Impaired presynaptic regulation of norepinephrine in schizophrenia. Effects of clonidine in schizophrenic patients and normal controls

Recent studies have found elevated levels of norepinephrine (NE) in CSF and brain specimens from schizophrenic patients. Presynaptic inhibitory alpha 2-adrenergic receptors regulate NE release in the brain. The hypothesis that the functional sensitivity of this presynaptic regulation of NE is impaired in schizophrenia was tested by evaluating, in schizophrenic patients and age-matched normal controls, the ability of clonidine, an alpha 2 agonist, to lower plasma levels of the NE metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and to lower blood pressure (BP). Clonidine produced a significant decrease in plasma MHPG levels in the normal control group, but did not lower plasma MHPG levels in the schizophrenic patients. Clonidine decreased BP equally in both groups. These results suggest that there is a functional subsensitivity of the inhibitory presynaptic alpha 2-adrenergic receptor in schizophrenia, which may relate to an impaired regulation of NE turnover.     

Decreased sympathetic neuronal uptake in idiopathic orthostatic hypotension

The disappearance rates from plasma of intravenously administered levo-norepinephrine (l-NE), dextro-norepinephrine (d-NE), and isoproterenol (ISO) were measured in normal subjects and in patients with either multiple-system atrophy (MSA) or idiopathic orthostatic hypotension (IOH). The two isomers, l-NE and d-NE, were removed at similar rates in all groups. In normal subjects, the d and l isomers of norepinephrine were cleared more rapidly than ISO. In patients with IOH, the initial rates of disappearance of the NE isomers from plasma were slower than normal and similar to the rate for ISO disappearance. Plasma NE levels, NE clearance, and the apparent release rate of NE into plasma from sympathetic neurons were significantly lower in patients with IOH than in normal subjects. Only the apparent NE secretion rate was related to the baseline plasma NE level. Sympathetic neuronal dysfunction in IOH is attended by a reduction in the clearance of NE. The very low plasma NE levels, in association with the striking reduction in NE clearance, suggest that in IOH there is a marked decrease in NE release. NE clearance and apparent NE secretion rate are normal in MSA, consistent with a central nervous system dysfunction in regulating the sympathetic nervous system. Neuronal uptake of NE in humans does not appear to be stereoselective.     

Sympathetic nervous system activity in panic disorder

To assess sympathetic nervous system (SNS) activity in panic disorder, arterialized venous norepinephrine (NE) and epinephrine (EPI) were measured in 10 patients and 10 age- and weight-matched controls. In addition, arterialized plasma NE kinetics were determined using a tritiated NE isotope dilution technique. There were no significant differences between patients and controls for resting, supine plasma NE levels, plasma NE appearance rate, plasma NE clearance, or plasma cortisol. However, plasma EPI levels were significantly higher in panic patients (103 +/- 23 vs. 33 +/- 16 pg/ml). Furthermore, there was a significant correlation between anxiety ratings and plasma EPI levels in panic disorder patients. These findings suggest that during the resting state, panic disorder is associated with a selective activation of the adrenomedullary component of the SNS.     

The metabolic course of Reye's syndrome: distinction between survivors and nonsurvivors

We compared the levels of hormones and metabolites in the plasma of 37 survivors of Reye's syndrome with the levels in 8 fatal cases, at four time periods within 72 hours of admission. The most prominent differences were found for norepinephrine (NE), which was significantly elevated in fatal cases compared with survivors at all periods. Lactate and dopamine were elevated in the earlier periods. Epinephrine and alpha-amino acid nitrogen were also elevated in fatal cases, but the differences usually were not significant. NE elevation may reflect an increased sympathoadrenal medullary output associated with brain edema, compounded by impaired hepatic clearance of monoamines. Skeletal muscle ischemia from NE-induced vasoconstriction may explain the association between lactic acidemia and the severity of encephalopathy.     

