Biomedical subjects

D S Goldstein

Publications and source records attributed to D S Goldstein.

At least 127 records · Page 7Linked to original sources

PubMed1995

Differential actions of desipramine on sympathoadrenal release of noradrenaline and adrenaline.

Spillovers noradrenaline (NA) and adrenaline (A) into plasma were examined before and after i.v. administration of 0.3-0.5 mg kg-1 desipramine (DMI) in 19 normal volunteers. DMI decreased the total body spillover of NA by 20 +/- 4%, but increased that of A by 45 +/- 10%. The results indicate differential sympathoadrenal actions of DMI, characterized by inhibition of NA release from sympathetic nerves and stimulation of A secretion from the adrenals. These effects of DMI provide an explanation for some of the cardiovascular complications of tricyclic antidepressant therapy and may also help to explain how sympathoadrenal function is differentially regulated.

Adult↗

PubMed1995

Neurohumoral antecedents of vasodepressor reactions.

Vasodepressor (vasovagal) syncope, the most common cause of acute loss of consciousness, can occur in otherwise vigorously healthy people during exposure to stimuli decreasing cardiac filling. Antecedent physiological or neuroendocrine conditions for this dramatic syndrome are poorly understood. This study compared neurocirculatory responses to non-hypotensive lower body negative pressure (LBNP) in subjects who subsequently developed vasodepressor reactions during hypotensive LBNP with responses in subjects who did not. In 26 healthy subjects, LBNP at -15 and -40 mmHg was applied to inhibit cardiopulmonary and arterial baroreceptors. All the subjects tolerated 30 min of LBNP at -15 mmHg, but during subsequent LBNP at -40 mmHg 11 subjects had vasodepressor reactions, with sudden hypotension, nausea, and dizziness. In these subjects, arterial plasma adrenaline responses to LBNP both at -15 and at -40 mmHg exceeded those in subjects who did not experience these reactions. In 16 of the 26 subjects, forearm noradrenaline spillover was measured; in the eight subjects with a vasodepressor reaction, mean forearm noradrenaline spillover failed to increase during LBNP at -15 mmHg (delta = -0.06 +/- (SEM) 0.04 pmol min-1 100mL-1), whereas in the eight subjects without a vasodepressor reaction, mean forearm noradrenaline spillover increased significantly (delta = 0.31 +/- 0.13 pmol min-1 100mL-1). Plasma levels of beta-endorphin during LBNP at -15 mmHg increased in some subjects who subsequently had a vasodepressor reaction during LBNP at -40mmHg. The findings suggest that a neuroendocrine pattern including adrenomedullary stimulation, skeletal sympathoinhibition, and release of endogenous opioids can precede vasodepressor syncope.

Hemodynamics↗

PubMed1995

Production and metabolism of dopamine and norepinephrine in mesenteric organs and liver of swine.

Concentrations of catecholamines and their metabolites in plasma entering and exiting mesenteric organs, liver, and kidneys were examined to assess the regional production and metabolism of catecholamines in anesthetized swine. Higher portal venous than arterial plasma concentrations of norepinephrine and its metabolites, 3,4-dihydroxyphenylglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG), and of dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), indicated substantial production of both catecholamines by mesenteric organs, representing 45-50% of total body production. Most dopamine was not metabolized to norepinephrine, suggesting a large nonnoradrenergic contribution to total body dopamine production. Concentrations of norepinephrine, DHPG, normetanephrine, and MHPG were lower in plasma exiting than entering the liver, whereas concentrations of the end-product of norepinephrine metabolism, vanillylmandelic acid (VMA), were higher in outflowing than inflowing plasma. Over 94% of the VMA removed by the kidneys was produced in the liver, consistent with the hepatic source of this metabolite. Removal of DOPAC and HVA by the liver exceeded removal by the kidneys or production by mesenteric organs, indicating greater hepatic than renal elimination of these metabolites from the body and underestimation of mesenteric organ dopamine production based on summed spillovers of dopamine metabolites from the liver into the systemic circulation.

