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)

Using a radioimmunoassay procedure substance P-like activity was measured in samples of human CSF obtained from 12 patients with major depressive disorder, 12 with schizophrenia, and 15 control cases diagnosed as psychiatrically normal. Levels were significantly higher in CSF of patients with depressive disorder as compared with schizophrenic patients or controls. Chemical characterization revealed that the measured activity was less basic than substance P itself and might be due to C-terminal fragments. A component reacting with an antiserum highly specific for the substance P[1-7]fragment was found in CSF of patients with depressive disorder. The results indicate that substance P-related peptides may be biological markers in psychoses, particularly in major depressive disorder.
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PMID:Elevation of substance P-like peptides in the CSF of psychiatric patients. 620 62

These studies explore the distribution of putative neuroactive peptides in the human olfactory bulb. Localization of synaptophysin-, serotonin-, cholecystokinin-, substance P-, and somatostatin-like staining was examined by immunocytochemical protocols. The results provide new insights into the composition and laminar segregation of subpopulations of neurons and neuronal processes in the human olfactory bulb. The prominent synaptophysin-like immunoreactivity observed in the glomeruli of the human olfactory bulb is consistent with the notion that the density of synapses, and hence the density of synaptic vesicles, is highest in the glomeruli. Serotonin-like immunoreactivity suggested a variable innervation of glomeruli ranging from a dense tangled ball of fibers within the glomerulus to a sparse innervation by a single immunoreactive fiber. There was no evidence of serotonin-like immunoreactive cell bodies in either the olfactory bulb proper, anterior olfactory nucleus, or proximal regions of the lateral olfactory tract. Cholecystokinin-like immunoreactivity was limited to fibers found largely in the juxtaglomerular region of the glomerular layer. In the deeper layers of the olfactory bulb, cholecystokinin-like immunoreactive fibers did not show any of branching or arborization that was evident in the juxtaglomerular region. Substance P-like immunoreactivity was seen in varicose fibers distributed in all of the human olfactory bulb laminae. In addition, stained multipolar neurons were found in the area of the anterior olfactory nucleus. Somatostatin-like immunoreactivity was similar to that of substance P in that a plexus of stained fibers was found in all laminae of the olfactory bulb. Also, somatostatin-like immunoreactive cell bodies were found in the area of the anterior olfactory nucleus. However, as compared to substance P, somatostatin had a less dense plexus of immunoreactive fibers in the olfactory bulb. These results increase our understanding of the fundamental organization of the human olfactory system. The current data, coupled with prior studies, provide a foundation from which to study the cellular pathology of diseases with known olfactory system sequelae such as Alzheimer's, Parkinson's, and schizophrenia.
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PMID:Immunohistochemical analyses of the human olfactory bulb. 769 Mar 71

Because of a potent action of angiotensin converting enzyme (ACE) to degrade substance P (SP) and an association of the insertion/deletion (I/D) polymorphism of the ACE gene with ACE activity, an association between the SP level and the ACE I/D polymorphism were examined using 20 human postmortem brain samples. The results showed a significant association between the polymorphism and SP levels in the basal ganglia and substantia nigra, where both ACE and SP concentrate, and a higher SP level in the subjects with the DD genotype than in those with the II genotype, with an intermediate level in heterozygotes. Associations of the polymorphism with schizophrenia and affective disorders were also investigated in 292 unrelated Japanese schizophrenics, 65 patients with affective disorders, and 579 controls. The D allele was significantly more frequent in the patients with affective disorders than in the controls (p < .02), and the DD genotype was significantly more frequent in the patients with affective disorders than in the controls (p < .002). There is no significant difference in the frequencies of the allele and the genotype between the controls and schizophrenics. These results suggest that the ACE I/D polymorphism is one of the genetic factors for an interindividual variability of brain SP levels, and that the ACE polymorphism may contribute to the susceptibility to affective disorders.
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PMID:An insertion/deletion polymorphism in the angiotensin converting enzyme gene is associated with both brain substance P contents and affective disorders. 893 14

