Maprotiline treatment differentially influences cardiac β-adrenoreceptors expression under normal and stress conditions

Alterations in cardiac function were observed in antidepressants treated patients and published in several clinical reports. These detected changes could be either a consequence of the treatment or of depression itself, which has already been proved to be a risk factor in heart diseases. In order to determine a possible influence of chronic treatment with norepinephrinergic reuptake inhibitor, maprotiline, on the heart, we investigated gene expression of cardiac β-adrenoceptors both in controls and in animals with signs of depression. The rats were divided into two groups, unstressed controls and those exposed to chronic unpredictable mild stress (CUMS). The groups were further divided into two subgroups, one receiving daily intraperitoneal injections of vehicle (sterile water) and another one maprotiline (10 mg/kg) for four weeks. Tissue samples were collected after the last application. Gene expression of cardiac β1- and β2-adrenoceptor was determined using Real-time RT-PCR analysis. Our results show that in control animals expression of both adrenoreceptors was decreased in the right atria after 4 weeks of maprotiline application. Contrary, the same treatment led to a significant increase in expression of cardiac β1-adrenoceptor in the stressed rats, with no change in the characteristics of β2-adrenoceptor. Our findings might reflect the that molecular mechanisms are underlying factors involved in the development of cardiovascular diseases linked with antidepressant treatment.Vários relatórios clínicos observaram alterações de funcionamento cardíaco de pacientes depressivos que foram tratados com os antidepressivos. As alterações detectadas podem ser consequência do tratamento ou, por outro lado, da depressão que, como se tem provado, é um fator de risco no caso de doenças cardíacas. De modo a determinar a possível influência de tratamento crônico com o inibidor da recaptação de norepinefrina, maprotilina, no coração, foi investigada a expressão do gene aos receptores β-adrenérgicos cardíacos dos animais em grupos de controle e em grupos com sinais de depressão. Os ratos foram divididos em grupos de controle não estressados e os grupos de ratos submetidos ao estresse crônico moderado imprevisível (CUMS). Os grupos foram, ainda, divididos em dois subgrupos, que, durante quatro semanas, diariamente receberam injeções intraperitoneais de placebo (água estéril) ou de maprotilina (10 mg/kg). As amostras de tecido foram coletadas após a última aplicação. A expressão do gene aos receptores adrenérgicos β1 e β2 foi determinada utilizando a análise PCR quantitativa em tempo real (RT-PCR). Os nossos resultados demonstram a diminuição de expressão dos ambos os receptores adrenérgicos no átrio direito dos animais do grupo de controle depois de quatro semanas de aplicação de maprotilina. Em contraste, o mesmo tratamento conduziu ao aumento significativo na expressão do receptor β1-adrenérgico no coração dos ratos estressados, sem qualquer alteração nas características do receptor β2-adrenérgico. Estes resultados podem refletir os mecanismos moleculares envolvidos no desenvolvimento de doenças cardiovasculares associadas ao tratamento com os antidepressivos

Do RCAN1 proteins link chronic stress with neurodegeneration?

It has long been suspected that chronic stress can exacerbate, or even cause, disease. We now propose that the RCAN1 gene, which can generate several RCAN1 protein isoforms, may be at least partially responsible for this phenomenon. We review data showing that RCAN1 proteins can be induced by multiple stresses, and present new data also implicating psychosocial/emotional stress in RCAN1 induction. We further show that transgenic mice overexpressing the RCAN1-1L protein exhibit accumulation of hyperphosphorylated tau protein (AT8 antibody), an early precursor to the formation of neurofibrillary tangles and neurodegeneration of the kind seen in Alzheimer disease. We propose that, although transient induction of the RCAN1 gene might protect cells against acute stress, persistent stress may cause chronic RCAN1 overexpression, resulting in serious side effects. Chronically elevated levels of RCAN1 proteins may promote or exacerbate various diseases, including tauopathies such as Alzheimer disease. We propose that the mechanism by which stress can lead to these diseases involves the inhibition of calcineurin and the induction of GSK-3 beta by RCAN1 proteins. Both inhibition of calcineurin and induction of GSK-3 beta contribute to accumulation of phosphorylated tau, formation of neurofibrillary tangles, and eventual neurodegeneration.-Ermak, G., Pritchard, M. A., Dronjak, S., Niu, B., Davies, K. J. A. Do RCAN1 proteins link chronic stress with neurodegeneration? FASEB J. 25, 3306-3311 (2011). www.fasebj.or

Chronic fluoxetine treatment affects gene expression of catecholamine enzymes in the heart of depression model rats

