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Grimm, Wilhelm an [Frau R.] Siegfried (1 Brief)
No full textGRIMM, WILHELM AN [FRAU R.] SIEGFRIED (1 BRIEF)
Grimm, Wilhelm an [Frau R.] Siegfried (1 Brief) (Br2732)
Brief 2732 (Br2732
Presynaptic alpha2-adrenoceptor activity in the prefrontal and occipital cortex after chronic desipramine
No full textAcute administration of noradrenaline transporter blockers increases dopamine and noradrenaline extracellular levels in the prefrontal cortex (PfCX). On the other hand, reboxetine and desipramine, at doses fully effective in the PfCX, fail to modify extracellular DA in other cortical areas, such as occipital cortex (OCCX). This difference in the responsiveness of OCCX DA as compared to PfCX DA to NET blockade has been ascribed to a stronger inhibitory control exerted by NA on DA release via local α2 receptor. Electrophysiological and neurochemical evidences have been provided that prolonged exposure to antidepressants induces desensitization of autoreceptors . This change, in turn, has been attributed an important role in the mechanism of action of antidepressants. However, the evidence provided thus far has been obtained after interruption of antidepressant exposure, a condition not corresponded to the clinical situation. In the present study we monitored the effect of chronic NET blockade by desipramine on dialysate DA and NA in the PfCX and OCCX of rats challenged with DMI under blockade of α2 receptors by reverse dialysis with idazoxan 24 hours after the last DMI administration, when drug levels are at steady-state. Male Sprague Dawley rats (Harlan Italy) were chronically treated with desipramine (10 mg/kg, i.p. every 24 hours for 14 days) or saline (0.9% 3 ml/kg, same conditions). On the 14th day, the probe was implanted vertically in the PfCX, and in the OCCX; according to the atlas of Paxinos and Watson. On the 15th day, microdialysis experiments were carried out on freely moving rats. In following results were obtained: 1) chronic DMI increases extracellular DA and NA in PfCX and OCCX to levels superimposable to those reached after acute administration of the same dose to naive rats. 2) acute challenge with DMI 24 hours after the last dose of antidepressant, failed to further increase DA and NA in both areas. 3) α2 receptor blockade by idazoxan potentiated the effect of acute DMI to a larger extent in chronic DMI rats than in saline control. These observations challenge the hypothesis that desensitization of α2 receptors occurs during chronic antidepressant treatment
Neurobehavioural complications of sleep deprivation: Shedding light on the emerging role of neuroactive steroids
No full textSleep deprivation (SD) is associated with a broad spectrum of cognitive and behavioural complications, including emotional lability and enhanced stress reactivity, as well as deficits in executive functions, decision making and impulse control. These impairments, which have profound negative consequences on the health and productivity of many individuals, reflect alterations of the prefrontal cortex (PFC) and its connectivity with subcortical regions. However, the molecular underpinnings of these alterations remain elusive. Our group and others have begun examining how the neurobehavioural outcomes of SD may be influenced by neuroactive steroids, a family of molecules deeply implicated in sleep regulation and the stress response. These studies have revealed that, similar to other stressors, acute SD leads to increased synthesis of the neurosteroid allopregnanolone in the PFC. Whereas this up-regulation is likely aimed at counterbalancing the detrimental impact of oxidative stress induced by SD, the increase in prefrontal allopregnanolone levels contributes to deficits in sensorimotor gating and impulse control, signalling a functional impairment of PFC. This scenario suggests that the synthesis of neuroactive steroids during acute SD may be enacted as a neuroprotective response in the PFC; however, such compensation may in turn set off neurobehavioural complications by interfering with the corticolimbic connections responsible for executive functions and emotional regulation
Chronic desipramine and fluoxetine differentially affect extracellular dopamine in the rat prefrontal cortex
