Dopamine receptors in the parkinsonian brain

Summary Striatal dopamine receptors were studied in 44 patients with Parkinson disease by the radioligand-binding technique using³H-spiroperidol. The specific binding of³H-spiroperidol was either significantly increased or reduced in the caudate nucleus and putamen of parkinsonian patients without levodopa therapy. Scatchard analysis showed that there were corresponding changes in the receptor number, but no significant changes in the mean dissociation constant. The increased binding of³H-spiroperidol in the basal ganglia was also found in parkinsonian patients suffering from psychotic episodes and treated with neuroleptic drugs. Normal and low binding of³H-spiroperidol was found in patients treated with levodopa. Clinically, the patients with low binding were more disabled and had lost the beneficial response to levodopa. Thus in Parkinson disease in some patients a denervation supersensitivity seemed to develop and in some others a loss of postsynaptic dopamine receptor sites in the neostriaturn. The latter alteration may contribute to the decreased response of parkinsonian patients to chronic levodopa therapy.     

Immunohistochemical study of microglia in the Creutzfeldt-Jakob diseased brain

Immunohistochemical techniques have been used to investigate microglial reaction in Creutzfeldt-Jakob diseased (CJD) brains. Autopsy cases of six patients with CJD and age-matched controls were studied. Formalin-fixed, paraffin-embedded brain tissue samples were stained with antibodies against major histocompatibility complex (MHC) class II antigen (Ag), leukocyte common antigen (LCA), CDw75, CD68 and glial fibrillary acidic protein. Of the patients with CJD, two with a subacute spongiform encephalopathic type and short-survival periods after onset of the disease showed an increased number of reactive microglia labeled with anti-MHC class II Ag or LCA in the affected cerebral cortex. In advanced cases of the panencephalopathic type of CJD, in which both cerebral atrophy and astrocytosis were marked, the increase of reactive microglia was small. Some vacuoles developing in the neuropil of the CJD patients were surrounded by MHC class II Ag- or LCA-immunoreactive microglial cells. The number of ramified microglia in the affected lesions was decreased, although their number in the hippocampus was not affected. These results indicate that microglia can frequently be involved in the process of CJD and may be activated at the early stage of the disease.     

Role of drug efflux carriers in the healthy and diseased brain

The blood-brain barrier is a natural diffusion barrier, which expresses active carriers extruding drugs on their way to the brain back into the blood against concentration gradients. Whereas these so-called adenosine triphosphate-binding cassette (ABC) transporters prevent the brain entry of toxic compounds under physiological conditions, they complicate pharmacotherapies in neurological disease. Recent observations in animal models of ischemic stroke, drug-resistant epilepsy, and brain cancer showed that the prototype of ABC transporters, ABCB1, is upregulated on brain injury, deactivation of this carrier considerably enhancing the accumulation of neuroprotective, antiepileptic, and chemotherapeutic compounds. These studies provide the proof of concept that the efficacy of brain-targeting drugs may significantly be improved when drug efflux is blocked. Under clinical conditions, efforts currently are made to enhance drug accumulation by selecting new compounds that do not bind to efflux carriers or deactivating ABC transporters by targeted downregulation or pharmacological inhibition. We predict that strategies aiming at circumventing drug efflux may greatly facilitate progress in neurological therapies.     

Dopamine transporter immunoreactivity in rat brain

The dopamine transporter (DAT) is a primary site for the action of cocaine in inducing euphoria. Its action is necessary for the selectivities of dopaminergic neurotoxins that provide the best current experimental models of Parkinson's disease. In the present report, rat ddpamine transporter-like immunoreactivity (iDAT) was assessed by immunohistochemistry using newly developed polyclonal antisera raised against conjugated peptides corresponding to sequences found in the dopainine transporter's carboxy- and amino-termini. Dense iDAT was observed in patterns consistent with neural processes and terminals in the striatum, nucleus accumbens, olfactory tubercle, nigrostriatal bundle, and lateral habenula. Perikarya in the substantia nigra pars compacts, were immunostained with moderate intensity using one of two immunohistochemical methods, while scattered ventral tegmental area perikarya were stained with somewhat less intensity. Immunoreactive neuronal processes with axonal and dendritic morphologies were stained in the substantia nigra and the paranigral and parabrachialis pigmentosus nuclei of the ventral tegmental area, while sparser processes were noted more medially in the ventral tegmental area. Neuronal processes were found in several laminae in the cingulate cortex, with notable fiber densities in the superficial aspects of lamina I and laminae II/III. The intensities of immunoreactivities in striatum and cerebral cortex were dramatically attenuated ipsilateral to nigrostriatal bundle 6-hydroxydopamine lesions. Specificity of immunostaining was supported by agreement of the results using sera directed against two distinct DAT segments, studies with preimmune and preadsorbed sera and studies of the extracted protein. These antisera identify and reveal details of the distribution of DAT immunoreactivity in rat brain and display ivariations in levels of DAT expression of likely functional significance. © 1995 Wiley-Liss, Inc.     