771-775  Depression is associated with increased risk of coronary heart diseases. Selective serotonin reuptake inhibitors (SSRIs) have been proved to be very effective in normalizing symptoms of depression, but the data on possible influence of these drugs on cardiovascular function is controversial. Applying Taqman RT-PCR assay, the effect of chronic treatment with a SSRI antidepressant fluoxetine has been investigated on gene expression of catecholamine biosynthetic enzymes in all four heart chambers of rats with signs of depression. Depression was induced by exposing the animals to chronic unpredictable mild stress (CUMS). Tyrosine-hydroxylase (TH) and dopamine-ß-hydroxylase (DBH) mRNA levels were decreased both in right and left atria, while phenylethanolamine N-methyltransferase (PNMT) mRNAs were increased in left atria and both ventricles of depression model rats. Fluoxetine elevated gene expression of TH and DBH in atria, but did not influence this process in the ventricles.<span style="mso-ansi-language: EN" lang="EN"> Also, this antidepressant did not express a significant effect on the level of PNMT mRNA both in atria and ventricles. These results indicate that fluoxetine acted stimulating noradrenaline synthesis in the heart, which could lead to increased risk of heart disease. </span

Molecular basis of chronic stress-induced hippocampal lateral asymmetry in rats and impact on learning and memory

Neurochemical lateralization has been demonstrated in the rat brain suggesting that such lateralization might contribute to behavior. Thus, the aim of the present study was to examine neurochemical asymmetry in the hippocampus, molecular basis of neurochemical lateralization and its impact on spatial learning and memory. Changes in noradrenaline content, tyrosine hydroxylase (TH) were studied in the right and left hippocampus of naive control and chronically isolated rats, by applying TaqMan RT-PCR and Western blot analysis. Hippocampal-based spatial learning and memory were evaluated using the Barnes maze. In control rats an asymmetrical right-left distribution of noradrenaline content and gene expression of catecholamine synthesizing enzyme was found. Chronic psychosocial stress further emphasized asymmetry. Isolation stress reduced noradrenaline content only in the right hippocampus. No changes were observed in gene expression and protein levels of TH in the right hippocampus, whereas expression of catecholamine synthesizing enzyme was elevated in the left hippocampus. Reduced noradrenaline content in the right hippocampus did not cause impairment in spatial learning and memory. Our findings suggest that chronic psychosocial stress reduces noradrenaline stores in the right hippocampus which may be caused by molecular asymmetry, but it does not affect spatial learning and memory

DIFFERENT BEHAVIORAL EFFECTS OF MAPROTILINE AND FLUXILAN IN RATS

Abstract — Serotonin and noradrenaline are involved in the mechanisms of action of most antidepressant drugs. We examined the effects of chronic treatment with maprotiline, a selective inhibitor of noradrenaline reuptake, and fluxilan, a selective inhibitor of serotonin reuptake, on the behavior of unstressed controls and chronic unpredictable mild stress (CUMS) model rats in the forced swim test (FST) and elevated plus maze test. Both selective reuptake inhibitors resulted in a significant reduction of time spent in immobility. Climbing was significantly increased in maprotiline- and swimming was exclusively elicited in the fluxilan-treated unstressed control and CUMS rats. Maprotiline-treated animals displayed decreased anxiety and fluxilan-treated rats enhanced anxiety. The obtained results suggest that central noradrenergic and serotonergic systems might be affected differently during FST. The results also demonstrate that the anxiogenic effects of chronic fluxilan treatment are similar to those reported by many other studies. These differences observed for the effects of fluxilan in relation to those reported for maprotiline and probably due to the different pharmacological profiles of these drugs

Regulation of atrial catecholamine enzymes and adrenoceptor gene expression after chronic stress

Chronic stress is a risk factor for the development of numerous psychopathological conditions in humans including depression. Changes in gene expression of tyrosine-hydroxylase (TH), dopamine-β-hydroxylase (DBH) phenylethanolamine N-methyltransferase (PNMT), β1-, β2- and β3-adrenoceptors in right and left rat atria upon chronic unpredictable mild stress (CMS) were investigated. CMS decreased TH and DBH gene expression levels both in right and left atria and increased PNMT mRNA in left atria. No changes in mRNA levels of β1- and β2-adrenoceptors were recorded, whereas β3-adrenoreceptor mRNA level was significantly elevated in right atria of CMS rats. At the same time, CMS produced a significant increase of β1- and β2-adrenoreceptor mRNA levels in left atria, but did not affect β3-adrenoceptor mRNA level.The results presented here suggest that stress-induced depression expressed differential effects on catecholamine biosynthetic enzymes and β-adrenoceptors at molecular level in right and left atria of adult rat males. Elevated gene expression of PNMT in left atria of rats exposed to CMS can lead to altered physiological esponse and may play a role in the pathophysiology of cardiovascular function

