Withdrawal exposure with withdrawal regulation training for smoking cessation: a randomized controlled pilot trial.

Introduction: Although withdrawal processes form a key motivational basis for cigarette use, smoking cessation treatments appear to exert only modest effects on withdrawal. One treatment option for further reducing withdrawal severity would be to provide smokers with withdrawal regulation training. The objective of this study was to pilot a smoking cessation intervention comprising withdrawal exposure with withdrawal regulation training.

Tyrosine hydroxylase localization in the nucleus accumbens in schizophrenia.

The nucleus accumbens (NAcc) has been implicated in schizophrenia (SZ) pathology, based on antipsychotic action therein. However, recent imaging studies suggest that the NAcc may not be a locus of dopamine dysregulation in SZ. This study examined postmortem human tissue to determine if abnormalities are present in dopamine synthesis in the NAcc in SZ.

The Adverse Effects of Motherhood on Substance Use Treatment Program Outcomes Among Adolescent Women.

Objectives: Adolescent mothers have differing risks and responsibilities compared to adolescent women without children that may impact substance use treatment. This study sought to describe characteristics of adolescent women in a substance use treatment program and determine the effect of adolescent motherhood on treatment program outcomes.

Methods: Data were collected from standardized interviews of female adolescents in a case management criminal justice diversion program for substance-using adolescents and adults.

Inflammatory neuropathies: pathology, molecular markers and targets for specific therapeutic intervention.

Inflammatory neuropathies encompass groups of heterogeneous disorders characterized by pathogenic immune-mediated hematogenous leukocyte infiltration of peripheral nerves, nerve roots or both, with resultant demyelination or axonal degeneration or both. Inflammatory neuropathies may be divided into three major disease categories: Guillain-Barré syndrome (particularly the acute inflammatory demyelinating polyradiculoneuropathy variant), chronic inflammatory demyelinating polyradiculoneuropathy and nonsystemic vasculitic neuropathy (or peripheral nerve vasculitis). Despite major advances in molecular biology, pathology and genetics, the pathogenesis of these disorders remains elusive.

The Minority Are the Majority: Today's Smoker.

The smoking rate in America has decreased substantially over the past 50 years; however, this decrease is disproportionately accounted for by the high quit rates and lower initiation rates of middle class smokers with no medical or psychiatric comorbidities. The majority of modern smokers' cessations efforts are complicated by one or more forms of "disadvantage, " such as social, economic, legal, or psychiatric problems. The next step in reducing the national smoking prevalence is to reduce the prevalence in the most neglected portions of the population.

Pathogenetic and therapeutic applications of microRNAs in major depressive disorder.

As a class of noncoding RNAs, microRNAs (miRNAs) regulate gene expression by inhibiting translation of messenger RNAs. These miRNAs have been shown to play a critical role in higher brain functioning and actively participate in synaptic plasticity. Pre-clinical evidence demonstrates that expression of miRNAs is differentially altered during stress.

Greater freedom of speech on Web 2.0 correlates with dominance of views linking vaccines to autism.

Introduction: It is suspected that Web 2.0 web sites, with a lot of user-generated content, often support viewpoints that link autism to vaccines.

Methods: We assessed the prevalence of the views supporting a link between vaccines and autism online by comparing YouTube, Google and Wikipedia with PubMed.

An accurate method for the quantification of cytochrome C oxidase in tissue sections.

Cytochrome oxidase (COX) is the enzyme that constitutes the last step of the mitochondrial electron transport chain for the production of ATP. Measurement of COX activity can be achieved by histochemistry, thus providing information about the metabolic status of the brain. Brain regions with high metabolism will present high COX activity in histochemistry assays and vice versa.

Dual use of immunohistochemistry for film densitometry and light microscopy.

In the present study, we applied the principles of immunoblotting and light microscopy immunohistochemistry to develop a combined methodology that allows obtaining optical density data in films, as well as morphological and protein distribution data on slides using the same brain tissue section, thus maximizing the data obtained from a single sample. This is especially important when experiments are performed using very valuable or unique tissue samples, which is a very common case in the study of the human brain. The ideal methodology should combine the possibility of measuring levels of expression of a marker, and the capability to map accurately the distribution of that marker in the region of interest.

Regulation of cell survival mechanisms in Alzheimer's disease by glycogen synthase kinase-3.