No full textThe effect of chronic administration of desipramine or fluoxetine (10 mg/kg IP once a day for 2 weeks) on extracellular noradrenaline, serotonin and dopamine in the rat prefrontal cortex was studied by transcerebral microdialysis. Chronic desipramine increased extracellular noradrenaline and dopamine by three-fold as compared to saline controls. Acute challenge with 10 mg/kg desipramine increased by more than three-fold extracellular noradrenaline and dopamine in saline controls, but failed further to increase extracellular noradrenaline and dopamine in rats chronically administered desipramine. Chronic fluoxetine more than doubled the extracellular concentrations of serotonin but failed to change the extracellular concentrations of dopamine as compared to saline controls. Challenge with 5 mg/kg fluoxetine while almost doubling extracellular serotonin and dopamine concentrations in saline controls, failed further to increase extracellular serotonin and did not change extracellular dopamine in rats chronically exposed to fluoxetine. In contrast, challenge with 10 mg/kg desipramine normally increased extracellular dopamine in rats chronically exposed to fluoxetine. Therefore, chronic fluoxetine is associated with normal presynaptic dopamine transmission in the prefrontal cortex as a result of tolerance to fluoxetine-induced increase of extracellular dopamine, in contrast, chronic desipramine is associated with an increase of pre-synaptic dopamine transmission in the prefrontal cortex up to a level that cannot be further elevated by acute desipramine challenge. The results suggest that prefrontal cortex dopamine plays a different role in the antidepressant properties of desipramine and fluoxetine
Noradrenaline transporter blockers raise extracellular dopamine in medial prefrontal but not parietal and occipital cortex: differences with mianserin and clozapine
No full textThis study compared the interaction between noradrenaline (NA) and dopamine (DA) mechanisms in the prefrontal (PFCX) and in the parietal (ParCX) and occipital (OccCX) cortex. The effect of reboxetine and desipramine, two NA transporter blockers, of mianserin, an antagonist of alpha(2) and 5-HT2 receptors, and of clozapine, an atypical antipsychotic, on dialysate DA in the medial PFCX, ParCX and OccCX was studied. We also assessed the influence of a prior 6-hydroxydopamine (6-OHDA) lesion of the dorsal noradrenergic bundle (DNAB) on the effect of reboxetine and clozapine on dialysate DA in the PFCX and ParCX. Systemic administration of reboxetine and desipramine dose-dependently increased dialysate DA in the PFCX but not in the ParCX and OccCX. In contrast, mianserin and clozapine raised dialysate DA in the ParCX and OccCX to an even larger extent than in the PFCX. 6-OHDA lesions of DNAB abolished the increase of dialysate DA elicited by reboxetine in the PFCX and by clozapine both in the PFCX and in the ParCX. It is concluded that, although PFCX and ParCX/OccCX share the presence of a strong control of DA transmission by NA through alpha(2) receptors, they differ in the extent to which DA is cleared from the extracellular compartment by uptake through the NA transporter. This process, although extensive in the PFCX, appears insignificant in the ParCX and OccCX, probably as a result of the higher ratio of NA to DA resulting in exclusion of DA from NA transporter
LOCAL 5HT(3) RECEPTORS MEDIATE FLUOXETINE BUT NOT DESIPRAMINE-INDUCED INCREASE OF EXTRACELLULAR DOPAMINE IN THE PREFRONTAL CORTEX
No full textFluoxetine and desipramine, two antidepressants that block selectively the serotonin and the noradrenaline carrier, increase extracellular dopamine concentrations in the prefrontal cortex of freely-moving rats. This effect is calcium dependent and is prevented, in the case of fluoxetine but not desipramine, by systemic pretreatment with low doses or by low concentrations in the dialyzing Ringer of the potent 5-HT3 antagonist ICS 205930. Fluoxetine, but not desipramine, increases extracellular serotonin concentrations in the prefrontal cortex. The results indicate that selective serotonin reuptake blockers increase extracellular dopamine in the prefrontal cortex by stimulating local 5-HT3 receptors
Repurposing steroidogenesis inhibitors for the therapy of neuropsychiatric disorders: Promises and caveats
No full textSteroids exert a profound influence on behavioral reactivity, by modulating the functions of most neurotransmitters and shaping the impact of stress and sex-related variables on neural processes. This background - as well as the observation that most neuroactive steroids (including sex hormones, glucocorticoids and neurosteroids) are synthetized and metabolized by overlapping enzymatic machineries - points to steroidogenic pathways as a powerful source of targets for neuropsychiatric disorders. Inhibitors of steroidogenic enzymes have been developed and approved for a broad range of genitourinary and endocrine dysfunctions, opening to new opportunities to repurpose these drugs for the treatment of mental problems. In line with this idea, preliminary clinical and preclinical results from our group have shown that inhibitors of key steroidogenic enzymes, such as 5α-reductase and 17,20 desmolase-lyase, may have therapeutic efficacy in specific behavioral disorders associated with dopaminergic hyperfunction. While the lack of specificity of these effects raises potential concerns about endocrine adverse events, these initial findings suggest that steroidogenesis modulators with greater brain specificity may hold significant potential for the development of alternative therapies for psychiatric problems
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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