Animals↗

PubMed1995

Catecholaminergic effects of prolonged head-down bed rest.

Prolonged head-down bed rest (HDBR) provides a model for examining responses to chronic weightlessness in humans. Eight healthy volunteers underwent HDBR for 2 wk. Antecubital venous blood was sampled for plasma levels of catechols [norepinephrine (NE), epinephrine, dopamine, dihydroxyphenylalanine, dihydroxyphenylglycol, and dihydroxyphenylacetic acid] after supine rest on a control (C) day and after 4 h and 7 and 14 days of HDBR. Urine was collected after 2 h of supine rest during day C, 2 h before HDBR, and during the intervals 1-4, 4-24, 144-168 (day 7), and 312-336 h (day 14) of HDBR. All subjects had decreased plasma and blood volumes (mean 16%), atriopeptin levels (31%), and peripheral venous pressure (26%) after HDBR. NE excretion on day 14 of HDBR was decreased by 35% from that on day C, without further trends as HDBR continued, whereas plasma levels were only variably and nonsignificantly decreased. Excretion rates of dihydroxyphenylglycol and dihydroxyphenylalanine decreased slightly during HDBR; excretion rates of epinephrine, dopamine, and dihydroxyphenylacetic acid and plasma levels of catechols were unchanged. The results suggest that HDBR produces sustained inhibition of sympathoneural release, turnover, and synthesis of NE without affecting adrenomedullary secretion or renal dopamine production. Concurrent hypovolemia probably interferes with detection of sympathoinhibition by plasma levels of NE and other catechols in this setting. Sympathoinhibition, despite decreased blood volume, may help to explain orthostatic intolerance in astronauts returning from spaceflights.

Adult↗

PubMed1995

Decreased stress responsivity of central and peripheral catecholaminergic systems in aged 344/N Fischer rats.

We investigated the effects of stress on central and peripheral sympatho-adrenal and sympatho-neural functions in healthy, intact young (3-4 mo) and aged (24 mo) male Fischer 344/N rats. Extracellular fluid (ECF) levels of the catecholamines norepinephrine (NE), dihydroxyphenylglycol (DHPG), methoxyhydroxyphenylglycol (MHPG), and dihydroxyphenylacetic acid (DOPAC) were obtained by microdialysis in the paraventricular nucleus (PVN) of the hypothalamus at baseline and during immobilization (IMMO). The baseline levels of these substances were similar in both age groups, and their concentrations increased significantly in response to IMMO. The IMMO-induced increases of NE and MHPG, however, were significantly smaller in old than in young rats. Plasma levels of the catecholamines NE, DHPG, MHPG, DOPAC, dihydroxyphenylalanine (DOPA), epinephrine (EPI), dopamine (DA), and HVA were also determined in young and old rats during IMMO. Basal levels of these substances were significantly higher in old than in young rats. The magnitude of the IMMO-induced increases in the majority of these compounds however, was significantly smaller in old than in young rats. We conclude that, at the basal state, aging in the Fischer rat is associated with normal PVN ECF, but high plasma catecholamine levels; at stress state, however, old rats have substantially lesser activation of their central and peripheral catecholaminergic systems than young rats.

Adrenergic Fibers↗

PubMed1995

Decreased central and peripheral catecholaminergic activation in obese Zucker rats.

