuevo y probable modelo animal de depresión. Este modelo se basa, paradójicamente, en la administración de un antidepresivo, clomipramina, a ratas neonatas. Cuando los animales alcanzan la adultez, muestran alteraciones comportamentales que pueden ser interpretadas como depresivas, como hiperactividad, descenso en la búsqueda de placer, anormalidades en el sueño, entre otras. Se analizan los posibles mecanismos neurofisiológicos y neuroendocrinos involucrados. A pesar de las limitaciones que ofrece un modelo animal, es importante cómo logra reproducir algunos síntomas hallados en la depresión y debido a esto las ventajas del mismo son invaluables. Además, pueden estudiarse los mecanismos cerebrales implicados en la patogénesis y tratamiento del trastorno que por razones éticas son impensables de llevar a cabo en humanos. Por ello, se considera de gran valor el estudio realizado con el modelo de clomipramina con la perspectiva de que se siga trabajando en la validación del mismo.
RESUMO
In the present paper, we investigated the 5HTTLPR and STin2 polymorphisms in the promoter region of the serotonin transporter gene (SLC6A4), the G861C polymorphism (rs6296) of the serotonin receptor 1D beta (HTR1B), the T102C (rs6113) and C516T (rs6305) polymorphisms of the serotonin receptor gene subtype 2A (HTR2A), the DAT UTR, DAT intron 8 and DAT intron 14 of the dopamine transporter gene (SLC6A3), the Val-158-Met (rs4680) polymorphism of the COMT and the silent mutation G1287A (rs5569) in the norepinephrine transporter gene (SLC6A2). We genotyped 41 obsessive-compulsive disorder (OCD) outpatients, classified as good-responders (n=27) and poor-responders (n=14) to treatment with clomipramine according to the Yale Brown Obsessive-Compulsive Scale (YBOCS). Patients who achieved a reduction in symptoms of 40 percent or more in YBOCS after 14 weeks of treatment were considered good-responders. Genotypes and alleles distribution of the investigated polymorphisms were compared between both groups. We did not find association between the studied polymorphisms and clomipramine response in our sample.
No presente estudo, investigaram-se os polimorfismos 5HTTLPR e STin2 da região promotora do gene transportador de serotonina (SLC6A4), o G861C (rs6296) do receptor de serotonina 1D beta (HTR1B), os polimorfismos T102C (rs6113) e C516T (rs6305) do gene do receptor da serotonina subtipo 2A (HTR2A), os polimorfismos UTR, intron 8 e intron 14 do gene transportador de dopamina (SLC6A3), o Val-158-Met (rs4680) da COMT e a mutação G1287A (rs5569) do gene do transportador de norepinefrina (SLC6A2). Foram genotipados 41 pacientes com transtorno obsessivo-compulsivo (TOC), classificados como bons-respondedores (n=27) e maus-respondedores (n=14) ao tratamento com clomipramina, por meio do uso da Escala de Sintomas Obsessivos-Compulsivos Yale Brown (YBOCS). Foram considerados bons-respondedores os pacientes que tiveram redução nos sintomas em 40 por cento ou mais na YBOCS, após 14 semanas de tratamento. A distribuição dos genótipos e alelos estudados foi comparada entre os dois grupos. Não foi encontrada associação entre estes polimorfismos investigados e a resposta à clomipramina na amostra estudada.
Assuntos
Adulto , Feminino , Humanos , Masculino , Adulto Jovem , Antidepressivos Tricíclicos/uso terapêutico , Clomipramina/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , Transtorno Obsessivo-Compulsivo/genética , Receptores de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Frequência do Gene , Genótipo , Mutação , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Polimorfismo GenéticoRESUMO
INTRODUÇÃO: O processamento emocional pelo cérebro humano tem sido atualmente investigado através do uso de ressônancia magnética funcional (RMf). A RMf possibilita o estudo in vivo e não invasivo de mudanças na atividade cerebral regional em voluntários humanos saudáveis. O processamento emocional pode ser modulado através do uso de antidepressivos que influenciam sistemas neurais relacionados ao processamento emocional, através da modulação da ação de neurotransmissores como a serotonina e a noradrenalina. A clomipramina, um antidepressivo tricíclico, tem sido relacionada com efeitos de resposta clínica mesmo em voluntários saudáveis. Estudos utilizando a RMf permitem a investigação do efeito de antidepressivos nos sistemas neurais envolvidos no processamento emocional em indivíduos saudáveis que apresentam resposta ao uso destes medicamentos comparados a sujeitos que não apresentam resposta ao tratamento. MÉTODOS: Nesta tese, dezoito voluntários saudáveis foram investigados em relação a mudanças de atividade neural em resposta à indução emocional através da apresentação de fotografias do International Affective Pictures System (IAPS). Foram estudadas particularmente as emoções de raiva, felicidade e medo. Os voluntários foram submetidos ao tratamento prolongado com doses baixas de clomipramina por quatro semanas. A amostra foi subdividida em respondedores (n=6) e não respondedores (n=12) ao tratamento com clomipramina. A atividade neural foi estimada com o uso da RMf, através da mensuração do efeito blood oxygenation level dependent (BOLD). As imagens foram processadas e analisadas usando o programa Statistical Parametric Mapping (SPM). Indivíduos não respondedores foram comparados sob o efeito e na ausência de efeito da clomipramina, através de comparações planejadas utilizando t-teste pareado. Indivíduos respondedores foram comparados com os não respondedores sob o efeito da clomipramina através de t-teste não pareado. RESULTADOS: Nos voluntários...
INTRODUCTION: The emotional processing by the human brain has now been investigated through the use of functional magnetic resonance imaging (fMRI). The fMRI technique allows the noninvasive study of in vivo changes in regional brain activity in healthy human volunteers. The emotional processing may be modulated through the use of antidepressants that influence neural systems linked to emotional processing, by modulating the action of neurotransmitters such as serotonin and norepinephrine. Clomipramine, a tricyclic antidepressant, has been reported to elicit clinical response even in healthy volunteers. Studies using fMRI allow the investigation of the effect of antidepressants on neural systems involved in emotional processing in healthy subjects showing response to the use of antidepressant drugs compared to subjects who do not respond to treatment. METHODS: In this thesis, eighteen healthy volunteers were investigated in relation to changes in neural activity in response to emotional induction through the presentation of photos of the International Affective Picture System (IAPS). We studied especially the emotions of anger, happiness and fear. The volunteers were subjected to prolonged treatment with low doses of clomipramine for four weeks. The sample was divided into responders (n = 6) and non-responders (n = 12) to treatment with clomipramine. The neural activity was estimated by using fMRI, by measuring the blood oxygenation level dependent effect (BOLD). Images were processed and analyzed using the Statistical Parametric Mapping (SPM) program. Non-responders were compared under two conditions: when using clomipramine, and after drug washout, using paired t-tests. Individuals who responded to clomipramine treatment were compared with non-responders under the effect of the drug by independent t-test. RESULTS: In volunteers not responding to clomipramine, a comparison between the non-medicated versus medicated states showed less neural activity...