While several catecholaminergic systems are activated by stressful stimuli, the mesoprefrontal dopamine (DA) system appears to be particularly vulnerable to stress. Low intensity stressors that do not produce detectable effects in most ascending catecholaminergic systems activate mesoprefrontal DA neurons. Mesoprefrontal DA neurons are unique in that they lack or have decreased densities of specific autoreceptors affecting autoregulatory capabilities, which could contribute to the fact that mesoprefrontal DA neurons exhibit increased rates of burst firing and DA turnover relative to other midbrain dopaminergic projections. In addition, mesoprefrontal DA neurons are uniquely modulated by a number of chemically distinct afferent influences including gamma-aminobutyric acid (GABA), serotonin, excitatory amino acid, substance P, opiate, and noradrenergic systems. Any or all of these factors could contribute to the selective activation of mesoprefrontal DA neurons following exposure to low intensity stressors. The present review summarizes the possible mechanisms by which mesoprefrontal DA neurons are preferentially activated by stress. The operational significance of this unique neurochemical response to stress is discussed in terms of a possible coping versus anxiety function. Also discussed are the ramifications of a dysfunction of this system with respect to stress-related or exacerbated disorders such as post-traumatic stress disorder and schizophrenia.
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PMID:The role of mesoprefrontal dopamine neurons in stress. 897 88

In the central nervous system (CNS), dopamine is involved in the control of locomotion, cognition, affect and neuroendocrine secretion. These actions of dopamine are mediated by five different receptor subtypes, which are members of the large G-protein coupled receptor superfamily. The dopamine receptor subtypes are divided into two major subclasses: the D1-like and D2-like receptors, which typically couple to Gs and Gj mediated transduction systems. In the CNS, the various receptor subtypes display specific anatomical distributions, with D1-like receptors being mainly post-synaptic and D2-like receptors being both pre- and post-synaptic. D1 and D2 dopamine receptors, the most abundant subtypes in the CNS, appear to be expressed largely in distinct neurons. Substance P and dynorphin, which are expressed in D1 receptor-containing neurons, as well as pre-proenkephalin in D2 receptor-containing neurons, have been used as monitors of dopaminergic activity in the CNS. Expression of immediate early genes, in particular fos, has also been found to correlate with dopaminergic transmission. Dopamine released from the hypothalamus controls the synthesis and secretion of prolactin from the anterior pituitary via D2 dopamine receptors. As yet none of the dopamine receptor subtypes have been associated with the etiology of psychotic disorders, such as schizophrenia. However, the recent characterization of D3 and D4 receptors which are, interestingly, expressed in areas of the CNS mediating cognition and affect or showing increased affinity for certain neuroleptics, have renewed the interest and hope of finding effective neuroleptics devoid of side effects. Finally, the recent production of genetically-derived animals lacking several of these receptor genes should help elucidate which specific physiological paradigms the receptors mediate.
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PMID:Dopamine receptors and brain function. 902 98

The D3 dopamine receptor, a D2-like receptor, is selectively expressed in the ventral striatum, particularly in the shell of nucleus accumbens and islands of Calleja, where it is found in medium sized substance P neurons. The latter co-express the D1 receptor whose interaction with the D3 receptor was studied by treating rats with selective agonists and antagonists. In agreement with the opposite cAMP response, they mediate in cultured neuroblastoma cells, the D1 and D3 receptors exerted opposite influences on c-fos expression in islands of Calleja. However, in agreement with the synergistic influence of cAMP on D3 receptor-mediated mitogenesis on the same cultured cells, D1 and D3 receptor stimulation in vivo synergistically enhanced preprotachykinin mRNA in the shell of accumbens. This indicates that the two receptor subtypes may affect neurons in either synergy or opposition according to the cell or signal generated. Levodopa-induced behavioral sensitization in hemiparkinsonian rats is another example of D1/D3 receptor interaction. Hence repeated levodopa administration induces the ectopic appearance of the D3 receptor in substance P/dynorphin, striatonigral neurons of the dorsal striatum. This induction is secondary to D1 receptor stimulation in neurons of the denervated side and fully accounts for the sensitization, i.e. the increased behavioral responsiveness to levodopa. During brain development, a similar process could operate to control the late appearance of the D3 receptor in D1-receptor bearing neurons of the ventral striatum at a time at which they start to be innervated by dopamine neurons. Finally, taking into account a variety of genetic, developmental, neuroimaging and pharmacological data, we postulate that imbalances between the levels of D1 and D3 receptors in the same neurons could be responsible for schizophrenic disorders.
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PMID:Functional implications of multiple dopamine receptor subtypes: the D1/D3 receptor coexistence. 965 37

