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

Several findings suggest that glucocorticoid hormones influence the propensity of an individual to develop cocaine abuse. These hormones activate two related transcription factors, the glucocorticoid receptor and the mineralocorticoid receptor. We have shown previously that mice carrying a mutation of the glucocorticoid receptor gene specifically in neural cells, glucocorticoid receptor knock-out in the brain, show a dramatic decrease in cocaine-induced self-administration and no behavioral sensitization to this drug, two experimental procedures considered relevant models of addiction. Here, we investigated in glucocorticoid receptor knock-out in the brain mice the consequences of this mutation at the level of the expression of neuropeptide, dopamine receptor and glutamate receptor subunit mRNAs. We quantified mRNA levels in the cortex, striatum and accumbens under basal conditions and following acute or repeated cocaine treatments. Our results show that, under basal conditions, neuropeptide (substance P, dynorphin) and dopamine receptor (D1, D2) mRNAs were decreased in glucocorticoid receptor knock-out in the brain mice in the dorsal striatum but not in the accumbens. However, cocaine-induced changes in the levels of these mRNAs were not modified in glucocorticoid receptor knock-out in the brain mice. In contrast, mutant mice showed altered response in mRNA levels of N-methyl-D-aspartate, GLUR5 and GLUR6 glutamate receptor subunits as well as of enkephalin following cocaine administration. These modifications may be associated to decrease of behavioral effects of cocaine observed in glucocorticoid receptor knock-out in the brain mice.
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PMID:Gene expression regulation following behavioral sensitization to cocaine in transgenic mice lacking the glucocorticoid receptor in the brain. 1632 19

Antidepressant drugs were introduced into clinical practice in the mid-20th Century. While for the most part they have proven effective for the amelioration of depressive symptoms, they are associated with significant deficiencies. These well-recognized shortcomings have given impetus to the pursuit of new molecules that seek to improve on the efficacy, tolerability and safety of existing medications. The following article reviews several new compounds that may have antidepressant potential. Some are more advanced in development, having undergone clinical trials, whereas the clinical potential of others is yet to be explored. For this latter group of compounds, the antidepressant potential relies on their activity in validated animal models. Agomelatine and duloxetine are in the first category, having shown antidepressant efficacy in clinical trials. The blockade of cortisol secretion continues to be a focus of attention for the development of new antidepressants. Thus, synthesis inhibitors, nonpeptide antagonists of corticotropin-releasing factor and glucocorticoid receptor antagonists show some promise in clinical and preclinical tests. Antagonists of the neuropeptide substance P, vasopressin and neuropeptide Y represent a departure of approach from traditional monoamine receptor-based mechanisms. While the clinical results with one substance P antagonist have led to the cessation of further trials, other molecules are in development. Approaches to treatment based on glutamatergic transmission arose from observations in animal models. The clinical evaluation of such compounds awaits further development. The extent to which new agents can be judged to have met the goals of efficacy, tolerability and safety rely not only acute treatment trials but also on longer-term outcomes and postmarketing surveillance. Whether any of the new agents canvassed here prove to be significantly better than existing agents is clearly a judgement for the future.
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PMID:Emerging treatments for major depression. 1728 53

Glucocorticoids (GCs) are well known for their anti-inflammatory effects, which are elicited through a transcriptional mechanism via a cytosolic glucocorticoid receptor (cGR)-mediated genomic effect. However, recent in vitro studies report that GCs can act as a membrane glucocorticoid receptor (mGR). This study aimed to examine whether mometasone furoate (MF) influences the nasal symptoms induced by histamine, substance P, ATP. Furthermore, the influences of various compounds on MF action were studied in vivo. The mice were intranasally administered with nasal symptom-inciting agents, and the occurrences of sneezing and nasal rubbing were counted. MF repressed the nasal symptoms caused when it was administered 10, 30 and 60min before the induction of nasal symptoms. The repressive effect observed 10min after the administration of MF was inhibited by RU486, a GR antagonist, but not by actinomycin D, a transcriptional inhibitor. In contrast, the repressive effect observed 60min after the administration of MF was inhibited by RU486 and actinomycin D. Therefore, the effects observed 10 and 60min after the MF administration were classified as non-genomic and genomic effects, respectively. The non-genomic effect suppressed the nasal symptoms induced by m-3M3FBS, a phospholipase C (PLC) activator, and was inhibited by U-73122, a PLC inhibitor. The genomic effect was inhibited by N-(p-amylcinnamoyl) anthranilic acid, a phospholipase A2 (PLA2) inhibitor. These results indicate that MF has a non-genomic effect through repression of the activation of PLC via the mGR, and MF has also a genomic effect that was influenced by the inhibition of PLA2 through transcriptional regulation via cGR.
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PMID:Genomic and non-genomic effects of glucocorticoids on allergic rhinitis model in mice. 2358 58


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