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Investigations of the Role of Protein Kinase C in the Acute Sedative Effects of Ethanol
Author(s) -
Deitrich Richard A.,
Bludeau Pequita A.,
Baker Rodney C.
Publication year - 1989
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.1989.tb00413.x
Subject(s) - protein kinase c , cytosol , in vivo , phorbol , chemistry , endocrinology , in vitro , medicine , activator (genetics) , ethanol , pharmacology , enzyme , biochemistry , biology , receptor , microbiology and biotechnology
The activity of protein kinase C (PKC) in whole brain and brain areas of mice selectively bred for resistance (short sleep, SS) or sensitivity (long sleep, LS) to the acute ataxic effect of ethanol has been investigated. The cytosolic and membrane fractions of whole brain PKC activities are significantly less in LS mice than in SS mice. There are significant differences in PKC activity between brain areas in both the SS and LS lines. Ethanol given in ataxic doses results in significantly increased amounts in PKC activity in whole brain cytosolic fractions and in some brain areas but egually in both SS and LS mice. Ethanol added in vitro reduced enzyme activity slightly in SS brain membranes, suggesting that the mechanism of the increase in PKC activity seen after in vivo administration is indirect. These results indicate that PKC is not involved in the mechanism whereby LS and SS mice differ in alcohol sensitivity. Direct intracerebroventricular (ICV) injection of phorbol myristate acetate (PMA), an activator of PKC, resulted in increased sleep times in both SS and LS mice. ICV injection of PMA also caused a more marked decrease in body temperature in LS than in SS mice. The half‐life of PMA in brain was determined to be 9.6 hr and no metabolites could be detected. At limiting calcium concentrations, PMA added in vitro activated PKC equally well in both lines. However, PMA given ICV did not alter the level of PKC as determined in vitro. Administration of phorbol myristate‐acetate intraperitoneally (i.p.) to LS mice increased their sleep time response to ethanol and caused a prolonged depression of temperature when given alone. Similar treatment of SS mice caused no change or a decreased sleep time and a smaller temperature drop as compared to LS mice. There was no effect of i.p.‐administered PMA or PMA plus ethanol on PKC activity in whole brain cytosol or membrane fraction except for a decreased activity in membranes of SS mice given PMA alone. It was found that only small amounts of PMA given i.p. reached the brain. There appears to be different mechanisms by which phorbol esters alter sleep time in these mice, one via a central effect which is not related to why LS and SS mice differ and one via a peripherial effect that may be related to the SS and LS differences.