Effects of lifelong ethanol consumption on brain monoamine transmitters in alcohol-preferring Alko Alcohol (AA) rats

Peer reviewe

Agonist and antagonist effects of aripiprazole on D<inf>2</inf>-like receptors controlling rat brain dopamine synthesis depend on the dopaminergic tone

Supported by grants SAF2006-08240, SAF2009-12510, and Red de Trastornos Adictivos RD06/0001/0015. G.F.M. was the recipient of a CSC fellowship.Background: The atypical antipsychotic drug aripiprazole binds with high affinity to a number of G protein coupled receptors, including dopamine D2 receptors, where its degree of efficacy as a partial agonist remains controversial. Methods: We examined the properties of aripiprazole at D2-like autoreceptors by monitoring the changes of dopamine synthesis in adult rat brain striatal minces incubated ex vivo. The effects of the dopaminergic tone on the properties of aripiprazole were assayed by comparing a basal condition (2 mM K+, low dopaminergic tone) and a stimulated condition (15 mM K+ where dopamine release mimics a relatively higher dopaminergic tone). We also used 2 reference compounds: quinpirole showed a clear agonistic activity and preclamol (S-(-)-PPP) showed partial agonism under both basal and stimulated conditions. Results: Aripiprazole under the basal condition acted as an agonist at D2-like autoreceptors and fully activated them at about 10 nM, inhibiting dopamine synthesis similarly to quinpirole. Higher concentrations of aripiprazole had effects not restricted to D2-like autoreceptor activation. Under the stimulated (15 mM K+) condition, nanomolar concentrations of aripiprazole failed to decrease dopamine synthesis but could totally block the effect of quinpirole. Conclusions: Under high dopaminergic tone, aripiprazole acts as a D2-like autoreceptor antagonist rather than as an agonist. These data show that, ex vivo, alteration of dopaminergic tone by depolarization affects the actions of aripiprazole on D2-like autoreceptors. Such unusual effects were not seen with the typical partial agonist preclamol and are consistent with the hypothesis that aripiprazole is a functionally selective D2R ligand

Long-lasting impairment of mGluR5-activated intracellular pathways in the striatum after withdrawal of cocaine self-administration

Background: Cocaine addiction continues to be a major heath concern, and despite public health intervention there is a lack of efficient pharmacological treatment options. A newly identified potential target are the group I metabotropic glutamate receptors (mGluR1/5), with allosteric modulators showing particular promise. Methods: We evaluated the capacity of mGluR1/5 receptors to induce functional responses in ex vivo striatal slices from rats with 1) acute cocaine self-administration (CSA), 2) chronic CSA and 3) 60 days CSA withdrawal by westernblot and extracellular recordings of synaptic transmission. Results: We found that striatal mGluR5 are the principal mediator of the mGluR1/5 agonist DHPG-induced CREB phosphorylation. Both acute and chronic CSA blunted mGluR1/5 effects on CREB phosphorylation in the striatum, which correlated with the capacity to induce long-term depression, an effect which was maintained 60 days after chronic CSA withdrawal. In the nucleus accumbens, the principal brain region mediating the rewarding effects of drugs, chronic CSA blunted mGluR1/5 stimulation of ERK1/2 and CREB. Interestingly, the mGluR5 antagonist/inverse-agonist, MPEP, lead to a specific increase in CREB phosphorylation after chronic CSA specifically in the nucleus accumbens, but not in the striatum. Conclusions: Prolonged CSA, through withdrawal, leads to a blunting of mGluR1/5 responses in the striatum. In addition, specifically in the accumbens, mGluR5 signaling to CREB shifts from an agonist-induced to an antagonist-induced CREB phosphorylation

Cognitive Performance at Time of AD Diagnosis : A Clinically Augmented Register-Based Study

