Change of dopamine receptor mRNA expression in lymphocyte of schizophrenic patients

BACKGROUND: Though the dysfunction of central dopaminergic system has been proposed, the etiology or pathogenesis of schizophrenia is still uncertain partly due to limited accessibility to dopamine receptor. The purpose of this study was to define whether or not the easily accessible dopamine receptors of peripheral lymphocytes can be the peripheral markers of schizophrenia. RESULTS: 44 drug-medicated schizophrenics for more than 3 years, 28 drug-free schizophrenics for more than 3 months, 15 drug-naïve schizophrenic patients, and 31 healthy persons were enrolled. Sequential reverse transcription and quantitative polymerase chain reaction of the mRNA were used to investigate the expression of D3 and D5 dopamine receptors in peripheral lymphocytes. The gene expression of dopamine receptors was compared in each group. After taking antipsychotics in drug-free and drug-naïve patients, the dopamine receptors of peripheral lymphocytes were sequentially studied 2nd week and 8th week after medication. In drug-free schizophrenics, D3 dopamine receptor mRNA expression of peripheral lymphocytes significantly increased compared to that of controls and drug-medicated schizophrenics, and D5 dopamine receptor mRNA expression increased compared to that of drug-medicated schizophrenics. After taking antipsychotics, mRNA of dopamine receptors peaked at 2(nd) week, after which it decreases but the level was above baseline one at 8(th) week. Drug-free and drug-naïve patients were divided into two groups according to dopamine receptor expression before medications, and the group of patients with increased dopamine receptor expression had more severe psychiatric symptoms. CONCLUSIONS: These results reveal that the molecular biologically-determined dopamine receptors of peripheral lymphocytes are reactive, and that increased expression of dopamine receptor in peripheral lymphocyte has possible clinical significance for subgrouping of schizophrenis

The Effects of Tail Biopsy for Genotyping on Behavioral Responses to Nociceptive Stimuli

Removal of a small segment of tail at weaning is a common method used to obtain tissue for the isolation of genomic DNA to identify genetically modified mice. When genetically manipulated mice are used for pain research, this practice could result in confounding changes to the animals' responses to noxious stimuli. In this study, we sought to systematically investigate whether tail biopsy representative of that used in standard genotyping methods affects behavioral responses to a battery of tests of nociception. Wild-type littermate C57BL/6J and 129S6 female and male mice received either tail biopsies or control procedural handling at Day 21 after birth and were then tested at 6–9 weeks for mechanical and thermal sensitivity. C57BL/6J mice were also tested in the formalin model of inflammatory pain. In all tests performed (von Frey, Hargreaves, modified Randall Selitto, and formalin), C57BL/6J tail-biopsied animals' behavioral responses were not significantly different from control animals. In 129S6 animals, tail biopsy did not have a significant effect on behavioral responses in either sex to the von Frey and the modified Randall-Selitto tests of mechanical sensitivity. Interestingly, however, both sexes exhibited small but significant differences between tail biopsied and control responses to a radiant heat stimulus. These results indicate that tail biopsy for genotyping purposes has no effect on nocifensive behavioral responses of C57BL/6J mice, and in 129S6 mice, causes only a minor alteration in response to a radiant heat stimulus while other nocifensive behavioral responses are unchanged. The small effect seen is modality- and strain-specific

Structural, Metabolic, and Functional Brain Abnormalities as a Result of Prenatal Exposure to Drugs of Abuse: Evidence from Neuroimaging

Prenatal exposure to alcohol and stimulants negatively affects the developing trajectory of the central nervous system in many ways. Recent advances in neuroimaging methods have allowed researchers to study the structural, metabolic, and functional abnormalities resulting from prenatal exposure to drugs of abuse in living human subjects. Here we review the neuroimaging literature of prenatal exposure to alcohol, cocaine, and methamphetamine. Neuroimaging studies of prenatal alcohol exposure have reported differences in the structure and metabolism of many brain systems, including in frontal, parietal, and temporal regions, in the cerebellum and basal ganglia, as well as in the white matter tracts that connect these brain regions. Functional imaging studies have identified significant differences in brain activation related to various cognitive domains as a result of prenatal alcohol exposure. The published literature of prenatal exposure to cocaine and methamphetamine is much smaller, but evidence is beginning to emerge suggesting that exposure to stimulant drugs in utero may be particularly toxic to dopamine-rich basal ganglia regions. Although the interpretation of such findings is somewhat limited by the problem of polysubstance abuse and by the difficulty of obtaining precise exposure histories in retrospective studies, such investigations provide important insights into the effects of drugs of abuse on the structure, function, and metabolism of the developing human brain. These insights may ultimately help clinicians develop better diagnostic tools and devise appropriate therapeutic interventions to improve the condition of children with prenatal exposure to drugs of abuse

Cytoarchitectonic and chemoarchitectonic characterization of the prefrontal cortical areas in the mouse

This study describes cytoarchitectonic criteria to define the prefrontal cortical areas in the mouse brain (C57BL/6 strain). Currently, well-illustrated mouse brain stereotaxic atlases are available, which, however, do not provide a description of the distinctive cytoarchitectonic characteristics of individual prefrontal areas. Such a description is of importance for stereological, neuronal tracing, and physiological, molecular and neuroimaging studies in which a precise parcellation of the prefrontal cortex (PFC) is required. The present study describes and illustrates: the medial prefrontal areas, i.e., the infralimbic, prelimbic, dorsal and ventral anterior cingulate and Fr2 area; areas of the lateral PFC, i.e., the dorsal agranular insular cortical areas and areas of the ventral PFC, i.e., the lateral, ventrolateral, ventral and medial orbital areas. Each cytoarchitectonically defined boundary is corroborated by one or more chemoarchitectonic stainings, i.e., acetylcholine esterase, SMI32, SMI311, dopamine, parvalbumin, calbindin and myelin staining