The Zucker rat is an animal model of autosomal recessive obesity characterized by excessive hypothalamic-pituitary-adrenal (HPA) axis and parasympathetic activities and deficient sympathetic outflow. Alterations in norepinephrine (NE) release, reuptake, and metabolism in the hypothalamic paraventricular nucleus (PVN) could also contribute to dysregulation of the HPA axis in obese Zucker rats via effects on corticotropin-releasing hormone neurons or could be secondary to some other primary defect. The present study assessed whether the obese phenotype defect. The present study assessed whether the obese phenotype (fa/fa) compared to the lean phenotype (Fa/?) of this strain was also associated with alterations in basal and immobilization (IMMO) stress-induced noradrenergic activation in the PVN, using in vivo microdialysis. To evaluate concurrent activity of the peripheral sympathetic nervous system and the HPA axis, we also measured plasma concentrations of catecholamines, ACTH, and corticosterone. IMMO-induced increases in PVN NE levels were significantly lower in obese Zucker rats, as were elevations in plasma concentrations of dihydroxyphenylglycol and epinephrine. Basal and IMMO-stimulated plasma ACTH concentrations were similar in obese and lean rats. Basal plasma corticosterone concentrations were also similar in obese and lean rats; however, IMMO-stimulated corticosterone levels were significantly greater in obese than in lean animals. Basal plasma free corticosterone levels, measured by ultrafiltration, were significantly higher in obese than in lean rats, confirming the state of chronic hypercorticosteronism in these animals. These findings indicate that obese Zucker rats have diminished central noradrenergic and peripheral sympathetic nervous system responses to IMMO stress along with a chronically hyperactive HPA axis. We suggest that defective regulation of PVN NE reflects and contributes to the development and/or maintenance of obesity in Zucker rats via central hypoactivity of the sympathetic system. The hypercorticosteronism of these animals, apparently sustained by some nonadrenergic stimulatory input, might participate in the suppression of the sympathetic system.

Adrenocorticotropic Hormone↗

PubMed1995

Catecholaminergic inhibition by hypercortisolemia in the paraventricular nucleus of conscious rats.

Administration of glucocorticoids decreases the release of corticotropin-releasing hormone and in vitro turnover of norepinephrine (NE) in the paraventricular nucleus (PVN) of the hypothalamus, and immobilization (IMMO) markedly increases NE release and stimulates corticotropin-releasing hormone neurons in the PVN. This study assessed whether hypercortisolemia affects in vivo indexes of catecholaminergic activation in the PVN. Microdialysis was used to simultaneously measure PVN microdialysate concentrations of NE, the neuronal NE metabolite dihydroxyphenylglycol, the extraneuronal NE metabolite methoxyhydroxyphenylglycol, and the dopamine metabolite dihydroxyphenylacetic acid before, during, and after 2 h of IMMO. Catecholamine synthesis was examined based on elevations of 3,4-dihydroxyphenylalanine levels after local perfusion with NSD-1015, an inhibitor of L-aromatic acid decarboxylase. Cortisol (CORT; 25 mg/kg.day) or vehicle (VEH; saline) was infused sc for 7 days via an osmotic minipump. CORT-treated rats had lower basal NE, dihydroxyphenylglycol, methoxyhydroxyphenylglycol, and dihydroxyphenylacetic acid levels and significantly smaller levels of all these compounds during IMMO than VEH-treated rats. CORT-treated rats also had less NSD-1015-induced accumulation of microdialysate 3,4-dihydroxyphenylalanine at baseline and during IMMO than VEH-treated rats. Basal and IMMO-induced plasma ACTH and corticosterone responses were reduced in CORT-treated rats. The results indicate that chronic hypercortisolemia decreases basal levels and stress-induced increments in indexes of release, metabolism, turnover, and synthesis of catecholamines in the PVN and suggest that glucocorticoids restrain the limit of hypothalamo-pituitary-adrenocortical axis activation during stress by attenuating catecholamine synthesis and release in the PVN.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1995

Glucocorticoids, sympathetic activity, and presynaptic alpha 2-adrenoceptor function in humans.