Dopamine receptors in a songbird brain

Dopamine is a key neuromodulatory transmitter in the brain. It acts through dopamine receptors to affect changes in neural activity, gene expression, and behavior. In songbirds, dopamine is released into the striatal song nucleus Area X, and the levels depend on social contexts of undirected and directed singing. This differential release is associated with differential expression of activity‐dependent genes, such as egr1 (avian zenk), which in mammalian brain are modulated by dopamine receptors. Here we cloned from zebra finch brain cDNAs of all avian dopamine receptors: the D1 (D1A, D1B, D1D) and D2 (D2, D3, D4) families. Comparative sequence analyses of predicted proteins revealed expected phylogenetic relationships, in which the D1 family exists as single exon and the D2 family exists as spliced exon genes. In both zebra finch and chicken, the D1A, D1B, and D2 receptors were highly expressed in the striatum, the D1D and D3 throughout the pallium and within the mesopallium, respectively, and the D4 mainly in the cerebellum. Furthermore, within the zebra finch, all receptors, except for D4, showed differential expression in song nuclei relative to the surrounding regions and developmentally regulated expression that decreased for most receptors during the sensory acquisition and sensorimotor phases of song learning. Within Area X, half of the cells expressed both D1A and D2 receptors, and a higher proportion of the D1A‐only‐containing neurons expressed egr1 during undirected but not during directed singing. Our findings are consistent with hypotheses that dopamine receptors may be involved in song development and social context‐dependent behaviors. J. Comp. Neurol. 518:741–769, 2010. © 2009 Wiley‐Liss, Inc.     

Palmitoylethanolamide and other anandamide congeners. Proposed role in the diseased brain

Acylethanolamides are formed in the brain “on demand” from membrane phospholipids called N-acylated phosphatidylethanolamines. The acylethanolamides are signaling molecules of lipid nature, and this lipofilicity suggests an autocrine function. The acylethanolamides include palmitoylethanolamide (PEA), oleoylethanolamide (OEA), stearoylethanolamide (SEA), and several other quantitative minor species including anandamide (= arachidonoylethanolamide). PEA and OEA can activate several different receptors and inhibit some ion channels, e.g., PPARα, vanilloid receptor, K⁺ channels (Kv4.3, Kv1.5), and OEA can activate GPR119 and inhibit ceramidases. Targets for SEA are less clear, but it has some cannabimimetic actions in rats in vivo. All acylethanolamides accumulate during neuronal injury, and injected OEA has neuroprotective effects, and PEA has anti-inflammatory effects as studied in the peripheral system. Several of the pharmacological effects seem to be mediated via activation of PPARα. Recently, injected OEA has been found to consolidate memories in rats. Inhibitors of the acylethanolamide-degrading enzyme FAAH can increase levels of all acylethanolamides including annandamide, and some of the pharmacological effects caused by these inhibitors may be explained by increased cerebral levels of OEA and PEA, e.g., suppression of nicotine-induced activation of dopamine neurons. Furthermore, through activation of PPARα, OEA and PEA may stimulate neurosteroid synthesis, thereby modulating several biological functions mediated by GABA(A) receptors.The existence of acylethanolamides in the mammalian brain has been known for decades, but it is first within the last few years that the putative biological functions of the three most abundant acylethanolamides species are starting to emerge.     

Dopamine thioethers: formation in brain and neurotoxicity

Dopamine (DA) oxidation is proposed to be a significant contributor to some forms of neurodegeneration, although the mechanisms are not fully resolved. Recent results from in vitro and in vivo models have suggested that some products of oxidized DA metabolized along the mercapturic acid pathway (MAP) may contribute to dopaminergic neurodegeneration. Here we review recent findings on the localization of MAP enzymes in human brain, as well as the concentration and neurotoxicity of their DA thioether products.     

