Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We performed a neurochemical study of the brain of two unrelated patients, living in different continents, with neuroacanthocytosis. The levels of monoamines and their metabolites, gamma-aminobutyric acid and substance P, were measured in several brain areas and the monoamine metabolites in cerebrospinal fluid. The binding of 3H-spiperone to striatal membranes and to lymphocytes was also measured. Both patients had a progressive neurological disorder with onset in the third decade of life and characterized by a complex movement disorder, epilepsy, muscular wasting, and changes in behavior. The movement disorder initially manifested with oromandibular dystonia and limb chorea, but at the time of death was characterized by a severe dystonic syndrome. The chemical changes were similar in the two patients. The most important neurochemical findings were a depletion of dopamine and its metabolites in most brain areas, most notably in the striatum, and elevation of norepinephrine levels in the putamen and globus pallidus. Substance P was markedly reduced in the striatum and substantia nigra. Our findings may provide clues to the neurochemical mechanisms underlying dystonia.
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PMID:Neurochemical findings in neuroacanthocytosis. 290 27

Huntington's disease is a progressive degenerative neurological disorder which produces a characteristic movement disorder termed chorea. Although chorea is associated with dysfunction of the basal ganglia, the underlying mechanisms by which dyskinesias such as chorea are produced, are poorly understood. Recent studies in primates have led to experimental models of chorea with postulated involvement of specific neural pathways. In the present study we attempted to determine the validity of the experimental models by measuring concentrations of gamma-aminobutyric acid (GABA), glutamate, substance P and met-enkephalin in the basal ganglia of Huntington's disease patients who manifested either chorea or rigidity/bradykinesia within 6 months of death. We also characterized changes in the Huntington's disease patients according to pathological grade, since this may be a confounding factor. We analysed post-mortem brain tissue from 12 controls, and 11 grade 3 and 12 grade 4 Huntington's disease patients. The grade 3 and 4 cases consisted of eight adult-onset choreic, nine adult-onset rigid and six juvenile-onset rigid patients. We also analysed the putamen and globus pallidus from 11 grade 2 adult onset choreic Huntington's disease patients. A model of chorea based on experimental studies in primates proposes that a loss of striatal GABAergic inhibitory projections to the globus pallidus externa leads to increased activity of the inhibitory globus pallidus externa GABAergic neurons which project to the subthalamic nucleus. It is believed that the loss of GABAergic inputs to the globus pallidus externa precedes a loss of GABAergic input to the globus pallidus interna, which occurs later in the disease and is associated with the development of rigidity and bradykinesia. In the choreic Huntington's disease patients whom we studied, there was a greater loss of GABA in the globus pallidus externa than in the globus pallidus interna, and the globus pallidus interna: globus pallidus externa GABA ratio was significantly increased compared with rigid patients. There were also increases in GABA in the subthalamic nucleus in the choreic patients, although this did not reach significance. A differential loss of met-enkephalin in the globus pallidus externa compared with substance P loss in the globus pallidus interna was not observed in either the choreic patients with advanced disease or the grade II patients. There was a significant increase in GABA concentrations in the ventroanterior nucleus of the thalamus in the choreic patients compared with rigid/bradykinetic patients.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Neurochemical substrates of rigidity and chorea in Huntington's disease. 769 98

Of the five known dopamine receptors, D1A and D2 represent the major subtypes expressed in the striatum of the adult brain. Within the striatum, these two subtypes are differentially distributed in the two main neuronal populations that provide direct and indirect pathways between the striatum and the output nuclei of the basal ganglia. Movement disorders, including Parkinson disease and various dystonias, are thought to result from imbalanced activity in these pathways. Dopamine regulates movement through its differential effects on D1A receptors expressed by direct output neurons and D2 receptors expressed by indirect output neurons. To further examine the interaction of D1A and D2 neuronal pathways in the striatum, we used homologous recombination to generate mutant mice lacking functional D1A receptors (D1A-/-). D1A-/- mutants are growth retarded and die shortly after weaning age unless their diet is supplemented with hydrated food. With such treatment the mice gain weight and survive to adulthood. Neurologically, D1A-/- mice exhibit normal coordination and locomotion, although they display a significant decrease in rearing behavior. Examination of the striatum revealed changes associated with the altered phenotype of these mutants. D1A receptor binding was absent in striatal sections from D1A-/- mice. Striatal neurons normally expressing functional D1A receptors are formed and persist in adult homozygous mutants. Moreover, substance P mRNA, which is colocalized specifically in striatal neurons with D1A receptors, is expressed at a reduced level. In contrast, levels of enkephalin mRNA, which is expressed in striatal neurons with D2 receptors, are unaffected. These findings show that D1A-/- mice exhibit selective functional alterations in the striatal neurons giving rise to the direct striatal output pathway.
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PMID:Altered striatal function in a mutant mouse lacking D1A dopamine receptors. 780 78