Dose-Dependent Pharmacokinetics of Valproate in Guinea Pigs of Different Ages

The dose-dependence of sodium valproate (VPA) pharmacokinetics in relation to age was studied using guinea pigs. Sodium valproate in doses of 20, 200, and 600 mg/kg was administered by rapid intravenous infusion to male guinea pigs 3, 21, and 42 days old. Serum levels of VPA were determined by gas chromatography. Pharmacokinetic parameters were calculated based upon a two-compartment model. The area under the plasma concentration-time curve (AUC) increased out of proportion at the 600 mg/kg dose level in all groups. Other pharmacokinetic changes were as follows: in 3-day-old guinea pigs, the slow disposition rate constant (beta), the elimination rate constant from central compartment (K10), and the total clearance (Clt) were significantly decreased and the beta phase half-life (t 1/2) and the volume of central compartment (V1) were significantly increased at the 600 mg/kg dose level. In 21-day-old guinea pigs, beta and K10 were significantly decreased and t1/2 and V1 were significantly increased at doses of both 200 mg/kg and 600 mg/kg. In 42-day-old guinea pigs, however, only V1 and the volume of distribution at steady-state (Vss) showed significant increase after increasing doses. The extraction ratio (E) and the clearance of unbound drug (Clu), which were calculated based on unbound plasma levels, indicate that the dose-dependent kinetics of VPA are probably due to saturation of metabolism and that the metabolic capacity for VPA in the newborn group is the smallest among all groups.     

Plasma norepinephrine in sleep apnea syndrome

In 8 male patients suffering from sleep apnea syndrome, plasma norepinephrine (NE) levels were examined. At 22.00 and at 6.30 blood samples were obtained. In 3 cases, plasma NE levels displayed little changes between 22.00 and 6.30. In 2 cases, plasma NE levels at 6.30 increased 20% compared with those at 22.00. In 3 cases, plasma NE levels at 6.30 increased more than 40%. No significant correlation between apnea index and plasma NE levels was observed. Total time under 90% arterial oxygen saturation (SaO2) significantly correlated with the ratio of plasma NE levels at 6.30 to those at 22.00. In 2 cases of the 8 patients blood samples were drawn hourly (22.00-6.00) and at 6.30. In these 2 cases, when SaO2 decreased, plasma NE levels tended to increase. It is concluded that in sleep apnea syndrome plasma NE levels increased during sleep and did not correlate with apnea index but with oxygen desaturation.     

Patterns of cerebrospinal fluid catechols support increased central noradrenergic responsiveness in aging and Alzheimer's disease.

BACKGROUND: High cerebrospinal fluid (CSF) norepinephrine (NE) concentrations in aging and Alzheimer's disease (AD) could reflect decreased NE clearance from central nervous system (CNS) extracellular fluid or increased release of NE into CNS extracellular fluid. Measuring CSF concentrations of the intraneuronal NE metabolite dihydroxyphenylglycol (DHPG), an estimate of NE clearance, and the NE precursor dihydroxyphenylacetic acid (DOPA), an estimate of NE biosynthesis, can help differentiate these mechanisms. METHODS: NE, DHPG, and DOPA were determined by HPLC in CSF and plasma obtained following yohimbine, clonidine, and placebo. Ten AD, 10 older, and 11 young subjects were studied. RESULTS: CSF DOPA following yohimbine was higher in older and AD than in young subjects. CSF DHPG did not differ among groups. Plasma DOPA following yohimbine was higher in AD than in young subjects. CONCLUSIONS: During alpha-2 adrenoreceptor blockade in both aging and AD, there are increased responses of CNS NE biosynthesis and release with unchanged CNS NE clearance. This pattern is consistent with partial loss of CNS noradrenergic neurons with compensatory activation of remaining CNS noradrenergic neurons. Given the marked loss of locus coeruleus (LC) noradrenergic neurons in AD, achievement of high CSF NE suggests particularly prominent compensatory activation of remaining LC neurons in this disorder.     

Increase of tissue plasminogen activator in limbs during venous occlusion: a simple haemodynamic model

Venous occlusion of a limb is an established procedure for increasing the venous plasma concentration of tissue plasminogen activator (t-PA). In this paper a simple haemodynamic model was developed to describe the venous plasma t-PA concentration as a function of haemodynamic parameters and the local release rate of t-PA during venous occlusion of the limb. The venous plasma pool of a limb was regarded as a single well-mixed compartment with a constant input rate of t-PA. The intravascular volume, blood flow and total limb volume of the upper extremity were also measured in three healthy subjects in order to characterise the haemodynamics during venous occlusion. Venous occlusion was shown to cause such an intense decrease of blood flow through the limb that the postocclusion increase in concentration of t-PA need not be explained by an increased release rate of t-PA but could be attributed merely to the diminished dilution of the venous compartment by inflowing arterial plasma. According to our model and haemodynamic measurements, the significant differences in the postocclusion concentration of t-PA between the arm and leg can be explained by different local release rates of t-PA.     