A pivotal role has emerged for glycogen synthase kinase-3 (GSK3) as an important contributor to Alzheimer's disease pathology. Evidence for the involvement of GSK3 in Alzheimer's disease pathology and neuronal loss comes from studies of GSK3 overexpression, GSK3 localization studies, multiple relationships between GSK3 and amyloid β-peptide (Aβ), interactions between GSK3 and the microtubule-associated tau protein, and GSK3-mediated apoptotic cell death. Apoptotic signaling proceeds by either an intrinsic pathway or an extrinsic pathway.

Lithium ameliorates altered glycogen synthase kinase-3 and behavior in a mouse model of fragile X syndrome.

Fragile X syndrome (FXS), the most common form of inherited mental retardation and a genetic cause of autism, results from mutated fragile X mental retardation-1 (Fmr1). This study examined the effects on glycogen synthase kinase-3 (GSK3) of treatment with a metabotropic glutamate receptor (mGluR) antagonist, MPEP, and the GSK3 inhibitor, lithium, in C57Bl/6 Fmr1 knockout mice. Increased mGluR signaling may contribute to the pathology of FXS, and the mGluR5 antagonist MPEP increased inhibitory serine-phosphorylation of brain GSK3 selectively in Fmr1 knockout mice but not in wild-type mice.

Inhibition of lysosomal functions reduces proteasomal activity.

Protein accumulation and aggregation are signatures of several major neurodegenerative diseases. Proteasomal- and lysosomal-mediated protein degradation pathways are the two major pathways for intracellular protein degradation. Cross-regulation between these two pathways may be important for protein homeostasis.

Glycogen synthase kinase-3 regulates microglial migration, inflammation, and inflammation-induced neurotoxicity.

Microglia play a prominent role in the brain's inflammatory response to injury or infection by migrating to affected locations, secreting inflammatory molecules, and phagocytosing damaged tissue. However, because severe or chronic neuroinflammation exacerbates many neurological conditions, controlling microglia actions may provide therapeutic benefits in a diverse array of diseases. Since glycogen synthase kinase-3 (GSK3) promotes inflammatory responses in peripheral immune cells, we investigated if inhibitors of GSK3 attenuated microglia responses to inflammatory stimuli.

Forkhead box, class O transcription factors in brain: regulation and behavioral manifestation.

Background: The mammalian forkhead box, class O (FoxO) transcription factors function to regulate diverse physiological processes. Emerging evidence that both brain-derived neurotrophic factor (BDNF) and lithium suppress FoxO activity suggests a potential role of FoxOs in regulating mood-relevant behavior. Here, we investigated whether brain FoxO1 and FoxO3a can be regulated by serotonin and antidepressant treatment and whether their genetic deletion affects behaviors.

A new use for long-term frozen brain tissue: golgi impregnation.

The study of dendritic spine shape and number has become a standard in the analysis of synaptic transmission anomalies since a considerable number of neuropsychiatric and neurological diseases have their foundation in alterations in these structures. One of the best ways to study possible alterations of dendritic spines is the use of Golgi impregnation. Although usually the Golgi method implies the use of fresh or fixed tissue, here we report the use of Golgi-Cox for the staining of human and animal brain tissue kept frozen for long periods of time.

Neuroleptics and animal models: feasibility of oral treatment monitored by plasma levels and receptor occupancy assays.

The administration of neuroleptics in animal models has been extensively reported and plays an important role in the study of schizophrenia. Our study was designed to address the following questions: (1) Is it possible to achieve steady-state receptor occupancy levels administering neuroleptics in drinking water? (2) Is there an appropriate dose to obtain clinically comparable receptor occupancies? (3) Is there a correlation between plasma drug levels and receptor occupancy? Thus, we tested three neuroleptic drugs administered in drinking water for 7 days. Plasma drug levels were measured, and in vivo receptor occupancy assays were performed in order to determine peak and trough dopamine D(2) receptor occupancies in striatal brain samples.

Tau is hyperphosphorylated at multiple sites in mouse brain in vivo after streptozotocin-induced insulin deficiency.