Spatial Distribution of Calcium-Gated Chloride Channels in Olfactory Cilia

Background: In vertebrate olfactory receptor neurons, sensory cilia transduce odor stimuli into changes in neuronal membrane potential. The voltage changes are primarily caused by the sequential openings of two types of channel: a cyclic-nucleotide-gated (CNG) cationic channel and a calcium-gated chloride channel. In frog, the cilia are 25 to 200 mm in length, so the spatial distributions of the channels may be an important determinant of odor sensitivity. Principal Findings: To determine the spatial distribution of the chloride channels, we recorded from single cilia as calcium was allowed to diffuse down the length of the cilium and activate the channels. A computational model of this experiment allowed an estimate of the spatial distribution of the chloride channels. On average, the channels were concentrated in a narrow band centered at a distance of 29 % of the ciliary length, measured from the base of the cilium. This matches the location of the CNG channels determined previously. This non-uniform distribution of transduction proteins is consistent with similar findings in other cilia. Conclusions: On average, the two types of olfactory transduction channel are concentrated in the same region of the cilium

Analysis of Area-Specific Expression Patterns of RORbeta, ER81 and Nurr1 mRNAs in Rat Neocortex by Double In Situ Hybridization and Cortical Box Method

BACKGROUND: The mammalian neocortex is subdivided into many areas, each of which exhibits distinctive lamina architecture. To investigate such area differences in detail, we chose three genes for comparative analyses, namely, RORbeta, ER81 and Nurr1, mRNAs of which have been reported to be mainly expressed in layers 4, 5 and 6, respectively. To analyze their qualitative and quantitative coexpression profiles in the rat neocortex, we used double in situ hybridization (ISH) histochemistry and cortical box method which we previously developed to integrate the data of different staining and individuals in a standard three-dimensional space. PRINCIPAL FINDINGS: Our new approach resulted in three main observations. First, the three genes showed unique area distribution patterns that are mostly complementary to one another. The patterns revealed by cortical box method matched well with the cytoarchitectonic areas defined by Nissl staining. Second, at single cell level, RORbeta and ER81 mRNAs were coexpressed in a subpopulation of layer 5 neurons, whereas Nurr1 and ER81 mRNAs were not colocalized. Third, principal component analysis showed that the order of hierarchical processing in the cortex correlates well with the expression profiles of these three genes. Based on this analysis, the dysgranular zone (DZ) in the somatosensory area was considered to exhibit a profile of a higher order area, which is consistent with previous proposal. CONCLUSIONS/SIGNIFICANCE: The tight relationship between the expression of the three layer specific genes and functional areas were revealed, demonstrating the usefulness of cortical box method in the study on the cerebral cortex. In particular, it allowed us to perform statistical evaluation and pattern matching, which would become important in interpreting the ever-increasing data of gene expression in the cortex

Dopamine, affordance and active inference.

The role of dopamine in behaviour and decision-making is often cast in terms of reinforcement learning and optimal decision theory. Here, we present an alternative view that frames the physiology of dopamine in terms of Bayes-optimal behaviour. In this account, dopamine controls the precision or salience of (external or internal) cues that engender action. In other words, dopamine balances bottom-up sensory information and top-down prior beliefs when making hierarchical inferences (predictions) about cues that have affordance. In this paper, we focus on the consequences of changing tonic levels of dopamine firing using simulations of cued sequential movements. Crucially, the predictions driving movements are based upon a hierarchical generative model that infers the context in which movements are made. This means that we can confuse agents by changing the context (order) in which cues are presented. These simulations provide a (Bayes-optimal) model of contextual uncertainty and set switching that can be quantified in terms of behavioural and electrophysiological responses. Furthermore, one can simulate dopaminergic lesions (by changing the precision of prediction errors) to produce pathological behaviours that are reminiscent of those seen in neurological disorders such as Parkinson's disease. We use these simulations to demonstrate how a single functional role for dopamine at the synaptic level can manifest in different ways at the behavioural level

Endpoints in pediatric pain studies

Assessing pain intensity in (preverbal) children is more difficult than in adults. Tools to measure pain are being used as primary endpoints [e.g., pain intensity, time to first (rescue) analgesia, total analgesic consumption, adverse effects, and long-term effects] in studies on the effects of analgesic drugs. Here, we review current and promising new endpoints used in pediatric pain assessment studies

Adult-Age Inflammatory Pain Experience Enhances Long-Term Pain Vigilance in Rats

Background: Previous animal studies have illustrated a modulatory effect of neonatal pain experience on subsequent painrelated behaviors. However, the relationship between chronic pain status in adulthood and future pain perception remains unclear. Methodology/Principal Findings: In the current study, we investigated the effects of inflammatory pain experience on subsequent formalin-evoked pain behaviors and fear conditioning induced by noxious stimulation in adult rats. Our results demonstrated an increase of the second but not the first phase of formalin-induced pain behaviors in animals with a history of inflammatory pain that have recovered. Similarly, rats with persistent pain experience displayed facilitated acquisition and prolonged retention of pain-related conditioning. These effects of prior pain experience on subsequent behavior were prevented by repeated morphine administration at an early stage of inflammatory pain. Conclusions/Significance: These results suggest that chronic pain diseases, if not properly and promptly treated, may have a long-lasting impact on processing and perception of environmental threats. This may increase the susceptibility of patients to subsequent pain-related disorders, even when chronic pain develops in adulthood. These data highlight th