Immunohistochemical detection and gene expression of tyrosine hydroxylase and vesicular monoamine transporter type 2 in intrinsic cardiac ganglia of socially isolated rats

Social isolation induced a significant increase in resting heart rate and reduction in heart rate variability. Dysfunction of the intrinsic cardiac nervous system is implicated in the genesis of cardiovascular diseases. Previous evidence suggests that cardiac ganglia contain noradrenergic neurons. Thus, immunohistochemical expression of catecholamine-synthesizing enzyme tyrosine hydroxylase (TH) and vesicular monoamine transporter 2 (VMAT2) were analyzed, as well as the effects of social isolation stress on mRNA and protein levels of this enzyme and transporter in the intrinsic cardiac nervous system of adult rats. Our results indicate that cardiac ganglion neurons express TH and VMAT2 immunoreactivity. Chronic isolated stress of rats caused a decrease in TH mRNA and VMAT2 mRNA in the neurons of intrinsic cardiac ganglia. No significant alterations in the protein levels of TH and VMAT2 were observed in these neurons. These data indicate that the neurons of intrinsic cardiac ganglia express TH as well as VMAT2 but that social isolation stress does not change their protein levels

Differential in vivo regulation of TH and DBH mRNA in rat atria by maprotiline and fluoxetine

It is well known that antidepressants affect central monoaminergic neurotransmission and that they also modulate hormone release in peripheral tissues. Repeated maprotiline (a noradrenaline reuptake inhibitor) and fluoxetine (a serotonin reuptake inhibitor) treatment on gene expression of the catecholamine biosynthetic enzymes were examined in rat atria and ventricles in vivo. Maprotiline decreased the gene expression of tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH) in the rat atrium. Fluoxetine increased gene expression of TH and DBH, but not of phenylethanolamine N-methyltransferase (PNMT). Chronic application of antidepressants did not change the expression of these enzymes in the ventricles. We conclude that repeated administration of fluoxetine enhances gene transcription of TH and DBH and subsequently stimulates noradrenaline synthesis in rat atria in vivo

DOI:10.2298/ABS0702113S EFFECTS OF CHRONIC DIAZEPAM TREATMENTS ON BEHAVIOR ON INDIVIDUALLY HOUSED RATS

Abstract – The present study analyzed the effects of chronic treatment with low doses of diazepam on body weight, defecations and urinations, vertical rears, the elevated platform test, and self-grooming in male rats exposed for 21 days to social isolation. The rats were treated for 21 days with diazepam (0.2 mg/kg, i.p) or its vehicle. Social isolation led to decreased body weight and vertical rears, more defecations and urinations, increased reluctance to step down from the test platform, shorter duration of grooming, and longer reluctance to start grooming. Chronic diazepam in individually housed rats produced increase in body weight and vertical rears, decrease in the number of defecations and urinations, and shortening of the time of reluctance to step down from the platform. The number of grooming bouts, their duration, and reluctance to start grooming were not altered by diazepam, but it decreased the percentage of incorrect transitions. The obtained data indicate that chronic diazepam treatment of socially isolated rats changes non-grooming behavior and some grooming behavior parameters. Key words: Diazepam, social isolation, elevated platform test, grooming analysis algorith

Hippocampal asymmetry in expression of catecholamine synthesizing enzyme and transporters in socially isolated rats

OBJECTIVES: Right-left asymmetry of human brain function has been known for a century. Brain asymmetry and lateralization has been observed at the neurochemical level. At the neurochemical level, it is important to further correlate changes in monoaminergic activity with the synthesis and reuptake of these monoamines. The aim of the present study was to analyze the effect of social isolation on catecholamine stores as well as on the regulation of catecholamine synthesis and uptake in the right and left hippocampus. METHODS: We examined changes in protein levels of dopamine-beta-hydroxylase (DBH), norepinephrine transporter (NET) and vesicular monoamine transporter 2 (VMAT2) in the right and left hippocampus of socially isolated adult male rats during 12 weeks by Western blot analysis. RESULTS: Chronic isolation stress reduced norepinephrine content in the right hippocampus. No changes were observed in protein levels of DBH and NET in the right hippocampus, whereas expression of this norepinephrine synthetizing enzyme and transporter were elevated in the left hippocampus. On the other hand, chronic isolation stress caused reduction of VMAT2 protein in the right hippocampus. CONCLUSION: Our results reveale not only the lateralization of stress regulatory system but they also show that long-term isolation stress produces right-left asymmetry of the hippocampus norepinephrine, different regulation of the catecholamines synthesis and reuptake