The sympathetic nervous system and the pituitary-adrenocortical system are two of the body's main stress effector systems. Animal studies have indicated that exogenously administered glucocorticoids inhibit sympathetic outflows and interfere with the function of presynaptic alpha 2-adrenoceptors modulating neuronal norepinephrine (NE) release. The present study tested whether glucocorticoids produce similar effects in humans. In a randomized, double-blind, placebo-controlled cross-over experiment, 15 healthy subjects took 20 mg prednisone or placebo orally daily each morning for 1 week, followed by the other drug after a 1-week washout. On the last day of each treatment week, blood samples were drawn for assays of plasma levels of catechols and ACTH before and after iv infusion of the alpha 2-adrenoceptor antagonist yohimbine (YOH) (0.125 mg/kg bolus, 0.001 mg.kg-1.min-1 infusion). In 7 subjects, directly recorded peroneal skeletal muscle sympathetic nerve activity (MSNA) was also measured at baseline and after YOH infusion at the end of both treatment weeks. Prednisone decreased plasma NE levels and MSNA compared with levels after placebo (1.09 +/- 0.11 nmol/L vs. 1.40 +/- 0.13 nmol/L, P < 0.01; 30 +/- 4 bursts/min vs. 36 +/- 3 bursts/min, P < 0.05) without affecting blood pressure or pulse rate. YOH increased mean arterial blood pressure by 12% (P < 0.001) and heart rate by 7% (P < 0.05); prednisone did not alter these effects of YOH. YOH-induced proportionate increments in plasma NE levels averaged about 10 times those in MSNA. Prednisone did not affect the YOH-induced proportionate increments in plasma NE levels (placebo, 243%; prednisone, 237%) or MSNA (placebo, 22%; prednisone, 23%). The decrements in MSNA and plasma NE levels after prednisone treatment indicate that glucocorticoids inhibit sympathoneural outflows in humans. The 10-fold larger NE than MSNA response to YOH confirms substantial inhibitory modulation of NE release by alpha 2-adrenoceptors on noradrenergic terminals, and the similarity of responses to YOH after prednisone or placebo suggests that glucocorticoid-induced sympathoinhibition occurs independently of altered modulatory function of alpha 2-adrenoceptors on noradrenergic terminals.

Adult↗

PubMed1995

Is there a third peripheral catecholaminergic system? Endogenous dopamine as an autocrine/paracrine substance derived from plasma DOPA and inactivated by conjugation.

In mammals, the sympathetic neurotransmitter is norepinephrine (NE), and the main adrenomedullary hormone is epinephrine (EPI). The sources and physiological roles of the third endogenous catecholamine, dopamine (DA), outside the brain have been obscure. Several lines of evidence suggest that in the periphery, rather than DA serving only as the precursor for the active compounds, released from sympathetic nerves and the adrenal medulla, DA may also act as an autocrine/paracrine regulator of local organ function. Thus, in the kidneys, most of DA formation appears to be from proximal tubular uptake of plasma DOPA, and binding of locally formed DA to dopaminergic receptors decreases Na/K ATPase activity and thereby accentuates natriuresis. In the gastric mucosa, DA may modulate sodium absorption and acid secretion. Recent clinical and laboratory animal evidence has indicated that the lungs and mesenteric organs contribute substantially to total body production and metabolism of DA. Generation of DA in non-noradrenergic, non-adrenergic cells can explain why human urine contains higher concentrations of DA and its metabolites than of NE and its metabolites. The vast preponderance of plasma DA in humans is sulfoconjugated. Since patients with sympathoneural failure have normal plasma levels of DA sulfate, one may speculate that the sulfoconjugating mechanism is relatively independent of sympathetic nerves and acts to localize DA effects and inactivate DA entering the circulation. These considerations lead to the concept of a third peripheral catecholaminergic system, where DA derived from plasma DOPA acts as an autocrine/paracrine substance and is inactivated by conjugation.

Animals↗

PubMed1994

The neuronal and extraneuronal origins of plasma 3-methoxy-4-hydroxyphenylglycol in rats.

