The level of cerebral DC potentials in children with attention deficit-hyperactivity disorder

The level of cerebral DC potentials (LDCPs) was studied in 92 healthy children aged seven to eight years and 39 age-matched children with attention deficit-hyperactivity disorder. Analysis of the distribution of the LDCPs was carried out by mapping the DC potentials obtained using monopolar measurement and calculating deviations in each of the derivations from the average values recorded in all the regions of the head. The characteristic features of the distribution of the LDCPs in children aged seven to eight years with attention deficit-hyperactivity disorder, such as a decrease in the total DC potential value, a sharp decrease in the level of DC potentials in the frontal region, a decrease in their relations with the LDCP of other cerebral structures, and changes in the interhemispheric asymmetry were found.     

High vitamin A intake during pregnancy modifies dopaminergic reward system and decreases preference for sucrose in Wistar rat offspring

High multivitamin (HV) content in gestational diets has long-term metabolic effects in rat offspring. These changes are associated with in utero modifications of gene expression in hypothalamic food intake regulation. However, the role of fat-soluble vitamins in mediating these effects has not been explored. Vitamin A is a plausible candidate due to its role in gene methylation. Vitamin A intake above requirements during pregnancy affects the development of neurocircuitries involved in food intake and reward regulation. Pregnant Wistar rats were fed AIN-93G diets with the following content: recommended multivitamins (1-fold multivitamins: RV), high vitamin A (10-fold vitamin A: HA) or HV with only recommended vitamin A (10-fold multivitamins, 1-fold vitamin A: HVRA). Body weight, food intake and preference, mRNA expression and DNA methylation of hippocampal dopamine-related genes were assessed in male offspring brains at different developmental windows: birth, weaning and 14 weeks postweaning. HA offspring had changes in dopamine-related gene expression at all developmental windows and DNA hypermethylation in the dopamine receptor 2 promoter region compared to RV offspring. Furthermore, HA diet lowered sucrose preference but had no effect on body weight and expression of hypothalamic genes. In contrast, HVRA offspring showed only at adulthood changes in expression of hippocampal genes and a modest effect on hypothalamic genes. High vitamin A intake alone in gestational diets has long-lasting programming effects on the dopaminergic system that are further translated into decreased sucrose preference but not food intake.     

Cigarette smoke and dopaminergic system

It has been reported that there is an ameliorative effect of cigarette smoking on certain neurological responses and neurodegenerative disorders. The purpose of this study was to examine the neurochemical and neurobehavioral response of cigarette smoke (CS) in the adult male guinea pig brain. Both acute and chronic CS exposure enhanced locomotor behavior and caused a decrease in midbrain dopamine (DA) levels and corresponding increase in 3,4-dihydroxyphenylacetic acid (DOPAC) levels. In addition, CS caused a significant increase in the protein levels of the dopamine D1 and D2 receptors. CS caused a significant increase in the binding capacity of the D1 receptor and a significant decrease in the binding capacity of D2. Furthermore, CS caused a significant increase in the binding capacity of the dopamine transporter (DAT). The mechanism by which cigarette smoke exposure increases locomotor activity remains to be elucidated but may include modulation of dopamine neuron activity that emerges after repeated direct smoke exposure.     

Pyrethroids and the striatal dopaminergic system in vivo

1. Type I (permethrin and allethrin) or type II (cypermethrin and fenvalerate) pyrethroids caused 23-37% increases in the striatal content of the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC). 2. Toxicity symptoms and increases in DOPAC were associated with higher brain concentrations for type I (2.6-5.8 micrograms/gm) than type II pyrethroids (0.4-0.6 micrograms/gm). 3. No specific difference in the interaction between type I and II pyrethroids and the striatal dopaminergic system were recognized.     