Glucose, insulin and sympathoadrenal activation

Selective activation of the two components of the sympatho-adrenal system (SAS) was produced by infusing male Sprague-Dawley rats with glucose or insulin. Intravenous glucose (0.5, 1 or 2 g/kg) raised plasma levels of glucose and insulin associated with a predominant activation of the sympathetic nervous system (SNS) as indicated by increased plasma norepinephrine (NE) levels. Glucose-induced release of NE was still seen in hypoinsulinemic, streptozotocin-treated rats but was absent after ganglionic blockade with chlorisondamine or following mannitol or saline infusions which failed to alter glucose or insulin levels. Insulin-induced (10 or 20 U/kg) hyperinsulinemia with its associated hypoglycemia produced predominant activation of the adrenal medulla producing increased plasma epinephrine (E) levels. But significant SNS activation also occurred with a concomitant increase in NE levels (14-22% of E) which appeared to be primarily from sympathetic nerves since increases still occurred following adrenal demedullectomy. Therefore, changes in plasma glucose levels alone and possibly altered intracellular concentrations or rates of glucose utilization can act as an important determinant of the pattern SAS activation although this may require pathological changes in plasma glucose levels to occur.     

New studies and perspectives on the noradrenergic receptor system in depression: effects of the alpha 2-adrenergic agonist clonidine

In an attempt to understand the dynamics of noradrenergic function in depression, we evaluated neuroendocrine, biochemical, cardiovascular, and behavioral responses to the acute intravenous administration of the alpha 2-adrenergic agonist, clonidine, in depressed patients and normal controls. Significantly more variance was observed in the depressed patients than the controls for most indices of basal noradrenergic output including plasma norepinephrine (NE) and 3-methoxy-4-hydroxyphenylglycol (MHPG). Growth hormone, plasma MHPG, and heart rate responses to clonidine were reduced in the depressed patients compared to the controls, all suggesting reduced responsiveness of alpha 2-adrenergic receptors in depression. Baseline levels of cortisol were elevated in the depressed patients compared to the controls. Clonidine decreased cortisol to normal levels in the depressed patients but had little effect in the controls. Thus the depressed patients manifested a significantly increased cortisol response to clonidine. These data raise the possibility that the hypercortisolemia of depression may be related to noradrenergic dysfunction. Clonidine also significantly reduced anxiety in the depressed patients, particularly those with elevated basal plasma MHPG, but not in controls. These results suggest that diminished alpha 2-adrenergic responsiveness as documented by decreased endocrine, biochemical, and physiological responses to clonidine may be related to the depressive and anxiety symptoms as well as the neuroendocrine disturbances characteristic of many depressed patients.     

Heparin clearance and ex vivo recovery in newborn piglets and adult pigs

The newborn infant requires more heparin per kg body weight than the adult to achieve similar heparin plasma levels. Possible mechanisms include altered heparin pharmacokinetics and/or a decreased expression of anticoagulant activity of heparin in newborn plasma because of low levels of antithrombin III (AT-III). We measured the pharmacokinetics and the anticoagulant activity of heparin in the pig (AT-III level:100%), in the piglet (levels of AT-III: 50% of adult) and the piglet given exogenous porcine AT-III. All pigs were bolused with ¹²⁵I-heparin (25 or 100 units/kg) and blood samples collected for the measurement of ¹²⁵I-radioactivity, and antifactor Xa activity. The half-life of ¹²⁵I-heparin was dose-dependent and similar in pigs and piglets; however, the volume of distribution was greater in the newborn resulting in an increased total clearance compared to the pig. The anti-factor Xa activity disappeared earlier in the piglet than in the pig. Both the kinetics and the absolute recovery of anti-factor Xa activity were normalized to pig values (after correction for different volumes of distribution) when the piglets were infused with exogenous AT-III. Thus apparent heparin resistance of the newborn is due to both an increased volume of distribution and the low AT-III level which limits the measurement of the anticoagulant activity of heparin in conventional anti-factor Xa assays.     