3-Methoxy-4-hydroxyphenylglycol (MHPG) is formed by the sequential actions of monoamine oxidase (MAO) and catechol-O-methyltransferase on norepinephrine within extraneuronal tissues or by extraneuronal O-methylation of 3,4-dihydroxyphenylglycol (DHPG) produced intraneuronally from norepinephrine. This study examined the contributions of neuronal and extraneuronal norepinephrine metabolism to formation of MHPG in rats. Spillover of MHPG into plasma (605 +/- 28 pmol/kg per min) was higher than spillover of DHPG (463 +/- 15 pmol/kg per min), norepinephrine (165 +/- 9 pmol/kg per min) and normetanephrine (56 +/- 4 pmol/kg per min). Comparison of MHPG spillover with the increment in normetanephrine spillover after MAO inhibition (81 pmol/kg per min) combined with the spillover of MHPG derived from circulating normetanephrine (21 pmol/kg per min) indicated that only 17% of plasma MHPG is derived from the extraneuronal deamination and O-methylation of norepinephrine; the remaining 83% is from DHPG produced by deamination of norepinephrine within neurons. The production of MHPG from infused DHPG indicated that 30% of the MHPG in plasma is produced by O-methylation of DHPG after entry of DHPG into the bloodstream and 53% (83-30) from metabolism of DHPG before its entry into the bloodstream. Metabolism of circulating norepinephrine made a minor (1-3%) contribution to plasma concentrations of DHPG and MHPG, but a much larger (46%) contribution to plasma normetanephrine. The results provide a comprehensive examination of norepinephrine metabolism by O-methylation and deamination pathways. Since MHPG is the principal norepinephrine metabolite excreted in the rat, the findings also show that total body turnover of norepinephrine is dependent mainly on neuronal metabolism of the transmitter; at rest extraneuronal pathways contribute as little as 15% to norepinephrine turnover.

Animals↗

PubMed1994

Improved assay for plasma dihydroxyphenylacetic acid and other catechols using high-performance liquid chromatography with electrochemical detection.

Several modifications of an HPLC-electrochemical assay method for plasma levels of norepinephrine (NE), epinephrine (EPI), dopamine (DA), dihydroxyphenylglycol (DHPG), dihydroxyphenylalanine (DOPA) and dihydroxyphenylacetic acid (DOPAC) that improve the accuracy and reliability of DHPG, DOPA, and DOPAC measurements are described. In batch alumina extractions, increasing the amount of alumina decreased analytical recoveries of DHPG, DOPA, and especially DOPAC, and increasing the strength of the eluting acid increased recoveries of these catechols, without affecting recoveries of the amines NE, EPI and DA. Refrigeration (4 degrees C) until injection stabilized DOPAC in aqueous solution and therefore improved the reproducibility of plasma DOPAC measurements. Circulation of chilled water (15 degrees C) around the column using a water jacket decreased variability in retention times of the catechols and thereby facilitated identification of peaks, while enhancing separation of DHPG from the solvent front. Use of 6-fluoro-DOPA and 6-fluoro-DOPAC as internal standards did not improve inter-assay reliability. We recommend that in assays of plasma catechols including DOPAC, small (5 mg), precisely measured amounts of alumina be used, with a relatively strong eluting solution (e.g. 0.04 M phosphoric acid-0.2 M acetic acid, 20:80, v/v), and that the samples be refrigerated until injection, with column temperature held constant at less than 20 degrees C.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

Modification of cerebral cortical noradrenaline release by chronic inhibition of MAO-A.

Chronic treatment of rats with clorgyline (1 mg/kg i.p. daily for 21 days) caused a highly significant increase in the concentration of noradrenaline in microdialysate from the frontal cortex of the awake animal. Acute (one injection, 2 mg/kg) or subacute (1 mg/kg daily for 3 days) treatment did not lead to a significant increase in microdialysate noradrenaline. Concentrations of deaminated metabolites (DPHG, MHPG, DOPAC) in the microdialysate decreased with time of treatment, reaching a minimum after 21 days.

Animals↗

PubMed1994

Prostate cancer screening: role of the digital rectal examination and prostate-specific antigen.

