Antidepresszivumok, stresszorok es a szerotonin 1A receptor.

5-HT1A receptor is a receptor of surprises. Buspirone, an anxiolytic drug with a then yet unidentified mechanism of action had been marketed for years when it was discovered that it is a 5-HT1A partial agonist. Several more years had to pass before it was accepted that this receptor plays the key role in the action mechanism of buspirone. This was followed by further surprises. It was discovered that in spite of its anxiolytic effect buspirone activates the hypothalamic-pituitary-adrenal (HPA) stress axis, furthermore, it increases peripheral noradrenaline and adrenaline concentration via a central mechanism. Thus activation of this receptor leads to ACTH/corticosterone and catecholamine release and also increases beta-endorphine, oxytocin and prolactin secretion while decreasing body temperature, increasing food uptake, eliciting characteristic behavioural responses in rodents and also playing a role in the development of certain types of epilepsy. Human genetic studies revealed the role of 5-HT1A receptors in cognitive processes playing a role in the development of depression such as impulsiveness or response to environmental stress. This exceptionally wide spectrum of effects is attributable to the presence of 5-HT1A receptors in serotonergic as well as other, for example glutamatergic, cholinergic, dopaminergic and noradrenergic neurons. The majority of the effects of 5-HT1A receptors is manifested via the mediation of Gi proteins through the hyperpolarisation or inhibition of the neuron carrying the receptor. 5-HT1A receptors on serotonergic neurons can be found in the somatodendritic area and play a significant role in delaying the effects of antidepressants which is an obvious disadvantage. Therefore the newest serotonergic antidepressants including vilazodone and vortioxetine have been designed to possess 5-HT1A receptor partial agonist properties. In the present paper we focus primarily on the role of 5-HT1A receptors in stress and antidepressant response

Nem pszichiátriai gyógyszerek szorongást és depressziót kiváltó mellékhatásai

Annak ellenére, hogy számos szomatikus betegség kezelésére alkalmazott – például daganatellenes, antimikrobás, immunmoduláns, neurológiai, illetve hormonháztartásra ható – gyógyszer hathat negatív irányban a hangulatra, ezt egészen a rimonabant 2008-ban emiatt történt visszavonásáig nem kezelték jelentőségének megfelelően. A szerzők a teljes gyógyszerpalettát áttekintve tárgyalják a szorongást és a depressziót, mint gyógyszer-mellékhatásokat. A gyógyszerválasztásnál minden esetben fi gyelembe kell venni, ha a betegeknél magas a depresszió kialakulásának a kockázata, például, ha már korábban előfordult vagy jelenleg is fennáll a depressziós epizód vagy betegség, ha a családi anamnézisben előfordul depresszió, illetve ha a betegnél olyan neurotikus személyiségvonások állnak fenn, amelyek következtében sérülékenyebb a depressziót kiváltó hatásokkal szemben. A veszélyt jelentő gyógyszerek felírása előtt emellett célszerű fi gyelembe venni az alkalmazni kívánt szer hatékonyságát, a rendelkezésre álló alternatív gyógyszeres és nem gyógyszeres terápiás lehetőségeket, és minden esetben biztosítani kell a beteg monitorozását a kezelés során az esetleges depressziós vagy szorongásos tünetek mihamarabbi észlelése érdekében

Acute and long-term effects of a single dose of MDMA on aggression in Dark Agouti rats

MDMA causes selective depletion of serotonergic terminals in experimental animals and the consequent decrease in synaptic 5-HT may, inter alia, increase impulsivity. To study the effects of MDMA upon brain function, the behaviour of male Dark Agouti rats exposed to MDMA (15 mg/kg i.p.), two 5-HT1B agonists (CGS-12066A and CP-94,253, both 5 mg/kg i.p.) or saline were investigated in the resident-intruder test. Studies were performed in drug-naive rats and also in rats exposed to MDMA (15 mg/kg i.p.) 21 d earlier. In parallel experiments the functional neuroanatomy of MDMA effects were assessed using 2-deoxyglucose imaging of local cerebral metabolic rate of glucose utilization (LCMRGlu) and neurotoxicity was assessed by measuring [H-3]paroxetine binding. There was no significant difference in aggressive behaviour (biting, boxing, wrestling and their latencies) between drug-naive rats and rats previously exposed to MDMA 21 d earlier, despite reduced social behaviour, decreased LCMRGlu in several brain areas involved in aggression, and reductions in paroxetine binding by 30-60'% in the forebrain. CGS12066A, CP-94,253 and acute MDMA produced marked decreases in aggressive behaviours, especially in biting, boxing and kicking found in drug-naive rats. In animals previously exposed to the drug, acute antiaggressive effects of MDMA were, in general, preserved as were MDMA-induced increases in LCMRGlu. Our studies provide evidence that in the resident-intruder test, where social isolation is a requirement, aggressive behaviour and acute anti-aggressive effects of MDMA and 5-HT,I, receptor agonists remain intact 3 wk after a single dose of the drug despite significant damage to the serotonergic system

A változásmenedzselés tapasztalatai néhány magyar tulajdonú kis- és középvállatnál