We aimed to evaluate the feasibility of using real-world register data for identifying persons with mild Alzheimer's disease (AD) and to describe their cognitive performance at the time of diagnosis. Patients diagnosed with AD during 2010-2013 (aged 60-81 years) were identified from the Finnish national health registers and enlarged with a smaller private sector sample (total n = 1,268). Patients with other disorders impacting cognition were excluded. Detailed clinical and cognitive screening data (the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery [CERAD-nb]) were obtained from local health records. Adequate cognitive data were available for 389 patients with mild AD (31%) of the entire AD group. The main reasons for not including patients in analyses of cognitive performance were AD diagnosis at a moderate/severe stage (n = 266, 21%), AD diagnosis given before full register coverage (n = 152, 12%), and missing CERAD-nb data (n = 139, 11%). The cognitive performance of persons with late-onset AD (n = 284), mixed cerebrovascular disease and AD (n = 51), and other AD subtypes (n = 54) was compared with that of a non-demented sample (n = 1980) from the general population. Compared with the other AD groups, patients with late-onset AD performed the worst in word list recognition, while patients with mixed cerebrovascular disease and AD performed the worst in constructional praxis and clock drawing tests. A combination of national registers and local health records can be used to collect data relevant for cognitive screening; today, the process is laborious, but it could be improved in the future with refined search algorithms and electronic data.Peer reviewe

Education-Based Cutoffs for Cognitive Screening of Alzheimer’s Disease

Introduction: The educational background and size of the elderly population are undergoing significant changes in Finland during the 2020s. A similar process is likely to occur also in several European countries. For cognitive screening of early Alzheimer’s disease (AD), using outdated norms and cutoff scores may negatively affect clinical accuracy. The aim of the present study was to examine the effects of education, age, and gender on the Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological battery (CERAD-nb) in a large register-based, clinical sample of patients with mild AD and nondemented at-risk persons from the general population (controls) and to examine whether corrected cutoff scores would increase the accuracy of differentiation between the 2 groups. Methods: CERAD-nb scores were obtained from AD patients (n = 389, 58% women, mean age 74.0 years) and from controls (n = 1,980, 52% women, mean age 68.5 years). The differences in CERAD-nb performance were evaluated by univariate GLM. Differentiation between the 2 groups was evaluated using a receiver operating characteristic (ROC) curve, where a larger area under the ROC curve represents better discrimination. Youden’s J was calculated for the overall performance and accuracy of each of the measures. Results: Of the demographic factors, education was the strongest predictor of CERAD-nb performance, explaining more variation than age or gender in both the AD patients and the controls. Education corrected cutoff scores had better diagnostic accuracy in discriminating between the AD patients and controls than existing uncorrected scores. The highest level of discrimination between the 2 groups overall was found for two CERAD-nb total scores. Conclusions: Education-corrected cutoff scores were superior to uncorrected scores in differentiating between controls and AD patients especially for the highest level of education and should therefore be used in clinical cognitive screening, also as the proportion of the educated elderly is increasing substantially during the 2020s. Our results also indicate that total scores of the CERAD-nb are better at discriminating AD patients from controls than any single subtest score. A digital tool for calculating the total scores and comparing education-based cutoffs would increase the efficiency and usability of the test.Peer reviewe

Spontaneous changes in brain striatal dopamine synthesis and storage dynamics ex vivo reveal end-product feedback-inhibition of tyrosine hydroxylase