Evaluation of the sympathetic nervous system in trisomy-21 (Down's syndrome).

Dopamine-β-hydroxylase (DBH) is the enzyme which converts dopamine to norepinephrine (NE) and plasma DBH activity is diminished in patients with Down's syndrome. We have investigated sympathetic, noradrenergic neurotransmission in Down's patients by measuring plasma levels of NE and DBH in patients with trisomy-21 and their parents and comparing them to healthy volunteers of similar age. The Down's patients, like normal control subjects, responded to the stress of venipuncture and to standing with a significant increase in plasma levels of NE, indicating intact sympathetic nervous system responsivity. In fact the patients had significantly (p < 0·05) higher circulating levels of NE while supine and standing. Despite the higher NE levels systolic blood pressure was significantly lower in the patients (p = 0·005). Plasma DBH activity was significantly (p < 0·005) diminished in the Down's patients when compared to their parents, to age-matched controls or adult controls. While DBH does not appear to be an index of deficient sympathetic nervous activity in Down's syndrome, it may reflect the chromosome abnormality. Despite low levels of DBH, the synthetic enzyme for NE, Down's patients have normal or increased levels of NE.     

Probenecid-induced norepinephrine elevations in plasma and CSF

Probenecid administered in divided oral doses totaling 100 mg/kg increased levels of norepinephrine (NE) in plasma and cerebrospinal fluid (CSF). This technique is commonly used to measure the rate of accumulation of acidic metabolites of certain brain neurotransmitter biogenic amines in CSF after blockade of their transport into blood. Since levels of 3-methoxy-4-hydroxy-phenylethyleneglycol, a neutral metabolite of NE, are also elevated after high oral doses of probenecid, the increases of CSF and plasma NE levels may be directly related to probenecid-induced release of this amine from noradrenergic neurons. In patients who experienced nausea or vomiting there were lower levels of probenecid in CSF, probably secondary to diminished absorption of the medication. These patients also had lower levels of NE in plasma than did patients who remained asymptomatic.     

The hyperactive child syndrome: Peripheral sympathetic nervous system function and the effect of d-amphetamine

We evaluated sympathetic nervous system function in medication-free hyperactive children by measuring plasma levels of norepinephrine (NE) and dopamine-β-hydroxylase and then comparing the effects of two therapeutic doses of d-amphetamine to placebo in these patients. The medication-free hyperactive patients and controls had similar plasma NE levels and blood pressures while recumbent, and similar increase in NE on standing, but the patients had a larger pressor response on standing. In the hyperactive patients d-amphetamine significantly increased blood pressure, pulse rate, and NE levels. The change in NE levels correlated with the change in amphetamine levels. The medication-free patients, when more anxious, had higher plasma NE levels.     

Modulation of catecholamine release by α2-adrenoceptors and I1-imidazoline receptors in rat brain

The physiological and pharmacological effects of imidazoli(di) ne derivatives, such as Clonidine, have been related not only to the interaction with α₂-adrenoceptors but also to their activity on non-adrenoceptor sites termed imidazoline receptors. The modulation of catecholamine release by imidazoline drugs was studied by monitoring extracellular levels of norepinephrine (NE), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) with microdialysis in cingulate cortex of rats, with or without irreversible α₂-adrenoceptor blockade. NE and DA levels were in the 1 nM range whereas DOPAC and HVA levels were ≅100 nM. NE and DA levels were increased when the uptake blocker desipramine (1 μM) or KCl (100 mm) were added to the perfusion medium. Clonidine induced a dose-dependent (0.3–1.2 mg/kg i.p.) decrease in NE (max 61%) and DA (max 40%) levels that was reversed by the c₂-adrenoceptor antagonist RX821002. After α₂-adrenoceptor irreversible blockade with the alkylating agent 7V-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), [³H] clonidine binding to α₂-adrenoceptors was reduced by 94 ± 1%. Under such conditions, clonidine elicited a paradoxical dose-dependent (0.6–2.4 mg/kg i.p.) increase of NE (max 56%) without modifications in DA, DOPAC and HVA levels. The stimulatory effect of clonidine was prevented by the imidazoline receptor antagonist idazoxan (10 mg/kg i.p.) but not by RX821002 (5 mg/kg i.p.). In rats pretreated with EEDQ, cirazoline (I₁/I₂-imidazoline receptor agonist), moxonidine (Iimidazoline receptor agonist), but not guanabenz (I₂-imidazoline receptor agonist) (1.2–2.4 mg/kg i.p.) elicited an increase of NE levels in a similar manner to clonidine (11–82%). Idazoxan also abolished these responses to cirazoline or moxonidine. In contrast to systemic administration, local perfusion of clonidine (10–100 μM) through the microdialysis probe under α₂-adrenoceptor alkylating conditions, did not modify extracellular levels of NE and DA suggesting an indirect mechanism. The results demonstrate that clonidine and related imidazoli(di) ne drugs are able not only to inhibit NE release in rat cerebral cortex involving an α₂-adrenoceptor mechanism, but also to induce a paradoxical NE release through an indirect extracortical mechanism. The findings evidence that the indirect modulation of NE levels by imidazoline drugs is mainly due to a functional activity on I₁-imidazoline receptors.     