A szerzők az elmúlt öt év konkrét tapasztalatainak az összefoglalásával ráirányítják a figyelmet a rendszerváltozás után alakult százszázalékosan magyar, magántulajdonú kis- és középvállalkozások helyzetére, problémáira. Az anyag harminchárom vállalatra kiterjedő minta alapján készült

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

Decrease in REM latency and changes in sleep quality parallel serotonergic damage and recovery after MDMA: a longitudinal study over 180 days

The recreational drug ecstasy [3,4-methylenedioxymethamphetamine (MDMA)], has been found to selectively damage brain serotonin neurons in experimental animals, and probably in human MDMA users, but detailed morphometric analyses and parallel functional measures during damage and recovery are missing. Since there is evidence that serotonin regulates sleep, we have compared serotonergic markers parallel with detailed analysis of sleep patterns at three time-points within 180 d after a single dose of 15 mg/kg MDMA in male Dark Agouti rats. At 7 d and 21 d after MDMA treatment, significant (30-40%), widespread reductions in serotonin transporter (5-HTT) density were detected in the cerebral cortex, hippocampus, most parts of the hypothalamus, and some of the brainstem nuclei. With the exception of the hippocampus, general recovery was observed in the brain 180 d after treatment. Transient increases followed by decreases were detected in 5-HTT mRNA expression of dorsal and median raphe nuclei at 7 d and 21 d after the treatment. Significant reductions in rapid eye movement (REM) sleep latency, increases in delta power spectra in non-rapid eye movement sleep and increased fragmentation of sleep were also detected, but all these alterations disappeared by the 180th day. The present data provide evidence for long-term, albeit, except for the hippocampus, transient changes in the terminal and cellular regions of the serotonergic system after this drug. Reduced REM latency and increased sleep fragmentation are the most characteristic alterations of sleep consistently described in depression using EEG sleep polygraphy

Purification of germline stem cells from adult mammalian ovaries: a step closer towards control of the female biological clock?

For decades it was believed that a non-renewable pool of oocyte-containing follicles is established in female mammals at birth. This cornerstone of reproductive biology was challenged 5 years ago by a study reporting on the presence of mitotically-active germ cells in juvenile and adult mouse ovaries. Additional findings presented in this study and others that followed further suggested that mammals retain the capacity to generate oocytes during adulthood; however, isolation of oocyte-producing germline stem cells (GSC) as unequivocal proof of their existence remained elusive. This piece of information now appears to have been provided by Ji Wu and colleagues. In addition to showing that proliferative germ cells resembling male spermatogonial stem cells can be purified from neonatal or adult mouse ovaries and maintained in vitro for months, transplantation studies demonstrated that these cells generate oocytes in ovaries of chemotherapy-sterilized recipients that fertilize and produce viable offspring. Although these findings do not establish that oogenesis occurs in adult females under physiological conditions, they strongly support the existence of GSC in adult mouse ovaries. If equivalent cells can be found in human ovaries, stem cell-based rejuvenation of the oocyte reserve in ovaries on the verge of failure may one day be realized

Histone H3K9 Trimethylase Eggless Controls Germline Stem Cell Maintenance and Differentiation

Epigenetic regulation plays critical roles in the regulation of cell proliferation, fate determination, and survival. It has been shown to control self-renewal and lineage differentiation of embryonic stem cells. However, epigenetic regulation of adult stem cell function remains poorly defined. Drosophila ovarian germline stem cells (GSCs) are a productive adult stem cell system for revealing regulatory mechanisms controlling self-renewal and differentiation. In this study, we show that Eggless (Egg), a H3K9 methyltransferase in Drosophila, is required in GSCs for controlling self-renewal and in escort cells for regulating germ cell differentiation. egg mutant ovaries primarily exhibit germ cell differentiation defects in young females and gradually lose GSCs with time, indicating that Egg regulates both germ cell maintenance and differentiation. Marked mutant egg GSCs lack expression of trimethylated H3K9 (H3k9me3) and are rapidly lost from the niche, but their mutant progeny can still differentiate into 16-cell cysts, indicating that Egg is required intrinsically to control GSC self-renewal but not differentiation. Interestingly, BMP-mediated transcriptional repression of differentiation factor bam in marked egg mutant GSCs remains normal, indicating that Egg is dispensable for BMP signaling in GSCs. Normally, Bam and Bgcn interact with each other to promote GSC differentiation. Interestingly, marked double mutant egg bgcn GSCs are still lost, but their progeny are able to differentiate into 16-cell cysts though bgcn mutant GSCs normally do not differentiate, indicating that Egg intrinsically controls GSC self-renewal through repressing a Bam/Bgcn-independent pathway. Surprisingly, RNAi-mediated egg knockdown in escort cells leads to their gradual loss and a germ cell differentiation defect. The germ cell differentiation defect is at least in part attributed to an increase in BMP signaling in the germ cell differentiation niche. Therefore, this study has revealed the essential roles of histone H3K9 trimethylation in controlling stem cell maintenance and differentiation through distinct mechanisms