Striatal tyrosine hydroxylase: comparison of the activation produced by depolarization and dibutyryl-cAMP.
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Biomedical subjects
Publications and source records attributed to R H Roth.
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At various time points following acute and chronic administration of morphine to rats, dopamine transmitter metabolism and neuronal activity were determined. Following acute injection of morphine (20 mg/kg intraperitoneally), dopamine cell firing rates increased slowly and steadily. This slow increase was accompanied by a similar slow increase in the accumulation of the dopamine metabolite, dihydroxyphenylacetic acid (DOPAC). Apparent in vivo tyrosine hydroxylase activity, measured by dopa accumulation following inhibition of dopa decarboxylase, also increased. In chronically treated animals the average firing rate of dopamine cells was measured two hours after the last injection of morphine. The distribution of dopamine cell firing rates was significantly higher than in controls. DOPAC levels and in vivo tyrosine hydroxylase activity were also increased at this time. When morphine (100 mg/kg intraperitoneally) was administered to chronically treated animals 12 hours after the last injection a slow increase of firing rates was observed similar to that seen in naive animals after an acute morphine injection. In chronically morphine treated animals naloxone caused a rapid dose-dependent decrease in firing rates and DOPAC levels. In vivo tyrosine hydroxylase activity was not changed.
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Gamma-Hydroxybutyric acid (GHB), a compound that has interesting neuropharmacological actions when administered systemically, was shown by means of gas chromatography-mass spectrometry to be present in postmortem samples of human brain in concentrations ranging from 2 to 20 nmol/g. Tissue samples from the basal ganglia contained 2 to 3 times as much GHB as tissue samples from cortical regions. The regional brain distribution of GHB was examined in the guinea pig and rhesus monkey and found to parallel the distribution observed in human brain. The levels of GHB found in the regional areas of human and monkey brain investigated were higher than the levels found in similar regions of guinea-pig brain. Additional studies demonstrated that there is a slow postmortem increase (about 2-fold) in the endogenous levels of GHB in bovine caudate and guinea-pig brain which is maximal about 6 hr postmortem. This postmortem increase could in part explain the higher levels of GHB found in human brain. However, postmortem changes could not account for the large differences observed in the levels of GHB found in bovine caudate and those found in guinea-pig, monkey and human caudate. Only traces of GHB could be detected in human blood and cerebrospinal fluid.
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A direct method for measuring the rate of production of neurotransmitter metabolites by the brain of awake monkeys is described. The method utilizes a coupling of a measure of cerebral blood flow with the determination of the difference in concentration of the metabolite under study in arterial and internal jugular bulb blood. A consistent veno-arterial difference for 3-methoxy-4-hydroxyphenethylenglycol (MHPG) has been found. The concentration of MHPG in blood obtained from the right and left venous outflows from brain were not significantly different indicating that blood from either the right or left internal jugular bulb may be used with this method. The rate of production of MHPG by the brain of thw awake monkey is estimated to be 24.1 ng/100 g brain/min. The rate of MHPG production by brain is increased by the administration of piperoxan and decreased by clonidine. Using the experimentally determined rate of production of MHPG by brain and extrapolating to the human it is suggested that a substantial fraction of the total body production of MHPG in man occurs in brain.
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