Central Norepinephrine Turnover Research Articles

Chronic desipramine treatment desensitizes the rat to anesthetic and antinociceptive effects of the alpha2-adrenergic agonist dexmedetomidine.

The effects of long-term administration of the tricyclic antidepressant agent desipramine on the hypnotic, antinociceptive, anesthetic-sparing, and central norepinephrine turnover suppressant action of short-term dexmedetomidine, a highly selective alpha2-adrenergic agonist, were studied in rats. Rats were given a 3- or 4-week course of twice daily administration of desipramine, 10 mg/kg, or saline. The effect of a hypnotic dose of dexmedetomidine, 250 microg/kg given intraperitoneally, on the duration of loss of righting reflex was determined. The tail flick latency response was determined before and after 50 microg/kg dexmedetomidine. The minimum anesthetic concentration of halothane and the central norepinephrine turnover rate were determined before and after administration of 30 microg/kg dexmedetomidine. Changes in the affinity and density of the alpha2-adrenergic receptor in locus coeruleus and spinal cord also were determined. Treatment with desipramine decreased dexmedetomidine-induced loss of righting reflex duration by 67% and eliminated the antinociceptive effect of dexmedetomidine. Dexmedetomidine produced a 55% decrease in minimum anesthetic concentration in the control group but no reduction in desipramine-treated rats. Desipramine did not change the receptor density or binding affinity of alpha2 receptors at the site for hypnotic (locus coeruleus) or antinociceptive (spinal cord) responses. No decrement in the central norepinephrine turnover rate was noted in the locus coeruleus of dexmedetomidine after 3 weeks of treatment with desipramine. The alpha1-adrenergic antagonist prazosin at 1 or 5 mg/kg completely (minimum anesthetic concentration reduction), almost completely (antinociceptive), or partially (hypnotic) restored responsiveness to normal. These data indicate that treatment with desipramine induces hyporesponsiveness to the hypnotic, analgesic, and minimum anesthetic concentration-reducing, but not to the suppression of central norepinephrine turnover, properties of dexmedetomidine. The hyporesponsiveness appears to involve an alpha1-adrenergic mechanism.

Central neural mechanism contributing to attenuation of angiotensin II-induced hypertension in rats on dietary calcium supplementation.

The effect of dietary calcium (Ca) supplementation on blood pressure (BP) and the central nervous system (CNS) mechanism underlying this effect were studied in angiotensin II (Ang II)-induced hypertensive rats. The effects of dietary Ca (0.5, 2, 4%) on systolic blood pressure (SBP), ionized Ca concentration (Ca++) in cerebrospinal fluid (CSF) and central norepinephrine (NE) turnover were investigated in male Wistar rats receiving subcutaneous infusion of Ang II (100 ng/min). Central NE turnover was studied by measuring 3-methoxy-4-hydroxyphenylglycol (MHPG) concentration in CSF with multiple electrode liquid chromatography. Ang II significantly increased SBP, and dietary Ca dose-dependently attenuated the increase. SBP inversely correlated with Ca++ and MHPG in CSF. Intracerebroventricular injection of CaCl2 more markedly reduced BP in Ang II-treated rats than that in control rats. These results suggest that modulation of central NE turnover possibly caused by the increase in CNS Ca++ is involved in the anti-hypertensive mechanism of dietary Ca supplementation in Ang II-induced hypertensive rats.

The evaluation of 4-hydroxy-3-methoxyphenylglycol sulfate as a possible marker of central norepinephrine turnover. Studies in healthy volunteers and depressed patients

Much evidence indicates that urinary 4-hydroxy-3-methoxyphenylethyleneglycol (MHPG) is an insensitive measure of central norepinephrine metabolism. This conclusion, however, seems to apply mainly to total urinary MHPG, since previous findings point to the possibility that the major proportion of urinary MHPG sulfate originates in the CNS, while most urinary MHPG glucuronide originates in peripheral organs. To examine this hypothesis, experiments were performed by which we altered MHPG turnover in man at two different stages: firstly, strong physical exercise (ergometer) increased the urinary excretion rate of MHPG glucuronide and not that of MHPG-sulfate; secondly, ethanol (1 g/kg), which is known to block the metabolism of MHPG to vanilmandelic acid in the liver, increases the urinary excretion rate of the glucuronide and not that of sulfate. Both experiments indicate that alteration of peripheral norepinephrine turnover changes the urinary excretion of MHPG glucuronide only and not that of sulfate, thus providing strong, albeit indirect, evidence for a primarily central origin of MHPG sulfate. Preliminary experiments in 32 depressed patients showed little difference in both MHPG fractions compared with healthy controls, apart from a slightly reduced excretion rate of glucuronide. These findings fail to provide any evidence of central, and only small changes in peripheral norepinephrine metabolism in depression.

The effects of caffeine on plasma MHPG, subjective anxiety, autonomic symptoms and blood pressure in healthy humans

The effects of oral administration of caffeine (10 mg/kg) on plasma free 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) levels, behavioral ratings, blood pressure, and autonomic symptoms was determined in eleven healthy subjects. Caffeine produced robust increases in subject rated anxiety and nervousness and small elevations in blood pressure and a decrease in heart rate. Caffeine did not alter plasma MHPG in a consistent fashion and there was no correlation between changes in plasma MHPG and changes in anxiety or other ratings. Caffeine may produce symptoms of anxiety-nervousness without increasing central norepinephrine turnover.

Action of antihypertensive drugs in the central nervous system.

Several major antihypertensive agents appear to act by stimulating alpha receptors in the central nervous system. Other agents which lower blood pressure by peripheral mechanisms also have important central effects. Recent studies suggest that by enhancing norepinephrine turnover in the brain one can obtain a reduction in blood pressure in experimental animals. We have studied the enhancement of central norepinephrine turnover by tyrosine administration and by the antihypertensive agent Prazosin.

Origin of free 3-methoxy-4-hydroxyphenylethyleneglycol.

The origin of free 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG, a major metabolite of norepinephrine) in rat cerebrospinal fluid (CSF) was investigated using brain and spinal cord perfusions with artificial CSF, electrical stimulation of the locus coeruleus (LC) and the technique of retrograde cell labelling with horseradish peroxidase (HRP). The rates of appearance of MHPG into ventricular-cisternal and lumbar-cisternal perfusates were about 12.4 and 19.2 ng/hour respectively. Probenecid (200 mg/kg i.p.) did not alter the MHPG output in either preparation. Intravenous administration of 3 micrograms MHPG did not substantially enhance the outflow of the metabolite in the ventricular-cisternal perfusate, indicating that MHPG found in the perfusate is of central origin. Maximal activation of central norepinephrine (NE)-containing neurons of the LC by electrical stimulation induced a 50% increase of MHPG levels in the ventricular-cisternal perfusate. In addition HRP was found to be retrogradely transported from the lateral ventricle to these LC-neurons. These findings indicate that MHPG in CSF originates, at least in part from NE of nerve terminals adjacent to the cerebral ventricles, which have their origin in the LC. We calculated that the fraction of MHPG formed in the central nervous system, that was released into the CSF was about 34%. It is concluded that MHPG in CSF is a measure for changes in central NE turnover and that a considerable portion is dependent upon the activity of LC neurons.