Plasma dihydroxyphenylglycol and the intraneuronal disposition of norepinephrine in humans.

Abstract

We examined plasma levels of the sympathetic neurotransmitter norepinephrine (NE) and its deaminated metabolite dihydroxyphenylglycol (DHPG) during supine rest in healthy human subjects and in sympathectomized patients, during physiological (tilt) or pharmacological (yohimbine, clonidine) manipulations known to affect sympathetically mediated NE release, during blockade of neuronal uptake of NE (uptake-i) using desipramine, and during intravenous infusion of NE. Healthy subjects had a mean arteriovenous increment in plasma DHPG in the arm (10%, P < 0.05), whereas sympathectomized patients had a mean arteriovenous decrement in DHPG in the affected limb (mean decrease 21%, P < 0.05 compared with healthy subjects). Tilt and yohimbine, which stimulate, and clonidine, which inhibits, release of endogenous NE, produced highly correlated changes in plasma NE and DHPG (r = 0.94). Pretreatment with desipramine abolished DHPG responses to yohimbine while enhancing NE responses. To attain a given increase in plasma DHPG, about a tenfold larger increment in arterial NE was required during NE infusion than during release of endogenous NE. When plasma NE was markedly suppressed after administration of clonidine, plasma DHPG decreased to a plateau level of 700-800 pg/ml. The results indicate that (i) plasma DHPG in humans is derived mainly from sympathetic nerves; (ii) increments in plasma DHPG during stimulation of NE release result from uptake of NE into sympathetic nerve endings and subsequent intraneuronal conversion to DHPG; (ii) plasma DHPG under basal conditions probably is determined mainly by net leakage of NE into the axonal cytoplasm from storage vesicles; and (iv) increments in NE concentrations at neuronal uptake sites can be estimated by simultaneous measurements of DHPG and NE during NE infusion and NE release. Measurement of NE and DHPG provides unique clinical information about sympathetic function.

Effects of Risperidone on the Peripheral Noradrenegic System in Patients with Schizophrenia A Comparison with Clozapine and Placebo

“…Production of 3 H-DHPG in patients on risperidone was similar to what was found in patients on placebo and those treated with clozapine, with or without correction of 3 H-DHPG levels for concurrent plasma 3 H-NE levels. As 3 H-DHPG production in this setting results virtually exclusively from metabolism of 3 H-NE in the sympathetic axoplasm (Goldstein et al 1988;Goldstein 1995), the finding of normal 3 H-DHPG and 3 H-DHPG/ 3 H-NE ratio responses would appear to eliminate decreased neuronal reuptake as the mechanism of high plasma NE levels in risperidone-treated patients.…”

“…Clearly, even a small amount of inhibition of reuptake would augment the amount of NE entering the plasma for a given rate of exocytotic release from the terminals. The finding of high plasma NE levels in patients treated with risperidone without a corresponding increase in plasma DHPG would suggest that impaired NE reuptake might be involved in the NE increase, because plasma DHPG reflects the metabolism of axoplasmic NE (Goldstein et al 1988;Goldstein 1995). All other things being the same, decreased reuptake of NE would increase NE spillover but decrease plasma DHPG levels.…”

“…Because formation of 3 H-dihydroxyphenylglycol (DHPG) from 3 H-NE requires both neuronal uptake and intraneuronal deamination by MAO, measurement of plasma 3 H-DHPG responses furnished the basis for examining the effects of risperidone. Plasma levels of the NE precursor, dihydroxyphenylalanine (DOPA), and of the dopamine metabolite, dihydroxyphenylacetic acid (DOPAC), were also measured to provide information about NE synthesis (Goldstein et al 1987;Goldstein 1995) and about intraneuronal metabolism by monoamine oxidase (MAO; Goldstein 1995).…”

“…Because formation of 3 H-dihydroxyphenylglycol (DHPG) from 3 H-NE requires both neuronal uptake and intraneuronal deamination by MAO, measurement of plasma 3 H-DHPG responses furnished the basis for examining the effects of risperidone. Plasma levels of the NE precursor, dihydroxyphenylalanine (DOPA), and of the dopamine metabolite, dihydroxyphenylacetic acid (DOPAC), were also measured to provide information about NE synthesis (Goldstein et al 1987;Goldstein 1995) and about intraneuronal metabolism by monoamine oxidase (MAO; Goldstein 1995).Our previous work suggested that clozapine has complex effects on the noradrenergic system, producing a robust increase in NE, but without an expected proportional increase in DHPG (Breier et al 1994b;Elman et al 1999). We hypothesized, based on the receptor binding profile of risperidone, that patients treated with the drug would display different characteristics of the noradrenergic response than their clozapine-treated counterparts.…”

“…Specifically, risperidone's very potent antagonism at the ␣ 1 and ␣ 2 adrenoceptors (Schotte et al 1993;Richelson 1999) was expected to increase sympathetic outflow, caused by vasodilatation (from ␣ 1 effects) and blockade of inhibitory ␣ 2 adrenoceptors on sympathetic nerves, thus producing high NE spillover. This would be combined with heightened intraneuronal NE metabolism and production of DHPG, as adrenoceptor blockade usually produces increases in DHPG plasma levels that parallel the NE increases (Breier 1994;Goldstein 1995). …”