Az ecstasy hatása a kognitív funkciókra

Az ecstasy főleg entaktogén és eufóriát okozó hatásai miatt közkedvelt kábítószer a fiatalok körében. Akutan az ecstasy a visszavételi mechanizmusok megfordításával megemeli az agyi monoaminok koncentrációját és ezen keresztül fokozza az ébrenlétet, emeli a testhőmérsékletet, valamint csökkenti az agyi vérátáramlást és a táplálékfelvételt. Hosszú távon ugyanakkor az agyi szerotonin koncentrációk és szerotonerg markerek mennyiségének csökkenése figyelhető meg a felhasználókban. Ezzel párhuzamosan funkcionális károsodások is megjelenhetnek, mint például az alvás- és hangulatzavarok, valamint a szorongás és az agresszivitás fokozódása. Mindemellett az ecstasy egyik legjellemzőbb hosszú távú mellékhatása a kognitív deficit. Különösen a szert rendszeresen fogyasztó felhasználók esetén csökkent retro- és prospektív memória, valamint károsodott végrehajtó funkciók figyelhetők meg. Számos tanulmány a szerotonerg károsodás mellett felvetette az endokannabinoid rendszer, az alvásszabályzás és a hypothalamus-hypophysis-mellékvesekéreg tengely szerepét e folyamatban. Ugyanakkor ismert, hogy a fenti rendszerek egymás működését is képesek befolyásolni. Jelen tanulmányunkban a szerotonerg károsodás, az endokannabinoid rendszer és a fenti szabályozó mechanizmusok hatásait külön-külön, valamint egymásra gyakorolt lehetséges interakcióikat is tárgyaljuk, amelyek magyarázhatják az ecstasy által okozott hosszan tartó kognitív funkciócsökkenést

Interconnections of Reactive Oxygen Species Homeostasis and Circadian Rhythm in Neurospora crassa.

Abstract Significance: Both circadian rhythm and the production of reactive oxygen species (ROS) are fundamental features of aerobic eukaryotic cells. The circadian clock enhances the fitness of organisms by enabling them to anticipate cycling changes in the surroundings. ROS generation in the cell is often altered in response to environmental changes, but oscillations in ROS levels may also reflect endogenous metabolic fluctuations governed by the circadian clock. On the other hand, an effective regulation and timing of antioxidant mechanisms may be crucial in the defense of cellular integrity. Thus, an interaction between the circadian timekeeping machinery and ROS homeostasis or signaling in both directions may be of advantage at all phylogenetic levels. Recent Advances: The Frequency-White Collar-1 and White Collar-2 oscillator (FWO) of the filamentous fungus Neurospora crassa is well characterized at the molecular level. Several members of the ROS homeostasis were found to be controlled by the circadian clock, and ROS levels display circadian rhythm in Neurospora. On the other hand, multiple data indicate that ROS affect the molecular oscillator. Critical Issues: Increasing evidence suggests the interplay between ROS homeostasis and oscillators that may be partially or fully independent of the FWO. In addition, ROS may be part of a complex cellular network synchronizing non-transcriptional oscillators with timekeeping machineries based on the classical transcription-translation feedback mechanism. Future Directions: Further investigations are needed to clarify how the different layers of the bidirectional interactions between ROS homeostasis and circadian regulation are interconnected. Antioxid. Redox Signal. 00, 000-000

The small G protein RAS2 is involved in the metabolic compensation of the circadian clock in the circadian model Neurospora crassa.

Accumulating evidence from both experimental and clinical investigations indicate a tight interaction between metabolism and circadian timekeeping; however, knowledge of the underlying mechanism is still incomplete. Metabolic compensation allows circadian oscillators to run with a constant speed at different substrate levels and therefore is a substantial criterion of a robust rhythm in a changing environment. Because previous data have suggested a central role of RAS2-mediated signaling in the adaptation of yeast to different nutritional environments, we examined the involvement of RAS2 in the metabolic regulation of the clock in the circadian model organism Neurospora crassa. We show that in a ras2-deficient strain, the period is longer than in the control. Moreover, unlike in wild type (wt), in Deltaras2 operation of the circadian clock was affected by glucose: compared with starvation conditions, the period was longer and the oscillation of expression of the frequency (frq) gene was dampened. In constant darkness the delayed phosphorylation of the FRQ protein and the long-lasting accumulation of FRQ in the nucleus were in accordance with the longer period and the less robust rhythm in the mutant. Whereas glucose did not affect the subcellular distribution of FRQ in wt, highly elevated FRQ levels were detected in the nucleus in Deltaras2. RAS2 interacted with the RAS-binding domain of the adenylate cyclase in vitro, and the cAMP analogue 8-Br-cAMP partially rescued the circadian phenotype in vivo. We propose therefore that RAS2 acts via a cAMP-dependent pathway and exerts significant metabolic control on the Neurospora circadian clock