Synaptic events are important to define treatment strategies for brain disorders. In the present paper, freshly obtained rat brain striatal minces were incubated under different times and conditions to determine dopamine biosynthesis, storage, and tyrosine hydroxylase phosphorylation. Remarkably, we found that endogenous dopamine spontaneously accumulated during tissue incubation at 37 °C ex vivo while dopamine synthesis simultaneously decreased. We analyzed whether these changes in brain dopamine biosynthesis and storage were linked to dopamine feedback inhibition of its synthesis-limiting enzyme tyrosine hydroxylase. The aromatic-L-amino-acid decarboxylase inhibitor NSD-1015 prevented both effects. As expected, dopamine accumulation was increased with L-DOPA addition or VMAT2-overexpression, and dopamine synthesis decreased further with added dopamine, the VMAT2 inhibitor tetrabenazine or D auto-receptor activation with quinpirole, accordingly to the known synaptic effects of these treatments. Phosphorylation activation and inhibition of tyrosine hydroxylase on Ser31 and Ser40 with okadaic acid, Sp-cAMP and PD98059 also exerted the expected effects. However, no clear-cut association was found between dopamine feedback inhibition of its own biosynthesis and changes of tyrosine hydroxylase phosphorylation, assessed by Western blot and mass spectrometry. The later technique also revealed a new Thr30 phosphorylation in rat tyrosine hydroxylase. Our methodological assessment of brain dopamine synthesis and storage dynamics ex vivo could be applied to predict the in vivo effects of pharmacological interventions in animal models of dopamine-related disorders.This work was supported by Spanish Government grants SAF2006-08240 (J.O.), SAF2009-12510 (J.O.), SAF2014-58396 (J.G, J.O.), SAF2017-87199-R (J.G, J.O.), SAF2016-77541-R (M.V.), The Michael J. Fox Foundation (ID15291, M.V.), “la Caixa” Foundation (ID 100010434), under the agreement LCF/PR/HR17/52150003 (M.V.). The Biological and Environmental Proteomics laboratory is a member of Proteored-PRB3 and is supported by grant PT17/0019/0008 of the PE I + D + i 2013–2016, funded by ISCIII and FEDER. M.G.S. enjoyed a Spanish government FPI fellowship. G.M received a fellowship from the China Scholarship Council. We thank the skillful technical assistance of Susana Benítez

Spontaneous changes in brain striatal dopamine synthesis and storage dynamics ex vivo reveal end-product feedback-inhibition of tyrosine hydroxylase

Altres ajuts: acord transformatiu CRUE-CSICAltres ajuts: , The Michael J. Fox Foundation (ID15291), "la Caixa" Foundation (ID 100010434), under the agreement LCF/PR/HR17/52150003Synaptic events are important to define treatment strategies for brain disorders. In the present paper, freshly obtained rat brain striatal minces were incubated under different times and conditions to determine dopamine biosynthesis, storage, and tyrosine hydroxylase phosphorylation. Remarkably, we found that endogenous dopamine spontaneously accumulated during tissue incubation at 37 °C ex vivo while dopamine synthesis simultaneously decreased. We analyzed whether these changes in brain dopamine biosynthesis and storage were linked to dopamine feedback inhibition of its synthesis-limiting enzyme tyrosine hydroxylase. The aromatic-l-amino-acid decarboxylase inhibitor NSD-1015 prevented both effects. As expected, dopamine accumulation was increased with l-DOPA addition or VMAT2-overexpression, and dopamine synthesis decreased further with added dopamine, the VMAT2 inhibitor tetrabenazine or D2 auto-receptor activation with quinpirole, accordingly to the known synaptic effects of these treatments. Phosphorylation activation and inhibition of tyrosine hydroxylase on Ser31 and Ser40 with okadaic acid, Sp-cAMP and PD98059 also exerted the expected effects. However, no clear-cut association was found between dopamine feedback inhibition of its own biosynthesis and changes of tyrosine hydroxylase phosphorylation, assessed by Western blot and mass spectrometry. The later technique also revealed a new Thr30 phosphorylation in rat tyrosine hydroxylase. Our methodological assessment of brain dopamine synthesis and storage dynamics ex vivo could be applied to predict the in vivo effects of pharmacological interventions in animal models of dopamine-related disorders

