Acute effects of alcohol on brain perfusion monitored with arterial spin labeling magnetic resonance imaging in young adults

While a number of studies have established that moderate doses of alcohol increase brain perfusion, the time course of such an increase as a function of breath alcohol concentration (BrAC) has not yet been investigated, and studies differ about regional effects. Using arterial spin labeling (ASL) magnetic resonance imaging, we investigated (1) the time course of the perfusion increase during a 15-minute linear increase of BrAC up to 0.6 g/kg followed by a steady exposure of 100 minutes, (2) the regional distribution, (3) a potential gender effect, and (4) the temporal stability of perfusion effects. In 48 young adults who participated in the Dresden longitudinal study on alcohol effects in young adults, we observed (1) a 7% increase of global perfusion as compared with placebo and that perfusion and BrAC are tightly coupled in time, (2) that the increase reaches significance in most regions of the brain, (3) that the effect is stronger in women than in men, and (4) that an acute tolerance effect is not observable on the time scale of 2 hours. Larger studies are needed to investigate the origin and the consequences of the effect, as well as the correlates of inter-subject variations.     

JuSpace: A tool for spatial correlation analyses of magnetic resonance imaging data with nuclear imaging derived neurotransmitter maps

Recent studies have shown that drug‐induced spatial alteration patterns in resting state functional activity as measured using magnetic resonance imaging (rsfMRI) are associated with the distribution of specific receptor systems targeted by respective compounds. Based on this approach, we introduce a toolbox (JuSpace) allowing for cross‐modal correlation of MRI‐based measures with nuclear imaging derived estimates covering various neurotransmitter systems including dopaminergic, serotonergic, noradrenergic, and GABAergic (gamma‐aminobutric acid) neurotransmission. We apply JuSpace to two datasets covering Parkinson''s disease patients (PD) and risperidone‐induced changes in rsfMRI and cerebral blood flow (CBF). Consistently with the predominant neurodegeneration of dopaminergic and serotonergic system in PD, we find significant spatial associations between rsfMRI activity alterations in PD and dopaminergic (D2) and serotonergic systems (5‐HT1b). Risperidone induced CBF alterations were correlated with its main targets in serotonergic and dopaminergic systems. JuSpace provides a biologically meaningful framework for linking neuroimaging to underlying neurotransmitter information.     

Trace amine-associated receptor 1: a multimodal therapeutic target for neuropsychiatric diseases

Introduction: The trace amines, endogenous amines closely related to the biogenic amine neurotransmitters, have been known to exert physiological and neurological effects for decades. The recent identification of a trace amine-sensitive G protein-coupled receptor, trace amine-associated receptor 1 (TAAR1), and subsequent development of TAAR1-selective small-molecule ligands, has renewed research into the therapeutic possibilities of trace amine signaling.

Areas covered: Recent efforts in elucidating the neuropharmacology of TAAR1, particularly in neuropsychiatric and neurodegenerative disease, addiction, and regulation of arousal state, will be discussed. Focused application of TAAR1 mutants, synthetic TAAR1 ligands, and endogenous biomolecules such as 3-iodothyronamine (T1AM) has yielded a basic functional portrait for TAAR1, despite a complex biochemistry and pharmacology. The close functional relationship between TAAR1 and dopaminergic signaling is likely to underlie many of its CNS effects. However, TAAR1’s influences on serotonin and glutamate neurotransmission will also be highlighted.

Expert opinion: TAAR1 holds great promise as a therapeutic target for mental illness, addiction, and sleep disorders. A combination of preclinical and translationally driven studies has solidified TAAR1 as a key node in the regulation of dopaminergic signaling. Continued focus on the mechanisms underlying TAAR1’s regulation of serotonin and glutamate signaling, as well as dopamine, will yield further disease-relevant insights.     

肾移植术后应用FK506的神经毒性作用

目的 观察肾移植患者术后应用ＦＫ５０６（普乐可复）的脑中枢神经系统症状。方法对７１例肾移植患者术后应用 ＦＫ５０６的血药浓度及神经系统症状和体征进行动态观察。结果对例患者中有１１例出现中枢神经系统异常,其中３例 出现严重神经系统并发症,此３例中１例脑电图及脑ＣＴ出现轻度异常。多数患者症状可自行消失,部分患者调低药物 浓度后可在短期内渐缓解,但严重者需停药较长时间后才可好转。结论ＦＫ５０６是一种高效抗排斥药物,多数患者用药 后精神神经症状缓和,神经系统体检及影像学检查无明显改变或仅有轻微异常改变,但少数患者即使在治疗剂量下亦 可产生严重的中枢神经系统并发症。     

The neuroscience of drug addiction: Rome built in a day

The Second Conference on the Neuroscience of Drug Addiction was a one-day meeting held in Rome, Italy at the Istituto Superiore di Sanità on 27 September 2002. Molecular, behavioral, pharmacological and clinical aspects of drug addiction were covered.     

