Different Classes of Antidepressants Inhibit the Rat α7 Nicotinic Acetylcholine Receptor by Interacting within the Ion Channel: A Functional and Structural Study.

Several antidepressants inhibit nicotinic acetylcholine receptors (nAChRs) in a non-competitive and voltage-dependent fashion. Here, we asked whether antidepressants with a different structure and pharmacological profile modulate the rat α7 nAChR through a similar mechanism by interacting within the ion-channel. We applied electrophysiological (recording of the ion current elicited by choline, ICh, which activates α7 nAChRs from rat CA1 hippocampal interneurons) and in silico approaches (homology modeling of the rat α7 nAChR, molecular docking, molecular dynamics simulations, and binding free energy calculations). The antidepressants inhibited ICh with the order: norfluoxetine ~ mirtazapine ~ imipramine < bupropion ~ fluoxetine ~ venlafaxine ~ escitalopram. The constructed homology model of the rat α7 nAChR resulted in the extracellular vestibule and the channel pore is highly negatively charged, which facilitates the permeation of cations and the entrance of the protonated form of antidepressants. Molecular docking and molecular dynamics simulations were carried out within the ion-channel of the α7 nAChR, revealing that the antidepressants adopt poses along the receptor channel, with slightly different binding-free energy values. Furthermore, the inhibition of ICh and free energy values for each antidepressant-receptor complex were highly correlated. Thus, the α7 nAChR is negatively modulated by a variety of antidepressants interacting in the ion-channel.

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.

Psychotropic drugs in the treatment of obesity: what promise?

Obesity is a chronic and highly prevalent medical condition associated with increased risk for the development of numerous and sometimes fatal diseases. Despite its severity, there are few anti-obesity agents available on the market. Although psychotropic agents are not approved for the treatment of obesity, they have been used by clinicians as a therapeutic tool in daily clinical practice. The purpose of this article is to review the rationale, as well as the evidence, for the potential use of these agents in obesity treatment. Evidence for the efficacy of psychotropic agents in obesity treatment comes from different sources. The first type of evidence is weight loss observed with treatment in clinical trials of patients with neuropsychiatric syndromes (e.g. mood disorders, epilepsy). A recent example of such findings is the weight reduction reported in clinical trials involving obese patients with binge eating disorder. While randomised, controlled trials specifically designed to investigate the weight loss properties of psychotropic agents in obese patients are the most appropriate source of evidence of anti-obesity action, such trials remain scarce. The most studied psychotropic agents in obesity trials are drugs used in the treatment of mood disorders, i.e. mainly antidepressants and antiepileptics. SSRIs (e.g. fluoxetine, sertraline and fluvoxamine) were amongst the first psychotropic agents investigated in the treatment of obesity. Additional data have also been published for other antidepressants (e.g. venlafaxine, citalopram and bupropion) and antiepileptics (e.g. topiramate and zonisamide). Based on the available data for the efficacy of psychotropic agents in obesity and other related conditions, SSRIs may be considered for the management of certain subgroups of obese individuals with comorbid conditions such as depression, binge eating disorder and type 2 diabetes mellitus. In addition, some newer agents, such as bupropion, topiramate and zonisamide, appear to be promising candidates for selective use in the treatment of obesity. However, further studies are needed to define their possible role as new pharmacological options in the treatment of obesity.

La depresion en los ancianos

Una persona de edad avanzada suele tener múltiples factores de riesgo para depresión, entre ellos enfeermedad sintomática, dolor crónico, el uso de numerosos medicamentos, transtornos del sueño y situaciones productoras de estrés adicional, como la pérdida del cónyuge o dificultades económicas. Reconocer oportunamente este cuadro es algo tan fundamental como en ocaciones difícil

Avances en terapeútica antidepresiva: la nueva generación de I.M.A.O / New trends in anti-depressive treatment the new generation of I.M.A.O

Se realiza un breve recuento histórico desde el advenimiento de las drogas antidepresivas e investigaciones basadas en diferentes fundamentos teóricos para perfeccionar la cura de la depresión, hasta el descubrimiento de las isoenzimas MAO-A y MAO-B a partir de lo cual se sintetizaron nuevos IMAO selectivos y reversibles que permiten minimizar efectos secundarios como el efecto presor de la Tiramina, teniendo igual eficacia que el resto de los antidepresivos, vislumbrándose como la nueva alternativa de la terapeútica farmacológica para la depresión (AU)

Avances en terapeútica antidepresiva: la nueva generación de I.M.A.O / New trends in anti-depressive treatment the new generation of I.M.A.O

Se realiza un breve recuento histórico desde el advenimiento de las drogas antidepresivas e investigaciones basadas en diferentes fundamentos teóricos para perfeccionar la cura de la depresión, hasta el descubrimiento de las isoenzimas MAO-A y MAO-B a partir de lo cual se sintetizaron nuevos IMAO selectivos y reversibles que permiten minimizar efectos secundarios como el efecto presor de la Tiramina, teniendo igual eficacia que el resto de los antidepresivos, vislumbrándose como la nueva alternativa de la terapeútica farmacológica para la depresión

Pharmacology of locus coeruleus spontaneous and sensory-evoked activity.

Neuroendocrine and catecholamine dysfunctions in depression may be linked by corticotropin-releasing factor (CRF) effects on locus coeruleus (LC) neurons. One consequence of CRF hypersecretion in depression would be persistent elevated levels of LC discharge and diminished responses to phasic sensory stimuli. The hypothesis that antidepressants could reverse these changes was tested by characterizing effects of pharmacologically distinct antidepressants on LC sensory-evoked discharge, LC activation by stress, and LC activation by CRF. The most consistent effect of all of the antidepressants tested was a decrease in LC sensory-evoked discharge after acute administration. However, tolerance occurs to these effects after chronic administration. With chronic administration each of the antidepressants produced effects which could potentially interfere with CRF function in the LC. Desmethylimipramine and mianserin attenuated LC activation by a stressor which requires endogenous CRF, suggesting that these antidepressants attenuate stress-elicited release of CRF and perhaps the hypersecretion that occurs in depression. The serotonin reuptake inhibitor, sertraline (SER), enhanced the signal-to-noise ratio of the LC sensory response, an effect opposite to that of CRF. Thus, SER could serve as a functional antagonist of CRF that is hypersecreted in depression. The finding that three pharmacologically distinct antidepressants share the potential to interfere with CRF function in the LC implies that this may be an important common mechanism for antidepressant activity.