BACKGROUND: This study was designed to determine the efficacy of digital rectal examination (DRE) and serum prostate-specific antigen (PSA) for early detection of prostate cancer in men > or = 50 years of age. METHODS: A prospective single-center clinical trial was conducted to screen 644 asymptomatic men, who were elicited by newspaper and radio advertisements, with DRE and PSA. Quadrant biopsy examinations of the prostate were performed if PSA > 4 ng/ml or if DRE was suspicious. RESULTS: Thirty-seven percent of the men (n = 241) had an abnormality of DRE or elevated PSA. Of the 163 patients who underwent transrectal ultrasound and quadrant biopsies of the prostate, 77% had normal biopsies, 14 (8%) had prostatic intraepithelial neoplasia, and 24 (15%) had carcinoma of the prostate. PSAs ranged from 0.3 to 65.5 ng/ml, with a mean of 2.35 and a median of 1.6. Ninety-five patients had a PSA > 4 ng/ml, of whom 17 had a PSA > 10 ng/ml. Sensitivity of PSA was 75% and specificity 87%; for DRE the sensitivity was 75% and the specificity 69%. Clinical stage of patients who underwent radical prostatectomy was B1 in 15 and B2 in five. Fifteen of 20 patients (75%) had organ-confined disease; the other five had specimen-confined disease. No patient was found to have nodal involvement. CONCLUSION: The combination of PSA and DRE seems to improve the stage of diagnosis of patients with prostate cancer. Larger, randomized studies will be necessary to evaluate the effect of screening on overall survival.

Aged↗

PubMed1994

New approaches to evaluate sympathoadrenal system activity in experiments on earth and in space.

In previous studies the activity of the sympathoadrenal system (SAS) in cosmonauts during space flights was evaluated by measuring plasma catecholamines (CA) levels and urinary CA and their metabolites concentrations. Plasma CA levels are accepted indicators of SAS activity, however, they are determined by the plasma clearances as well as the rates of CA release (spillover-SO) into the bloodstream. Nowadays methods are available which evaluate not only plasma levels of CA but also their release, spillover, uptake, reuptake, degradation and also CA synthesis in vivo measured by plasma levels of dihydroxyphenylalanine (DOPA). Plasma concentrations of DOPA, the CA noradrenaline (NE), adrenaline (ADR), and dopamine (DA), the deaminated catechol metabolites dihydroxyphenylglycol (DHPG) and dihydroxyphenylacetic acid (DOPAC), and the O-methylated metabolites methoxyhydroxyphenylglycol (MHPG) and homovanillic acid (HVA) were measured during immobilization stress (IMO) in conscious rats. Radiotracer methods were used to measure NE SO. IMO markedly increased arterial NE levels but NE SO was less elevated because the NE clearance was slightly reduced in IMO rats. Simultaneous measurements of plasma CA and their metabolites provide another means to obtain information about SAS function. For instance, dissociation between changes of plasma DHPG and NE levels can indicate changes in neuronal reuptake of NE. We found marked parallel increases in plasma NE and DHPG levels during acute IMO; however after repeated IMO, plasma NE levels were increased but DHPG responses were less pronounced suggesting a reduced NE reuptake. DOPA, the CA precursor, circulates in plasma at a concentration higher than NE. During stress, increased sympathoneural outflow stimulates DOPA synthesis and release into the circulation supporting the view that changes in plasma DOPA levels during stress reflect in vivo changes in the rate of CA synthesis. We propose to measure the new plasma indicators of SAS activity in cosmonauts and/or in animals before, during and after space flights.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

Urinary excretion rate of endothelin-1 in patients with essential hypertension and salt sensitivity.

To assess the possible role of ET-1 in the pathogenesis of hypertension and salt sensitivity levels of immunoreactive endothelin-1 (irET-1) were measured in plasma and urine of 17 patients with essential hypertension and in 19 normotensive control subjects. Effects of alterations in dietary sodium content on urinary irET-1 levels also were assessed. Plasma levels of irET-1 did not differ between the hypertensives and normotensive groups (1.1 +/- 0.3 and 1.3 +/- 0.1 pg/ml). Urine samples of both groups contained high concentrations of irET-1. However, the mean daily urinary excretion of irET-1 in the hypertensives was less than one-third that in controls (29 +/- 3 vs. 109 +/- 21 ng/day, respectively, P < 0.01). Changing dietary sodium content in the hypertensives had no effect on mean irET-1 excretion. However, on either low, intermediate, or high salt diet, "salt sensitive" hypertensives had lower levels of the peptide than "salt resistant" patients (23 +/- 3 vs. 36 +/- 5 ng/day, respectively, P < 0.05). The data demonstrate a marked reduction in irET-1 excretion in patients with essential hypertension, despite normal plasma levels of the peptide. Since ET-1 has diuretic and natriuretic properties, the decreased renal excretion of ET-1 may be of relevance to the pathophysiology of hypertension and salt sensitivity.

