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)

The different types of striatal neuron show a range of vulnerabilities to a variety of insults. This can be clearly seen in Huntington's disease where a well mapped pattern of pathological events occurs. Medium spiny projection (MSP) neurons are the first striatal cells to be affected as the disease progresses whilst interneurons, in particular the NADPH diaphorase positive ones, are spared even in the late stages of the disease. The MSP neurons themselves are also differentially affected. The death of MSP neurons in the patch compartment of the striatum precedes that in the matrix compartment and the MSP neurons of the dorsomedial caudate nucleus degenerate before those in the ventral lateral putamen. The enkephalin positive striatopallidal MSP neurons are also more vulnerable than the substance P/dynorphin MSP neurons. We review the potential causes of this selective vulnerability of striatopallidal neurons and discuss the roles of endogenous glutamate, nitric oxide and calcium binding proteins. It is concluded that MSP neurons in general are especially susceptible to disruptions of cellular respiration due to the enormous amount of energy they expend on maintaining unusually high transmembrane potentials. We go on to consider a subpopulation of enkephalinergic striatopallidal neurons in the rat which are particularly vulnerable. This subpopulation of neurons readily undergo apoptosis in response to experimental manipulations which affect dopamine and/or corticosteroid levels. We speculate that the cellular mechanisms underlying this cell death may also operate in degenerative disorders such as Huntington's disease thereby imposing an additional level of selectivity on the pattern of degeneration. The possible contribution of the selective death of striatopallidal neurons to a number of clinically important psychiatric conditions including obsessive compulsive disorders and Tourette's syndrome is also discussed.
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PMID:The selective vulnerability of striatopallidal neurons. 1084 58

Prior studies have suggested a common etiology involved in Tourette's syndrome and several comorbid conditions and symptomatology. Reportedly, current medications used in Tourette's syndrome have intolerable side-effects or are ineffective for many patients. After thoroughly researching the literature, I hypothesize that magnesium deficiency may be the central precipitating event and common pathway for the subsequent biochemical effects on substance P, kynurenine, NMDA receptors, and vitamin B6 that may result in the symptomatology of Tourette's syndrome and several reported comorbid conditions. These comorbid conditions and symptomatology include allergy, asthma, autism, attention deficit hyperactivity disorder, obsessive compulsive disorder, coprolalia, copropraxia, anxiety, depression, restless leg syndrome, migraine, self-injurious behavior, autoimmunity, rage, bruxism, seizure, heart arrhythmia, heightened sensitivity to sensory stimuli, and an exaggerated startle response. Common possible environmental and genetic factors are discussed, as well as biochemical mechanisms. Clinical studies to determine the medical efficacy for a comprehensive magnesium treatment option for Tourette's syndrome need to be conducted to make this relatively safe, low side-effect treatment option available to doctors and their patients.
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PMID:The central role of magnesium deficiency in Tourette's syndrome: causal relationships between magnesium deficiency, altered biochemical pathways and symptoms relating to Tourette's syndrome and several reported comorbid conditions. 1186 98

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