Deficient signaling by insulin, as occurs in diabetes, is associated with impaired brain function, and diabetes is associated with an increased prevalence of Alzheimer's disease. One of the hallmark pathological characteristics of Alzheimer's disease is the presence of neurofibrillary tangles containing hyperphosphorylated tau, a microtubule-associated protein. Therefore, we tested the hypothesis that insulin depletion caused by administration of streptozotocin may cause tau hyperphosphorylation in mouse brain by using site-specific phosphorylation-dependent tau antibodies to obtain precise identification of the phosphorylation of tau on individual residues.

The role of tau phosphorylation and cleavage in neuronal cell death.

The microtubule-associated protein tau is the primary component of the intracellular filamentous deposits found in Alzheimer's disease (AD) brain and also in a family of neurodegenerative diseases called 'tauopathies', where tau pathology is the primary, defining characteristic with little or no amyloid-beta (Abeta) pathology. It has been demonstrated that tau modifications such as hyperphosphorylation and truncation might be important events in the process leading to tau intracellular aggregation and neuronal cell death. The discovery of tau gene mutations in frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) reinforced the predominant role attributed to tau proteins in the pathogenesis of neurodegenerative disorders.

Glycogen synthase kinase-3 (GSK3) in psychiatric diseases and therapeutic interventions.

Glycogen synthase kinase-3 (GSK3) has recently been linked to mood disorders and schizophrenia, and the neurotransmitter systems and therapeutic treatments associated with these diseases. GSK3 is a widely influential enzyme that is capable of phosphorylating, and thereby regulating, over forty known substrates. Four mechanisms regulating GSK3 (phosphorylation, protein complexes, localization, and substrate phosphorylation) combine to provide substrate-specific regulation of the actions of GSK3.

The protein phosphatase-1/inhibitor-2 complex differentially regulates GSK3 dephosphorylation and increases sarcoplasmic/endoplasmic reticulum calcium ATPase 2 levels.

The ubiquitously expressed protein glycogen synthase kinase-3 (GSK3) is constitutively active, however its activity is markedly diminished following phosphorylation of Ser21 of GSK3alpha and Ser9 of GSK3beta. Although several kinases are known to phosphorylate Ser21/9 of GSK3, for example Akt, relatively much less is known about the mechanisms that cause the dephosphorylation of GSK3 at Ser21/9. In the present study KCl-induced plasma membrane depolarization of SH-SY5Y cells, which increases intracellular calcium concentrations caused a transient decrease in the phosphorylation of Akt at Thr308 and Ser473, and GSK3 at Ser21/9.

Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics.

Deciphering what governs inflammation and its effects on tissues is vital for understanding many pathologies. The recent discovery that glycogen synthase kinase-3 (GSK3) promotes inflammation reveals a new component of its well-documented actions in several prevalent diseases which involve inflammation, including mood disorders, Alzheimer's disease, diabetes, and cancer. Involvement in such disparate conditions stems from the widespread influences of GSK3 on many cellular functions, with this review focusing on its regulation of inflammatory processes.

The paradoxical pro- and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways.

Few things can be considered to be more important to a cell than its threshold for apoptotic cell death, which can be modulated up or down, but rarely in both directions, by a single enzyme. Therefore, it came as quite a surprise to find that one enzyme, glycogen synthase kinase-3 (GSK3), has the perplexing capacity to either increase or decrease the apoptotic threshold. These apparently paradoxical effects now are known to be due to GSK3 oppositely regulating the two major apoptotic signaling pathways.

Cellular stress increases RGS2 mRNA and decreases RGS4 mRNA levels in SH-SY5Y cells.

Modulation of the expression of regulator of G-protein signaling (RGS) proteins is a major mechanism used to modulate their actions. Besides control by second messengers, the expression of RGS proteins, particularly RGS2, can be regulated by cell stress. Because RGS2 and RGS4 expression can be regulated by the cell cycle, we examined if cell cycle signals are involved in their regulation following stress.

Akt1 is dynamically modified with O-GlcNAc following treatments with PUGNAc and insulin-like growth factor-1.

The Ser/Thr kinase Akt1 is activated by growth factors subsequent to its phosphorylation on Thr308 and Ser473. In the present study, Akt1 was found to be constitutively modified with O-GlcNAc. Treatment of SH-SY5Y cells with O(2-acetamido-2-deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc), which inhibits the enzymatic removal of O-GlcNAc from proteins, increased cytosolic O-GlcNAc-Akt1 levels.