The D3 receptor is recognized with high affinity by all antipsychotics and selectively expressed in limbic brain areas participating in the central of emotions, motivation and reward. In transfected cultured cells, stimulation of the D3 receptor inhibits cAMP formation and increases mitogenesis, which, in turn, is potentiated by activation of the cAMP cascade. This suggests that both opposite and synergistic interactions occur between the D3 receptor and the cydic AMP pathway, possibly underlying D1/D3 receptor interactions. In fact, D1 and D3 receptors colocalize in the islands of Calleja, in which they interact in opposition on c-fos mRNA expression, and in the shell of nucleus accumbens, in which they interact in synergy on substance P mRNA expression. The expression of the D3 receptor is highly dependent of the dopamine innervation: lesion of ascending dopamine neurons reduces D3 receptor mRNA and binding in the shell of nudeus accumbens, by deprivation of an unknown factor of dopamine neurons, distinct form dopamine and its cotransmitters. In agreement, expression of the D3 receptor in neurons during rat brain development starts after the settlement of dopamine innervation during the first postnatal week. However, in adult rats with a unilateral lesion of dopamine neurons, repeated treatment with levodopa rescues D3 receptor expression in the shell of nudeus accumbens and induces this expression in the dorsal striatum, a region controlling movements in which the D3 receptor is normally absent. This induction seems responsible for the behavioral sensitisation, i.e. increased responsiveness to levodopa. These observations suggest a role of the D3 receptor in the progressive increase in the therapeutic efficacy of levodopa in the initial treatment of Parkinson's disease, and/or its adversive motor and psychopathological effects during long-term treatment. Finally, various pharmacological and genetic data suggest a role of the D3 receptor in drug addiction and schizophrenia, the treatment of which could benefit from selective D3R agents.
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PMID:[Function and therapeutic potential of the dopamine D3 receptor]. 1010 7

Neuropeptides: corticotropin releasing factor (CRF), neuropeptide Y (NPY) and somatostatin (STS) have been associated with depression and anxiety, while neurotensin (NT), calcitonin gene-related peptide (CGRP) and tachykinins [neurokinin A (NKA) and substance P (SP)] are presumed to also play a role in the function of the dopaminergic system. Moreover, investigations in the past decade have shown that psychotomimetics and antipsychotic drugs as well as lithium affect brain synthesis, tissue concentrations, and release of some neuropeptides. In view of the above, experiments were carried out to explore whether changes in neuropeptides constitute one of the mechanisms of action of electroconvulsive treatment (ECT). Human cerebrospinal fluid (CSF) was studied before and after ECT, and brains from healthy and models of depression rats were investigated in electroconvulsive stimuli (ECS)-treated and sham-treated animals. The major findings were that a series of ECTs, in parallel to clinical recovery, increased CSF concentrations of NPY-like immunoreactivity (-LI), STS-LI, and CRF-LI, and in one study endothelin-LI. A series of ECS, but not a single treatment, reproducibly elevated concentrations of NPY-LI, NKA-LI, and STS-LI--but not NT-LI, SP-LI, galanin-LI, or CGRP-LI--in hippocampus, frontal cortex, and occipital cortex. No changes were measured in other regions, e.g., striatum. NPY and STS mRNAs were also increased indicating that ECS affects peptide synthesis. Generalized seizures induced by, e.g., kainic acid or pentylenetetrazole, had similar effects on neuropeptides. The changes persisted for at least 1 week after the last treatment. Pretreatment with compounds reducing seizures, such as benzodiazepines and MK-801; had no effect on magnitude of neuropeptide changes although the seizure duration was decreased by > 50%. On the basis of these findings, it is suggested that neuropeptides are involved in ECT's mechanisms of action. Since ECT is therapeutically efficient in both schizophrenia and depression and, taking into account that antipsychotic drugs and psychotomimetics as well as lithium selectively affect some neuropeptides, it is hypothesized that distinct combinations of neuropeptide and monoamine changes in selected neuronal populations constitute the underpinnings of ECT's effects on specific disease symptoms, conceivably independent of diagnosis.
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PMID:Neuropeptides and electroconvulsive treatment. 1018 19