Animal models have shown progressive development and have undoubtedly proven their supportive value in OCD research. Thus, various animal models have confirmed the importance of the 5-HT [72-74] and dopamine systems [104,111] in the neurobiology and treatment of OCD. Given the neurochemical, emotional, and cognitive complexity of the disorder, how-ever, animal models are being used to investigate more and more complicated neurochemical and behavioral theories purported to underlie OCD. The lever-press model, for example, has implicated deficient response feed-back in a neural system that regulates operant behavior [74]. Studies on stereotypic movement disorder [89] have opened a new avenue of investigation into the neurobiology of stereotypy that may be applicable to more complex syndromes such as OCD. Models that have focused on specific neuropsychologic aspects of OCD such as reward [74], displacement behavior[63,101], perseveration and indecisiveness [73,102], and spontaneous stereotypy [90,94] are important in their attempt to unify the diverse behavioral manifestations of this disorder. It is clear that for a deeper, more holistic understanding of OCD, multiple animal models will be needed to allow investigation of the various aspects of the disorder and to provide convergent validation of the research findings. The heterogeneous nature of OCD, the various subtypes that exist within the disorder, and the range of obsessive-compulsive spectrum disorders suggest that particular questions regarding OCD may be addressed best by us-ing a particular ethologic model, whereas other questions might require a pharmacologic model or a combination of both for meaningful results[62,115]. Genetic models will be extremely useful for studying the genetics of pathologic behavior and for relating these findings to neuroanatomic and neurochemical changes in the model (eg, DICT-7 mice as a model for Tourette's syndrome and OCD). Neither ethologic nor pharmacologic models, however, can assess whether the "compulsive" behavior is a response to an "obsessive" anxiety or fear. Perhaps the symptoms seen in patients who have OCD, which may be exacerbated by everyday stress, are analogous to displacement behaviors in animals and also reflect some form of anxiety or stress [98]. In this regard, the bank vole model [116]has provided evidence that previously developed stereotypies increase markedly after acute stress and argues that healthy individuals "habituate" to everyday stress, whereas patients who have OCD do not. Interindividual variation in behavioral response and attempts to replicate studies in different laboratories often is the nemesis of the behavioral scientist. Small within- and between-subject variability is usually desirable, how-ever, because there are cases in which the study of the variability of the model could lead to a better understanding of the disorder. Variability can-not always be considered an error; it is possible that previously disregarded neuronal systems may have a place in the observed variation and, indeed, in the pathophysiology of OCD. In this regard, SRIs are not always effective for OCD [6,29,30] such that a lack of effect in a model may reflect an un-known neurobiological basis for compulsive behavior in a sub-group of SRI refractory patients. Similarly, separating the afflicted (ie, working with animals that show greater behavioral change in a model and/or after drug treatment) would have distinct benefits. To increase successful implementation of an ethologic animal model, especially when reinforcement models or signal attenuation models are used,the laboratory must be equipped with the essential behavioral testing apparatus as well as the operant chambers/rooms in which to conduct the train-ing and data collection. Quantification of certain stereotypy behaviors also requires experienced or trained observers. An illustration of the difficulty in measuring behavioral changes is that in the rewarded alternation model,a good response to behavioral treatment (alternation training) may lead to a floor effect [73] which, after successful drug treatment of the animal,produces no residual persistence (ie, measurable behavioral change) on which a drug treatment can be tested. Clearly, the choice of ethologic, pharmacologic, or genetic models should be considered carefully. A well-validated model may quell many of the limitations and considerations described previously. Noninvasive neuroimaging(eg, the use of small-animal single-photon emission CT) to explore the neuroanatomic basis of OCD offers an exciting future challenge, especially if combined with pharmacologic or ethologic models, and could confirm or ex-tend knowledge of the neuroanatomy of OCD. Although studies to investigate further the interactive role of 5-HT, dopamine, GABA, and glutamate are still needed, the role of neuroactive peptides such as cholecystokinin, corticotrophin-releasing factor, neuropeptide Y, tachykinins (ie, substance P),and natriuretic peptides in OCD should also be considered. Genetically engineered animal models will become increasingly valuable in combination with new technologies such as gene-chip microarrays, RNA interference, and advanced proteomics that will help further the understanding of OCD. Animal models of OCD are poised to play a vital role in extending the knowledge of the disorder now and in the future.
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PMID:Animal models of obsessive-compulsive disorder: rationale to understanding psychobiology and pharmacology. 1665 Jul 14

Huntington's disease is caused by degeneration or malfunctioning of basal ganglia. Although the exact pathophysiology of this disease is not clear, it seems that abnormal glutamate release is involved in producing movement disorders. Few simulations are done on Huntington's disease. Since a complex movement disorder is seen in this disease, a mathematical model is needed to analyze it. We designed a computational model based on physiological findings. The model block diagram is proposed. The glutamate abnormality of the disease is considered as an environment noise and is designated as a random number generator in the model. To designate inhibitory and excitatory effect of neurotransmitters on each block, we used Hill functions. We designated the internal behavior of blocks using a closed loop system. Proper transfer functions are assumed for each block in our model. In order to separate normal and diseased conditions, we included noise in all glutamate related blocks and put it dependent to a parameter, g. All nominal quantities used in the model are chosen by try and error. The response of the model is presented for different values of g in health and illness states. In this study, we have designated g=1 for healthy and g=10 for illness states. In the healthy state, our model's output is zero. However, it produces an abrupt movement in Huntington's disease, like what is seen in chorea. While reducing g from 10 to 3 causes the size of answer to be reduced, putting the g below 3 will cause cessation of jerky movement. Some of our model's response properties, as the period between each two abrupt movements, size of movement and the shape of movement curve are completely stochastic, being another significant similarity between our model and the real conditions. According to all similarities between the model and Huntington's disease, any change in the model parameters can resemble real changes. We evaluated some parameters, as substance P and GABA levels, in the basal ganglia model and showed that increasing these variables are able to ameliorate the patient's symptoms. We suggest that prescribing drugs such as gabapentin could improve the symptoms. Surely, clinical trials are needed to validate this suggestion.
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PMID:A computational model for the Huntington disease. 1725 71