肥胖与神经调节

机体的能量获取和能量消耗,在一定时期内,是处于一种相对平衡的状态;获取的能量等于消耗的能量,在这一调节中,神经系统起有重要的作用,如果获取的能量（进食）大于消耗的能量,将产生肥胖,由于很多疾病与肥胖的产生有密切的关系,因此,对能量平衡调节的研究越来越受到重视。本文简要总结了近年来这方面的研究进展,内容包括：（１）饱感的产生与进食的终止;（２）机体脂肪储存信号与进食的调节;（３）与进食有关的中枢;（４）下丘脑中传递与进食有关信息的一级和二级神经元;（５）与临床的关系。     

雷特综合征与多巴胺系统功能障碍

雷特综合征(Rett syndrome)属于神经发育障碍类疾病,主要由X性染色体上mecp2基因突变所致,患者多数为女孩。临床症状于出生后6~18个月逐渐显现,主要表现为头部发育缓慢,已获得的语言及手部目的性运动技能消退,智力障碍,呼吸功能障碍及自闭倾向等。多巴胺系统的功能包括运动调节、奖赏学习、情感、内分泌调控以及药物成瘾等多个方面。由于多巴胺系统在运动和精神方面与雷特综合征部分临床症状存在表面相关性,早期有学者根据临床特征提出雷特综合征患者可能存在多巴胺系统功能障碍,但两者之间是否具有实质性的内在联系以及mecp2基因是否会通过影响多巴胺系统导致相关临床症状是目前雷特综合征研究的一个热点。本文将针对雷特综合征与多巴胺系统功能障碍的相关研究进展作一综述。     

Motivation and timing: clues for modeling the reward system

There is growing evidence that a change in reward magnitude or value alters interval timing, indicating that motivation and timing are not independent processes as was previously believed. The present paper reviews several recent studies, as well as presenting some new evidence with further manipulations of reward value during training vs. testing on a peak procedure. The combined results cannot be accounted for by any of the current psychological timing theories. However, in examining the neural circuitry of the reward system, it is not surprising that motivation has an impact on timing because the motivation/valuation system directly interfaces with the timing system. A new approach is proposed for the development of the next generation of timing models, which utilizes knowledge of the neuroanatomy and neurophysiology of the reward system to guide the development of a neurocomputational model of the reward system. The initial foundation along with heuristics for proceeding with developing such a model is unveiled in an attempt to stimulate new theoretical approaches in the field.     

Differentiation of noradrenergic and dopaminergic neurons in the cardiovascular system

Dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and norepinephrine (NE) are present in the rat cardiovascular system. All of the catechols can be partially depleted by administering 6-hydroxydopamine (6-HODA). When animals are pretreated with desipramine before 6-HODA, there is a selective partial depletion of DA and DOPAC. NE can be partially depleted with minimal effects on DA and DOPAC by administering N-(2-chloroethyl)N-ethyl-2-bromobenzylamine (DSP-4). These results are consistent with the hypothesis that independent dopaminergic and noradrenergic elements are present in the rat cardiovascular system and that DA is not solely a precursor for NE. NE, DA and DOPAC were assayed in human vessels and the pattern of distribution of the catechols is consistent with the results reported for animals.     

Food reward, hyperphagia, and obesity

Given the unabated obesity problem, there is increasing appreciation of expressions like "my eyes are bigger than my stomach," and recent studies in rodents and humans suggest that dysregulated brain reward pathways may be contributing not only to drug addiction but also to increased intake of palatable foods and ultimately obesity. After describing recent progress in revealing the neural pathways and mechanisms underlying food reward and the attribution of incentive salience by internal state signals, we analyze the potentially circular relationship between palatable food intake, hyperphagia, and obesity. Are there preexisting individual differences in reward functions at an early age, and could they be responsible for development of obesity later in life? Does repeated exposure to palatable foods set off a cascade of sensitization as in drug and alcohol addiction? Are reward functions altered by secondary effects of the obese state, such as increased signaling through inflammatory, oxidative, and mitochondrial stress pathways? Answering these questions will significantly impact prevention and treatment of obesity and its ensuing comorbidities as well as eating disorders and drug and alcohol addiction.     

