Deficits in odor discrimination versus odor identification in patients with schizophrenia and negative correlations with GABAergic and DNA methyltransferase mRNAs in lymphocytes.

Introduction: People with schizophrenia have been reported to show deficits in tests of olfactory function. DNA methylation and GABAergic input have been implicated in biochemical processes controlling odor in animal studies, but this has not been investigated in human studies.

Methods: In a study of measures of DNA methylation and GABAergic mRNAs in lymphocytes, we also measured odor identification and discrimination with the Sniffin' Sticks battery in 58 patients with chronic schizophrenia (CSZ) and 48 controls.

Changes in Expression of DNA-Methyltransferase and Cannabinoid Receptor mRNAs in Blood Lymphocytes After Acute Cannabis Smoking.

Background: Cannabis use is a component risk factor for the manifestation of schizophrenia. The biological effects of cannabis include effects on epigenetic systems, immunological parameters, in addition to changes in cannabinoid receptors 1 and 2, that may be associated with this risk. However, there has been limited study of the effects of smoked cannabis on these biological effects in human peripheral blood cells.

Gene Expression Of Methylation Cycle And Related Genes In Lymphocytes And Brain Of Patients With Schizophrenia And Non-Psychotic Controls.

Some of the biochemical abnormalities underlying schizophrenia, involve differences in methylation and methylating enzymes, as well as other related target genes. We present results of a study of differences in mRNA expression in peripheral blood lymphocytes (PBLs) and post-mortem brains of chronic schizophrenics (CSZ) and non-psychotic controls (NPC), emphasizing the differential effects of sex and antipsychotic drug treatment on mRNA findings. We studied mRNA expression in lymphocytes of 61 CSZ and 49 NPC subjects using qPCR assays with TaqMan probes to assess levels of DNMT, TET, GABAergic, NR3C1, BDNF mRNAs, and several additional targets identified in a recent RNA sequence analysis.

Racemization in Post-Translational Modifications Relevance to Protein Aging, Aggregation and Neurodegeneration: Tip of the Iceberg.

Homochirality of DNA and prevalent chirality of free and protein-bound amino acids in a living organism represents the challenge for modern biochemistry and neuroscience. The idea of an association between age-related disease, neurodegeneration, and racemization originated from the studies of fossils and cataract disease. Under the pressure of new results, this concept has a broader significance linking protein folding, aggregation, and disfunction to an organism's cognitive and behavioral functions.

Chiral Interface of Amyloid Beta (Aβ): Relevance to Protein Aging, Aggregation and Neurodegeneration.

Biochirality is the subject of distinct branches of science, including biophysics, biochemistry, the stereochemistry of protein folding, neuroscience, brain functional laterality and bioinformatics. At the protein level, biochirality is closely associated with various post-translational modifications (PTMs) accompanied by the non-equilibrium phase transitions (PhTs ). PTMs support the dynamic balance of the prevalent chirality of enzymes and their substrates.

Varenicline Effects on Smoking, Cognition, and Psychiatric Symptoms in Schizophrenia: A Double-Blind Randomized Trial.

Unlabelled: Schizophrenic patients have a high rate of smoking and cognitive deficits which may be related to a decreased number or responsiveness of nicotinic receptors in their brains. Varenicline is a partial nicotinic agonist which is effective as an antismoking drug in cigarette smokers, although concerns have been raised about potential psychiatric side-effects. We conducted a double-blind placebo controlled study in 87 schizophrenic smokers to evaluate the effects of varenicline (2 mg/day) on measures of smoking, cognition, psychiatric symptoms, and side-effects in schizophrenic patients who were cigarette smokers.

Effects of transcranial direct current stimulation (tDCS) on cognition, symptoms, and smoking in schizophrenia: A randomized controlled study.

Schizophrenia is characterized by cognitive deficits which persist after acute symptoms have been treated or resolved. Transcranial direct current stimulation (tDCS) has been reported to improve cognition and reduce smoking craving in healthy subjects but has not been as carefully evaluated in a randomized controlled study for these effects in schizophrenia. We conducted a randomized double-blind, sham-controlled study of the effects of 5 sessions of tDCS (2 milliamps for 20minutes) on cognition, psychiatric symptoms, and smoking and cigarette craving in 37 outpatients with schizophrenia or schizoaffective disorder who were current smokers.

DNA-methylation gene network dysregulation in peripheral blood lymphocytes of schizophrenia patients.

The epigenetic dysregulation of the brain genome associated with the clinical manifestations of schizophrenia (SZ) includes altered DNA promoter methylation of several candidate genes. We and others have reported that two enzymes that belong to the DNA-methylation/demethylation network pathways-DNMT1 (DNA-methyltransferase) and ten-eleven translocator-1(TET1) methylcytosine deoxygenase are abnormally increased in corticolimbic structures of SZ postmortem brain. The objective of this study was to investigate whether the expression of these components of the DNA-methylation-demethylation pathways known to be altered in the brain of SZ patients are also altered in peripheral blood lymphocytes (PBL).

Nicotine: alcohol reward interactions.

It is well established that the continued intake of drugs of abuse is reinforcing-that is repeated consumption increases preference. This has been shown in some studies to extend to other drugs of abuse; use of one increases preference for another. In particular, the present review deals with the interaction of nicotine and alcohol as it has been shown that smoking is a risk factor for alcoholism and alcohol use is a risk factor to become a smoker.

Effect of nicotine and cocaine on neurofilaments and receptors in whole brain tissue and synaptoneurosome preparations.