Adult↗

PubMed1994

Occipital horn syndrome and a mild Menkes phenotype associated with splice site mutations at the MNK locus.

We have found mutations in the Menkes disease gene (MNK) which impair, but do not abolish, correct mRNA splicing in patients with less severe clinical phenotypes. In one family, four males aged 2-36 years with a distinctive Menkes variant have a mutation at the +3 position of a splice donor site near the 3' end of the Menkes coding sequence that is associated with exon skipping and a stable mutant transcript. In an unrelated 15-year-old male with typical occipital horn syndrome, a point mutation at the -2 exonic position of a splice donor site in the middle of the gene causes exon-skipping and activation of a cryptic splice acceptor site. In both mutations, maintenance of some normal splicing is demonstrable by RT-PCR, cDNA sequencing and ribonuclease protection.

Adenosine Triphosphatases↗

PubMed1994

The effect of clozapine on plasma norepinephrine: relationship to clinical efficacy.

Clozapine is an atypical neuroleptic medication with superior efficacy to conventional antipsychotic agents for patients with chronic, symptomatic schizophrenia. Neurochemical characteristics that distinguish clozapine from other neuroleptics and contribute to its differential efficacy are not known. We assessed the effects of clozapine on plasma levels of norepinephrine (NE) in a double-blind, parallel groups comparison of clozapine (n = 11) and haloperidol (n = 15) in chronic schizophrenic outpatients who had been previously treated with fluphenazine. Simultaneous measurements were obtained for plasma levels of the catecholamine precursor dopa, the dopamine metabolite dihydroxyphenylacetic acid (DOPAC), the NE metabolite 3,4-dihydroxyphenylglycol (DHPG), adrenocorticotropin (ACTH), cortisol, and hemodynamic parameters. Clozapine produced marked increases (471%) in plasma NE levels, whereas haloperidol had no significant effects on plasma NE levels. Clozapine also increased dopa and tended to increase DOPAC levels, without effects on DHPG, ACTH, or cortisol levels and without consistent changes in blood pressure. Across patients, the magnitude of clozapine-induced increments in plasma NE levels was positively related to improvement in positive symptoms and global symptomatology and was unrelated to the occurrence of extrapyramidal symptoms. The results suggest that clozapine differs importantly from other neuroleptics in increasing plasma NE levels, with the peripheral noradrenergic stimulation related to its superior efficacy profile. The unchanged DHPG levels and absence of hypertension suggest a more complex mechanism of action of clozapine than heightened NE release alone.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

Endogenous serotonin stimulates striatal dopamine release in conscious rats.

Serotonin (5-HT) and dopamine (DA) are established neurotransmitters in the brain. This study examined whether, in conscious, free-moving rats, increased concentrations of endogenous 5-HT in extracellular fluid of the corpus striatum affect local release of endogenous DA. Administration of the 5-HT reuptake blocker alaproclate via a microdialysis probe increased striatal dialysate levels of DA and its metabolites dihydroxyphenylacetic acid and homovanillic acid as well as levels of 5-HT and the 5-HT metabolite 5-hydroxyindoleacetic acid. Whereas DA reuptake blockade with GBR-12909 did not prevent these effects of alaproclate, serotonergic ablation by i.c.v. administration of 5,7-dihydroxytryptamine markedly decreased basal levels of 5-HT and 5-hydroxyindoleacetic acid and abolished the effects of alaproclate on dialysate levels of DA, 5-HT and their metabolites. The results are consistent with a stimulatory action of endogenous 5-HT on striatal DA release in conscious animals.

5,7-Dihydroxytryptamine↗