It has been hypothesized that a deleterious key contribution to schizophrenia (SZ) development is a failure of migration and setting of young neurons into their appropriate cortical target sites, particularly in the entorhinal cortex (EC). To test this hypothesis in an animal model, we injected, in pregnant rats, on gestational day (GD) 9, or 10, or 11, or 12, the antimitotic compound methylazoxymethanolacetate (MAM) known to cause EC neuronal loss. We investigated whether or not EC disruption during prenatal development is able to affect behavior, including memory and learning, and brain nerve growth factor (NGF). Prenatally MAM treated young rats didn't display gross behavioral changes in social interaction, open-field and novel object investigation tests. By contrast, GD11 and GD12 MAM treated rats had a retardation in passive avoidance acquisition, while, in GD12 animals, pain sensitivity was reduced. GD12 animals also showed increased NGF in the EC and remaining cortex. MAM treated animals showed no changes in paw NGF or substance P levels suggesting that the altered nociceptive response is not related to local downregulation of these two molecules. The possibility that these behavioral and biochemical alterations might be associated with the onset of SZ is discussed.
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PMID:Prenatal methylazoxymethanol acetate alters behavior and brain NGF levels in young rats: a possible correlation with the development of schizophrenia-like deficits. 1046 89

We investigated the effects of a schizophrenomimetic drug, phencyclidine (PCP), on substance P (SP) contents in the discrete rat brain areas using an enzyme-immunoassay for SP. The acute intraperitoneal (i.p.) administration of PCP (10 mg/kg), which is a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) type glutamate receptor and a dopamine uptake inhibitor, reduced the concentration of the peptide in the prefrontal cortex, limbic forebrain, striatum, and substantia nigra, but not in the ventral tegmental area, at 60 or 120 min postinjection. A selective noncompetitive NMDA antagonist, dizocilpine hydrogen maleate ((+)-MK-801) (1 mg/kg, i.p.), also caused a decrease in the SP content in the prefrontal cortex and limbic forebrain but failed to alter the content in the other areas studied 30 min thereafter. Dopamine agonists, methamphetamine (4.8 mg/kg, i.p.) and apomorphine (4.4 mg/kg, i.p.), diminished the SP contents in the striatum and substantia nigra 60 min after their injection without effects in the prefrontal cortex, limbic forebrain, and ventral tegmental area. Furthermore, pretreatment with haloperidol (1 mg/kg, i.p.), a D2 preferable dopamine receptor antagonist and a typical antipsychotic, blocked the ability of PCP to decrease the SP concentrations in the substantia nigra but not in the prefrontal cortex. PCP, therefore, might diminish the SP levels by NMDA receptor-mediated and dopamine-independent mechanisms in the prefrontal cortex and limbic forebrain, but by NMDA receptor-independent and dopamine-dependent mechanisms in the striatum and substantia nigra. The haloperidol-insensitive reduction of the frontal SP could be involved in certain neuroleptic-resistant symptoms of PCP-treated animals, PCP psychosis, or schizophrenia.
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PMID:Differential effects of haloperidol on phencyclidine-induced reduction in substance P contents in rat brain regions. 1065 39


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