Endometrioosi ja vaihdevuodet

Paavola, Sofia & Raivio, Noora. Endometrioosi ja vaihdevuodet. Diak, syksy 2013, 72 sivua ja 2 liitettä. Diakonia-ammattikorkeakoulu, hoitotyön koulutusohjelma / terveydenhoitotyön suuntautumisvaihtoehto, terveydenhoitaja (AMK) / sairaanhoitaja (AMK). Opinnäytetyömme tavoitteena oli selvittää, vaikuttaako vaihdevuosi-ikä endometrioosia sairastaviin naisiin. Tarkoituksemme oli kuvailla vastausten yhteneväisyyksiä ja eroavaisuuksia sekä tulosten vastaavuutta tällä hetkellä vallitsevaan teoriatietoon. Tavoitteenamme oli myös tuottaa Endometrioosiyhdistys ry:lle, sen jäsenille ja hoitotyön ammattilaisille lisää tietoa endometrioosin ja vaihdevuosien yhteydestä toisiinsa. Opinnäytetyössämme käsittelimme endometrioosia sairautena, sen oireita, eri hoitomuotoja ja niiden vaikutusta naisen elämään. Lisäksi kävimme läpi vaihdevuosi-ikää ja siihen liittyviä hormonihoitaja sekä vaihtoehtoisia hoitomenetelmiä. Tutkimuksen lopussa analysoimme tutkimuksemme vastauksia, pohdimme omaa ammatillista kasvuamme, työn luotettavuutta ja eettisyyttä sekä koko opinnäytetyöprosessia. Opinnäytetyömme toteutettiin laadullisena tutkimuksena. Analysointimenetelmänä käytimme aineistolähtöistä sisällönanalyysimenetelmää. Opinnäytetyömme aineisto kerättiin Webropol-kyselynä endometrioosiyhdistyksen jäseniltä. Vastauksia saimme yhteensä kahdeksan. Johtopäätöksenä tutkimuksessa oli, että endometrioosin aiheuttamat fyysiset kivut helpottuvat vaihdevuosi-ikään tultaessa ja sen aikana. Fyysisten kipujen helpottumisella oli myös selkeä vaikutus sosiaalisen kanssakäymisen parantumiseen. Myös psyykkisen hyvinvoinnin osalta oli tulkittavissa kehitystä parempaan, kun sairauden käsittelyyn ja hyväksyntään oli ollut tarpeeksi aikaa. Vaihdevuodet olivat kuitenkin tuoneet uusia haasteita naisten psyykkiseen hyvinvointiin. Suurimpana haasteena koettiin hormoniepätasapaino. Asiasanat: endometrioosi, hoitomenetelmät, vaihtoehtolääkintä, estrogeeni, hyvinvointi, kipu, vaihdevuodet, kyselytutkimusPaavola, Sofia and Raivio, Noora. Endometriosis and menopause. 72 p., 2 appendices. Language: Finnish. Autumn 2013. Diaconia Univerisity of Applied Sciences. Degree programme in Nursing, Option in Health Care. Degree: Public Health Nurse / Option in Nursing. Degree: Nurse. Goal of this thesis was to investigate endometriosis and climacteric and how they affect each other. This thesis was made in co–operation with the Endometrioosi association. Results of this thesis were intended for Endometrioosi association and medical staff. This thesis processed endometriosis, symptoms and treatment and how these are related to climacteric and medication. Sources of material were used such as books, surveys, science articles and the Internet. This thesis also included our qualitative survey´s results, conclusions and discussions, as well as our survey´s ethic and reliability. This thesis was a qualitative survey. Method of analysis in this thesis was content analysis. Member of Endometrioosi association were asked to answer a Webropol questionnaire. The questionnaire gave eight replies. This thesis results were similar as in previous studies. However, some differences were found. The conclusion of this thesis was that women experienced physical pain during and after the climacteric. When the physical pain was milder, it also increased social welfare. Understanding and accepting the disease enhanced the women’s psychological well-being. Climacteric caused different kinds of challenges to women`s psychological well-being. The biggest challenge was the hormonal balance