Dopamine neuron systems in the brain: an update

The basic organization of the catecholamine-containing neuronal systems and their axonal projections in the brain was initially worked out using classical histofluorescence techniques during the 1960s and 1970s. The introduction of more versatile immunohistochemical methods, along with a range of highly sensitive tract-tracing techniques, has provided a progressively more detailed picture, making the dopamine system one of the best known, and most completely mapped, neurotransmitter systems in the brain. The purpose of the present review is to summarize our current knowledge of the diversity and neurochemical features of the nine dopamine-containing neuronal cell groups in the mammalian brain, their distinctive cellular properties, and their ability to regulate their dopaminergic transmitter machinery in response to altered functional demands and aging.     

Dopamine transporter and nitric oxide synthase in hypoxic-ischemic brain

Changes in dopamine transporter and neuronal nitric oxide synthase (nNOS) were investigated by immunohistochemistry in 18 cases of hypoxic-ischemic basal ganglia necrosis. Neuropil dopamine transporter immunostaining in the striatum was increased in seven cases, with relatively mild basal ganglia necrosis, and decreased in four cases, with marked basal ganglia necrosis, compared with age-matched control subjects. Correspondingly, some striatal neurons had increased immunoreactivity to dopamine transporter in the cases of increased immunostaining in the neuropil. nNOS-positive neurons did not obviously change in cases of basal ganglia necrosis within 2 days after birth and then decreased or were not detectable in cases of basal ganglia necrosis at more than 3 days after birth. The results suggest that the synthesis of dopamine transporter is up-regulated in relatively mild basal ganglia necrosis to compensate for the uptake of increased dopamine, that this compensative ability is lost in marked basal ganglia necrosis, and that nNOS-containing neurons in the striatum are relatively resistant to hypoxic ischemia. We speculate that glutamate excitotoxicity mediated by glutamate receptors 1, 2/3, and 4 and excessive dopaminergic excitatory activity may play important roles in hypoxic-ischemic basal ganglia necrosis and that nNOS does not contribute to that condition.     

Computer-assisted imaging to assess brain structure in healthy and diseased brains

Neuroanatomical structures may be profoundly or subtly affected by the interplay of genetic and environmental factors, age, and disease. Such effects are particularly true in healthy ageing individuals and in those who have neurodegenerative diseases. The ability to use imaging to identify structural brain changes associated with different neurodegenerative disease states would be useful for diagnosis and treatment. However, early in the progression of such diseases, neuroanatomical changes may be too mild, diffuse, or topologically complex to be detected by simple visual inspection or manually traced measurements of regions of interest. Computerised methods are being developed that can capture the extraordinary morphological variability of the human brain. These methods use mathematical models sensitive to subtle changes in the size, position, shape, and tissue characteristics of brain structures affected by neurodegenerative diseases. Neuroanatomical features can be compared within and between groups of individuals, taking into account age, sex, genetic background, and disease state, to assess the structural basis of normality and disease. In this review, we describe the strengths and limitations of algorithms of existing computer-assisted tools at the most advanced stage of development, together with available and foreseeable evidence of their usefulness at the clinical and research level.     

Dopamine as a growth differentiation factor in the mammalian brain

The catecholamine, dopamine, plays an important role in the central nervous system of mammals, including executive functions, motor control, motivation, arousal, reinforcement, and reward. Dysfunctions of the dopaminergic system lead to diseases of the brains, such as Parkinson's disease, Tourette's syndrome, and schizophrenia. In addition to its fundamental role as a neurotransmitter, there is evidence for a role as a growth differentiation factor during development. Recent studies suggest that dopamine regulates the development of γ-aminobutyric acidergic interneurons of the cerebral cortex. Moreover, in adult brains, dopamine increases the production of new neurons in the hippocampus, suggesting the promoting effect of dopamine on proliferation and differentiation of neural stem cells and progenitor cells in the adult brains. In this mini-review, I center my attention on dopaminergic functions in the cortical interneurons during development and further discuss cell therapy against neurodegenerative diseases.     

Magnetic resonance spectroscopy in multiple sclerosis: window into the diseased brain

Magnetic resonance spectroscopy provides noninvasive insight into the regional and global biochemical alterations that are concomitants of the dynamic processes that underlie the evolution of fundamental pathologic changes in multiple sclerosis. These include now well-recognized alterations of neuronal biochemical markers that accompany tissue destruction readily visualized by magnetic resonance imaging, but also dynamic changes in several metabolites that indicate pathological processes that precede the magnetic resonance imaging-defined lesion, or completely escape current high-resolution imaging.