A systematic review of circadian function,chronotype and chronotherapy in attention deficit hyperactivity disorder

Reports of sleep disturbances in attention deficit hyperactivity disorder (ADHD) are common in both children and adults; however, the aetiology of such disturbances is poorly understood. One potentially important mechanism which may be implicated in disrupted sleep in ADHD is the circadian clock, a known key regulator of the sleep/wake cycle. In this systematic review, we analyse the evidence for circadian rhythm changes associated with ADHD, as well as assessing evidence for therapeutic approaches involving the circadian clock in ADHD. We identify 62 relevant studies involving a total of 4462 ADHD patients. We find consistent evidence indicating that ADHD is associated with more eveningness/later chronotype and with phase delay of circadian phase markers such as dim light melatonin onset and delayed sleep onset. We find that there is evidence that melatonin treatment may be efficacious in addressing ADHD-related sleep problems, although there are few studies to date addressing other chronotherapeutic approaches in ADHD. There are only a small number of genetic association studies which report linkages between polymorphisms in circadian clock genes and ADHD symptoms. In conclusion, we find that there is consistent evidence for circadian rhythm disruption in ADHD and that such disruption may present a therapeutic target that future ADHD research might concentrate explicitly on.     

A theory of cerebral learning regulated by the reward system

Hypothetical mechanisms of the neocorticohippocampal system are presented. Neurophysiological and neuroanatomical findings concerning the system are integrated to demonstrate how animals associate sensory stimuli with rewarding actions: (1) cortical plasticity regulated by cholinergic/noradrenergic inputs from the hypothalamic reward system reinforces association connections between the most activated columns in the cortex; (2) the repetitive reinforcement forms association pathways connecting sensory cortical columns activated by the stimuli with motor cortical columns producing the rewarding actions; (3) after the pathways are formed, the cortex is capable of temporarily memorizing the stimuli by producing long-term potentiation through the cortico-hippocampal circuits; and (4) the memory allows the cortex to extend correct association pathways even in an environment where sensory stimuli rapidly change. A mathematical model of parts of the nervous system is presented to quantitatively examine the mechanisms. Membrane characteristics of single neurons are given by the Hodgkin-Huxley electric circuit. According to anatomical data, neural circuits of the neocortico-hippocampal system are composed by connecting populations of the model neurons. Computer simulation using physiological data concerning ion channels demonstrates how the mechanisms work and how to test the hypotheses presented.A preliminary version of this paper was presented at the Fifteenth Annual Meeting of the Japan Neuroscience Society, Tokyo, December 1991     

A comparative study of bipolar disorder and attention deficit hyperactivity disorder through the measurement of regional cerebral blood flow

Attention Deficit Hyperactivity Disorder (ADHD) and Bipolar Disorder (BPD) are two common neuropsychological disorders which are often present in a comorbid state. I used the results of cerebral blood flow studies made with Single Photon Emission Computer Tomography (SPECT), Positron Emission Tomography (PET) and Functional Magnetic Resonance Imaging (fMRI), to investigate a possible relationship between ADHD and BPD. The common areas of the brain involved in both BPD and ADHD appears to be the prefrontal cortex in its various components, the basal ganglia and possibly the cerebellum which, especially in the past, has been little studied by researchers in relation to ADHD and BPD. Among the differences the blood flow lateralization, present in BPD in states of altered mood, is evident with left hypoperfusion and right hyperperfusion during depression, the opposite in the case of manic state; in ADHD, the lateralization is less constant and of questionable interpretation. In BPD the involvement of a greater number of brain areas, especially the temporal lobe, is common. I advance the hypothesis that BPD progresses from ADHD secondary to expansion of perturbation in cerebral blood flow.     

Evidence for plasticity of the dopaminergic system in Parkinsonism

A series of compensatory mechanisms within the dopaminergic system have been shown to maintain clinical function in the presence of dopamine loss. Experimental evidence for increased presynaptic dopamine turnover owing to increased dopamine synthesis, release, and reduced reuptake exists. Direct evidence that these mechanisms maintain extracellular dopamine levels is provided by intracerebral microdialysis techniques. Postsynaptic denervation supersensitivity clearly occurs with D2 dopamine receptors, although this is less evident with D1 receptors. Similarly, mechanisms of plasticity have been shown to be relevant in human postmortem and Positron Emission Tomographic studies of patients with Parkinson's disease. However, although presynaptic increases in dopamine turnover are well documented, postsynaptic D1 and D2 receptor changes have been more difficult to establish, mainly because of methodological difficulties. D2, but not D1, receptor increases have been documented in drug naive Parkinsonian patients with PET techniques. In transplantation of adrenal gland to striatum in animal models and patients with Parkinsonism where clinical improvement occurs, plasticity of host response may be as important as plasticity of the graft. Although some elements of the compensatory mechanism of dopamine plasticity may be deleterious, such as dyskinesias owing to dopamine receptor supersensitivity, the overall effect of delay and minimization of the clinical expression of disease is advantageous. An even greater understanding of the mechanisms involved may assist in developing future therapeutic strategies.     

Histological changes of the dopaminergic nigrostriatal system in aging

Although the maximum human lifespan has not increased in recent history, average life expectancy has risen dramatically since the beginning of the last century. Lengthening of lifespan has little merit if the quality of life is not preserved. In the elderly, the decline in memory and cognitive abilities is of great concern, as is motor weakening, which increases with age. The dopaminergic system mediates some aspects of manual dexterity, in addition to cognition and emotion, and may be especially vulnerable to aging. Therefore, the aging of this system has both clinical and vocational aspects. This review includes studies quantitating age-related changes of the nigrostriatal system, with emphasis on the use of stereological methods, and provides tables of stereological studies performed in the nigrostriatal system.We acknowledge the Danish Parkinson Foundation and the Foundation of Stockbroker Henry Hansen and wife for financial support     

Neuronal mechanisms regulating ethanol effects on the dopaminergic system

Chronic ethanol consumption induces an increase in striatal ³H-Spiroperidol and ³H(?) Sulpiride specific binding by enhancing the affinity between the different dopaminergic recognition sites and the labelled ligands. Dopamine (DA) receptor supersensitivity is also suggested by the enhanced effect of neuroleptics in inducing hypomotility in rats treated with ethanol. The results, obtained by means of the administration of neuroleptics in comparison to ethanol treated rats, indicate a lack of cross tolerance between ethanol and other drugs acting on the dopaminergic recognition sites. These data suggest that ethanol effects on the dopaminergic system are mediated by events involving other neurotransmitter systems.     

Inflammation induces mitochondrial dysfunction and dopaminergic neurodegeneration in the nigrostriatal system

Evidence suggests that chronic inflammation, mitochondrial dysfunction, and oxidative stress play significant and perhaps synergistic roles in Parkinson's disease (PD), where the primary pathology is significant loss of the dopaminergic neurons in the substantia nigra. The use of anti-inflammatory drugs for PD treatment has been proposed, and inhibition of cyclo-oxygenase-2 (COX-2) or activation of peroxisome proliferator-activated receptor gamma (PPAR-gamma) yields neuroprotection in MPTP-induced PD. Lipopolysaccharide (LPS) induces inflammation-driven dopaminergic neurodegeneration. We tested the hypothesis that celecoxib (Celebrex, COX-2 inhibitor) or pioglitazone (Actos, PPAR-gamma agonist) will reduce the LPS-induced inflammatory response, spare mitochondrial bioenergetics, and improve nigral dopaminergic neuronal survival. Rats were treated with vehicle, celecoxib, or pioglitazone and were intrastriatally injected with LPS. Inflammation, mitochondrial dysfunction, oxidative stress, decreased dopamine, and nigral dopaminergic neuronal loss were observed post-LPS. Celecoxib and pioglitazone provided neuroprotective properties by decreasing inflammation and restoring mitochondrial function. Pioglitazone also attenuated oxidative stress and partially restored striatal dopamine as well as demonstrated dopaminergic neuroprotection and reduced nigral microglial activation. In summary, intrastriatal LPS served as a model for inflammation-induced dopaminergic neurodegeneration, anti-inflammatory drugs provided protective properties, and pioglitazone or celecoxib may have therapeutic potential for the treatment of neuro-inflammation and PD.     

Intracerebral grafting in the dopaminergic system: issues and controversy.

A review of work in the dopaminergic system reveals both progress and controversy. More than 100 papers on intracerebral grafting were published last year. Several groups have published the clinical outcome of fetal substantia nigra implants in Parkinsonian patients and studies suggest that sprouting of dopaminergic fibers in response to grafting procedures ameliorates the behavioral deficits of dopamine-depleted animals. Trophic factors for dopamine neurons have also been identified. In addition, genetically modified cells continue to be developed as an alternative method for delivering molecules to the brain. The speed with which neural grafting has become a therapeutic procedure in Parkinsonian patients continues to stimulate debate.