The present study examined the effect of repeated nicotine and cocaine administration on the expression of neurofilament proteins (NF-L, -M, and -H), actin, and on alpha-7 nicotinic, dopamine D1 and NMDA NR1 receptors in brain. Whole tissue homogenate and synaptoneurosomal preparations from hippocampus, striatum and cortex were assayed. C57BL/6By mice were treated for 2 weeks with a daily injection of nicotine (0.

Heterogeneity of reward mechanisms.

The finding that many drugs that have abuse potential and other natural stimuli such as food or sexual activity cause similar chemical changes in the brain, an increase in extracellular dopamine (DA) in the shell of the nucleus accumbens (NAccS), indicated some time ago that the reward mechanism is at least very similar for all stimuli and that the mechanism is relatively simple. The presently available information shows that the mechanisms involved are more complex and have multiple elements. Multiple brain regions, multiple receptors, multiple distinct neurons, multiple transmitters, multiple transporters, circuits, peptides, proteins, metabolism of transmitters, and phosphorylation, all participate in reward mechanisms.

Differences between nicotine and cocaine-induced conditioned place preferences.

In previous studies, we found differences between nicotine and cocaine-induced changes in the levels of neurotransmitters in various brain areas, which suggested differences in their reward - preference mechanisms. The present study was based on the idea that drug preference is modulated by a number of different factors, among them several neurotransmitters and their receptors, and antagonists of specific receptors will influence preference. We also assumed that the factors (components of reward mechanisms) involved are different in the case of different drugs.

The effects of acetaldehyde on nicotine-induced transmitter levels in young and adult brain areas.

The aim of the present study was to examine the effect of acetaldehyde administration on neurotransmitters in the presence of nicotine in brain areas associated with cognition and reward. We assayed these effects via microdialysis in conscious freely moving male Sprague-Dawley rats. It was reported that low doses of acetaldehyde enhance nicotine self-administration in young, but not in adult rats.

An upregulation of DNA-methyltransferase 1 and 3a expressed in telencephalic GABAergic neurons of schizophrenia patients is also detected in peripheral blood lymphocytes.

Several lines of schizophrenia (SZ) research suggest that a functional downregulation of the prefrontal cortex GABAergic neuronal system is mediated by a promoter hypermethylation, presumably catalyzed by an increase in DNA-methyltransferase-1 (DNMT-1) expression. This promoter hypermethylation may be mediated not only by DNMT-1 but also by an entire family of de novo DNA-methyltransferases, such as DNA-methyltransferase-3a (DNMT-3a) and -3b (DNMT-3b). To verify the existence of an overexpression of DNMT-3a and DNMT-3b in the brain of schizophrenia patients (SZP), we compared their mRNA expression in Brodmann's area 10 (BA10) and in the caudate nucleus and putamen obtained from the Harvard Brain Tissue Resource Center (Belmont, MA) from both nonpsychiatric subjects (NPS) and SZP.

GABAB/NMDA receptor interaction in the regulation of extracellular dopamine levels in rodent prefrontal cortex and striatum.

Deficits in N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission may underlie dopaminergic hyperactivity in schizophrenia. Dysregulation of the GABAergic system has also been implicated. In this study we investigated a role for GABA(B) receptors as an intermediate step in the pathway leading from NMDAR stimulation to DA regulation.

Cognitive and antismoking effects of varenicline in patients with schizophrenia or schizoaffective disorder.

Objective: Varenicline has been shown to be an effective anti-smoking treatment in smokers without identified psychiatric illness, and the drug's pharmacology suggests possibilities of pro-cognitive effects. However, recent reports suggest varenicline may have the potential for important psychiatric side-effects in some people. We present the first prospective quantitative data on the effects of varenicline on cognitive function, cigarette smoking, and psychopathology in a small sample of schizophrenic patients.

Nicotine-induced monoamine neurotransmitter changes in the brain of young rats.

A number of studies in various species including man indicated a greater risk of drug preference and addictive behavior in young as compared to adults. Such age dependent preference was also found with nicotine. To examine possible mechanisms for this difference in our continuing study of reward mechanisms, we compared nicotine-induced neurotransmitter changes in the brain regions of adult and young Sprague-Dawley rats, assaying the transmitters via microdialysis in conscious freely moving animals.

Interrelated mechanisms in reward and learning.

This brief review is focused on recent work in our laboratory, in which we assayed nicotine-induced neurotransmitter changes, comparing it to changes induced by other compounds and examined the receptor systems and their interactions that mediate the changes. The primary aim of our studies is to examine the role of neurotransmitter changes in reward and learning processes. We find that these processes are interlinked and interact in that reward-addiction mechanisms include processes of learning and learning-memory mechanisms include processes of reward.

Food reward-induced neurotransmitter changes in cognitive brain regions.

Recent evidence indicates that mechanisms involved in reward and mechanisms involved in learning interact, in that reward includes learning processes and learning includes reward processes. In spite of such interactions, reward and learning represent distinct functions. In the present study, as part of an examination of the differences in learning and reward mechanisms, it was assumed that food principally affects reward mechanisms.

The effects of glutamate and GABA receptor antagonists on nicotine-induced neurotransmitter changes in cognitive areas.

In the present study, we tested the effects of glutamate and GABA receptor antagonists on nicotine-induced neurotransmitter changes in the hippocampal (dorsal and ventral) and cortical (medial temporal and prefrontal) brain areas of conscious freely moving rats via microdialysis. Both the antagonists and nicotine were administered intracerebrally. The antagonists tested were NMDA, AMPA-kainate, and metabotropic glutamate receptor subtype antagonists (MK801, CNQX, and LY 341495, respectively) and GABA(A) and GABA(B) receptor subtype antagonists (bicuculline and hydroxysaclofen, respectively).