Optical platelet aggregometry does not appear useful as a means of assessing the risk of recurrent vascular events in aspirin-treated patients

Objectives –  To investigate whether the results of optical platelet aggregometry indicate the risk of recurrent ischemic events.
Materials and methods –  Cerebro- and cardiovascular patients taking aspirin for at least 30 days were studied retrospectively. Ischemic vascular events occurring prior to testing and the presence of vascular risk factors were recorded.
Results –  241 subjects were included. Among the 78 patients (32.4%) who displayed recurrent vascular episodes, the age (62.5 ± 10.6 vs. 58.4 ± 11.6, P  = 0.009) and the proportion of hypertensives (80.8% vs. 68.1%, P  = 0.040) were significantly higher when compared with the participants who exhibited single events. The degree of platelet aggregation did not differ significantly between the patients with and those without recurrent episodes. Logistic regression analysis identified only age (OR 1.033, 95% CI 1.008–1.058, P  = 0.010), and not aggregation values, as a risk condition for recurrent vascular episodes.
Conclusions –  Results of optical platelet aggregometry were not indicative of the risk of recurrent vascular events. The role of conventional risk factors appeared to be more important.     

Tau-targeted treatment strategies in Alzheimer's disease

With populations ageing worldwide, the need for treating and preventing diseases associated with high age is pertinent. Alzheimer's disease (AD) is reaching epidemic proportions, yet the currently available therapies are limited to a symptomatic relief, without halting the degenerative process that characterizes the AD brain. As in AD cholinergic neurons are lost at high numbers, the initial strategies were limited to the development of acetylcholinesterase inhibitors, and more recently the NMDA receptor antagonist memantine, in counteracting excitotoxicity. With the identification of the protein tau in intracellular neurofibrillary tangles and of the peptide amyloid-β (Aβ) in extracellular amyloid plaques in the AD brain, and a better understanding of their role in disease, newer strategies are emerging, which aim at either preventing their formation and deposition or at accelerating their clearance. Interestingly, what is well established to combat viral diseases in peripheral organs - vaccination - seems to work for the brain as well. Accordingly, immunization strategies targeting Aβ show efficacy in mice and to some degree also in humans. Even more surprising is the finding in mice that immunization strategies targeting tau, a protein that forms aggregates in nerve cells, ameliorates the tau-associated pathology. We are reviewing the literature and discuss what can be expected regarding the translation into clinical practice and how the findings can be extended to other neurodegenerative diseases with protein aggregation in brain.     

N-Acyl amino acids and N-acyl neurotransmitter conjugates: neuromodulators and probes for new drug targets

The myriad functions of lipids as signalling molecules is one of the most interesting fields in contemporary pharmacology, with a host of compounds recognized as mediators of communication within and between cells. The N-acyl conjugates of amino acids and neurotransmitters (NAANs) have recently come to prominence because of their potential roles in the nervous system, vasculature and the immune system. NAAN are compounds such as glycine, GABA or dopamine conjugated with long chain fatty acids. More than 70 endogenous NAAN have been reported although their physiological role remains uncertain, with various NAAN interacting with a low affinity at G protein coupled receptors (GPCR) and ion channels. Regardless of their potential physiological function, NAAN are of great interest to pharmacologists because of their potential as flexible tools to probe new sites on GPCRs, transporters and ion channels. NAANs are amphipathic molecules, with a wide variety of potential fatty acid and headgroup moieties, a combination which provides a rich source of potential ligands engaging novel binding sites and mechanisms for modulation of membrane proteins such as GPCRs, ion channels and transporters. The unique actions of subsets of NAAN on voltage-gated calcium channels and glycine transporters indicate that the wide variety of NAAN may provide a readily exploitable resource for defining new pharmacological targets. Investigation of the physiological roles and pharmacological potential of these simple lipid conjugates is in its infancy, and we believe that there is much to be learnt from their careful study.     

Is Glycogen Synthase Kinase-3 a Central Modulator in Mood Regulation?

Little is known regarding the mechanisms underlying the complex etiology of mood disorders, represented mainly by major depressive disorder and bipolar disorder. The 1996 discovery that lithium inhibits glycogen synthase kinase-3 (GSK3) raised the possibility that impaired inhibition of GSK3 is associated with mood disorders. This is now supported by evidence from animal biochemical, pharmacological, molecular, and behavioral studies and from human post-mortem brain, peripheral tissue, and genetic studies that are reviewed here. Mood disorders may result in part from impairments in mechanisms controlling the activity of GSK3 or GSK3-regulated functions, and disruptions of these regulating systems at different signaling sites may contribute to the heterogeneity of mood disorders. This substantial evidence supports the conclusion that bolstering the inhibitory control of GSK3 is an important component of the therapeutic actions of drugs used to treat mood disorders and that GSK3 is a valid target for developing new therapeutic interventions.