Reactive oxygen species can modulate circadian phase and period in Neurospora crassa

Reactive oxygen species (ROS) may serve as signals coupling metabolism to other cell functions. In addition to being by-products of normal metabolism, they are generated at elevated levels under environmental stress situations. We analyzed how reactive oxygen species affect the circadian clock in the model organism Neurospora crassa. In light/dark cycles, an increase in the levels of reactive oxygen species advanced the phase of both the conidiation rhythm and the expression of the clock gene frequency. Our results indicate a dominant role of the superoxide anion in the control of the phase. Elevation of superoxide production resulted in the activation of protein phosphatase 2A, a regulator of the positive element of the circadian clock. Our data indicate that even under nonstress conditions, reactive oxygen species affect circadian timekeeping. Reduction of their basal levels results in a delay of the phase in light/dark cycles and a longer period under constant conditions. We show that under entrained conditions the phase depends on the temperature and reactive oxygen species contribute to this effect. Our results suggest that the superoxide anion is an important factor controlling the circadian oscillator and is able to reset the clock most probably by activating protein phosphatase 2A, thereby modulating the activity of the White Collar complex. © 2012 Elsevier Inc. All rights reserved

Reactive oxygen species can modulate circadian phase and period in Neurospora crassa

Reactive oxygen species (ROS) may serve as signals coupling metabolism to other cell functions. In addition to being by-products of normal metabolism, they are generated at elevated levels under environmental stress situations. We analyzed how reactive oxygen species affect the circadian clock in the model organism Neurospora crassa. In light/dark cycles, an increase in the levels of reactive oxygen species advanced the phase of both the conidiation rhythm and the expression of the clock gene frequency. Our results indicate a dominant role of the superoxide anion in the control of the phase. Elevation of superoxide production resulted in the activation of protein phosphatase 2A, a regulator of the positive element of the circadian clock. Our data indicate that even under nonstress conditions, reactive oxygen species affect circadian timekeeping. Reduction of their basal levels results in a delay of the phase in light/dark cycles and a longer period under constant conditions. We show that under entrained conditions the phase depends on the temperature and reactive oxygen species contribute to this effect. Our results suggest that the superoxide anion is an important factor controlling the circadian oscillator and is able to reset the clock most probably by activating protein phosphatase 2A, thereby modulating the activity of the White Collar complex. © 2012 Elsevier Inc. All rights reserved

Az ecstasy hatasa a kognitiv funkciokra.

The recreational drug ecstasy is widely used among dance clubbers for its acute euphoric and entactogenic effects. Ecstasy exerts its acute effects by increasing the extracellular concentration of monoamines in the brain by reversing the functions of reuptake mechanisms. These elevations in extracellular monoamine concentrations result in wake promoting effects, body hyperthermia and reductions in local cerebral blood flow. However, on the long-run, ecstasy reduces serotonin concentration and density of serotonergic markers in several brain areas. Functional deficits, like sleep disturbances, anxiogenic- and aggressive behavioral responses and mood disorders also may occur. However, one of the most prominent adverse effects is related to the cognitive functions. Following ecstasy use attenuated retro- and prospective memory and defective higher order cognitive functions can be observed, especially in heavy users. Several studies indicated the involvement of the endocannabinoid system, the sleep regulating centers and the hypothalamic-pituitary-adrenal axis based on or parallel to serotonergic damage in these processes. Recent evidence, however, also showed that changes in one of the latter systems can influence the functions of each other. In this review we summarize the related literature, and propose a complex mechanism for the long-lasting cognitive deficits following heavy ecstasy use

A systems biological analysis of the ATF4-GADD34-CHOP regulatory triangle upon endoplasmic reticulum stress

Endoplasmic reticulum (ER) stress-dependent accumulation of incorrectly folded proteins leads to activation of the unfolded protein response. The role of the unfolded protein response (UPR) is to avoid cell damage and restore the homeostatic state by autophagy; however, excessive ER stress results in apoptosis. Here we investigated the ER stress-dependent feedback loops inside one of the UPR branches by focusing on PERK-induced ATF4 and its two targets, called CHOP and GADD34. Our goal was to qualitatively describe the dynamic behavior of the system by exploring the key regulatory motifs using both molecular and theoretical biological techniques. Using the HEK293T cell line as a model system, we confirmed that the life-or-death decision is strictly regulated. We investigated the dynamic characteristics of the crucial elements of the PERK pathway at both the RNA and protein level upon tolerable and excessive levels of ER stress. Of particular note, inhibition of GADD34 or CHOP resulted in various phenotypes upon high levels of ER stress. Our computer simulations suggest the existence of two new feedback loops inside the UPR. First, GADD34 seems to have a positive effect on ATF4 activity, while CHOP inhibits it. We claim that these newly described feedback loops ensure the fine-tuning of the ATF4-dependent stress response mechanism of the cell. © 2022 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies