ABSTRACT
Striatal-enriched protein tyrosine phosphatase (STEP) is abundantly expressed in the striatum, which strongly expresses dopamine and opioid receptors and mediates the effects of many drugs of abuse. However, little is known about the role of STEP in opioid receptor function. In the present study, we generated STEP-targeted mice carrying a nonsense mutation (C230X) in the kinase interaction domain of STEP by screening the N-ethyl-N-nitrosourea (ENU)-driven mutant mouse genomic DNA library and subsequent in vitro fertilization. It was confirmed that the C230X nonsense mutation completely abolished functional STEP protein expression in the brain. STEP(C230X−/−) mice showed attenuated acute morphine-induced psychomotor activity and withdrawal symptoms, whereas morphine-induced analgesia, tolerance and reward behaviors were unaffected. STEP(C230X−/−) mice displayed reduced hyperlocomotion in response to intrastriatal injection of the μ-opioid receptor agonist DAMGO, but the behavioral responses to δ- and κ-opioid receptor agonists remained intact. These results suggest that STEP has a key role in the regulation of psychomotor action and physical dependency to morphine. These data suggest that STEP inhibition may be a critical target for the treatment of withdrawal symptoms associated with morphine.
Subject(s)
Animals , Mice , Analgesia , Brain , Codon, Nonsense , Dopamine , Enkephalin, Ala(2)-MePhe(4)-Gly(5)- , Ethylnitrosourea , Fertilization in Vitro , Gene Library , Mass Screening , Morphine , Phosphotransferases , Protein Tyrosine Phosphatases , Receptors, Opioid , Reward , Illicit Drugs , Substance Withdrawal SyndromeABSTRACT
Glucocorticoids, dexamethasone, 6 alpha-methylprednisolone are routinely administered to brain tumor patients to reduce peritumoral edema before surgical removal of the tumor. In addition, the glucocorticoids can inhibit growth of several cell lines. Retinoic acid, a derivative of vitamin A is also known to inhibit growth of several cell lines. Sometimes inhibition of growth accompany morphological changes. In the present study, we compared the effects of dexamethasone, 6 alpha-methylprednisolone, and retinoic acid on the growth and on the morphology of a rat glioma cell line, C6. We found that all of them can maximally inhibit the growth of C6 by approximately 30%(p<0.0025) in the presence of 10 microM of either dexamethasone, 6 alpha-methylprednisolone or retinoic acid under our experimental conditions. However, only retinoic acid could induce the morphological changes of C6 at the concentrations over 1 microM concentration, which was elongation of the cells. The morphological changes were observed both at the subconfluent and confluent cell population. When mixture of 10 microM of dexamethasone and 10 microM of retinoic acid was added, no further increase in the inhibition of growth was observed compared with the inhibition obtained by adding 10 microM of dexamethasone only. The results suggest that the glucocorticoids might have effedts of growth inhibition of the glial tumor in vivo.
Subject(s)
Animals , Humans , Rats , Brain Neoplasms , Cell Line , Dexamethasone , Edema , Glioma , Glucocorticoids , Tretinoin , Vitamin AABSTRACT
No abstract available.