Alpha2-adrenoceptor-mediated restraint of norepinephrine synthesis, release, and turnover during immobilization in rats

Stress-related release of norepinephrine (NE) in the brain and periphery probably underlies several neuroendocrine and neurocirculatory responses. NE might influence its own synthesis, release, and turnover, by negative feedback regulation via alpha2-adrenoceptors. We examined central and peripheral noradrenergic function by measuring concentrations of NE, dihydroxyphenylglycol (DHPG), and dihydroxyphenylacetic acid (DOPAC) in hypothalamic paraventricular nucleus (PVN) microdialysate and arterial plasma simultaneously during immobilization (IMMO) in conscious rats. The alpha2-adrenoceptor antagonist yohimbine (YOH) was injected i.p. or perfused locally into the PVN via the microdialysis probe. The i.p. YOH increased plasma NE, epinephrine (EPI), DHPG, dihydroxyphenylalanine, and DOPAC levels by 4.3, 7.3, 2.5, 0.6 and 1.8-fold and PVN microdialysate NE, DHPG, and DOPAC by 1. 2, 0.6 and 0.5-fold. The i.p. YOH also enhanced effects of IMMO on plasma and microdialysate NE, DHPG, and DOPAC. YOH delivered via the PVN microdialysis probe did not affect microdialysate or plasma levels of the analytes at baseline and only slightly augmented microdialysate NE responses to IMMO. The results indicate that alpha2-adrenoceptors tonically restrain NE synthesis, release, and turnover in sympathetic nerves and limit IMMO-induced peripheral noradrenergic activation. In the PVN, alpha2-adrenoceptors do not appear to contribute to these processes tonically and exert relatively little restraint on IMMO-induced local noradrenergic activation.     

Effects of Continuous and Intermittent Cold (SART) Stress on Sympathoadrenal System Activity in Rats

We compared sympathoadrenal responses to intermittent cold (SART) stress (in which cold exposure is interrupted by 4-hourly intervals daily at room temperature) with those to continuous cold (?3°C) stress. Plasma levels of dihydroxyphenylalanine (DOPA), catecholamines and their metabolites as well as tyrosine hydroxylase (TH) activities in sympathetically innervated tissues were examined in rats exposed to each stressor for 1 day or for 5 days. Neither SART nor continuous exposure to cold for 1 day or 5 days altered plasma epinephrine (EPI) levels. However, norepinephrine (NE) and dihydroxyphenylglycol (DHPG) levels increased markedly during exposure to these stressors. On the first day of SART or continuous cold stress, NE levels were increased similarly, but the increments in DHPG levels were greater during SART stress. Since DHPG is formed in neurons, neural reuptake of NE may be more enhanced on the first day of SART stress than on the first day of continuous cold stress. After 5 days of SART stress plasma NE levels were significantly higher than those found after 5 days of continuous cold exposure. Plasma levels of DHPG were elevated to the same extent in both 5 days SART- and continuously cold-stressed rats, whereas plasma levels of methoxyhydroxyphenylglycol (MHPG) increased only by 5 days SART stress. Even at 1 h after the removal from 5 days SART stress, increased plasma levels of NE, DHPG and MHPG were still evident. These results suggest that 5 days SART stress elevates extraneuronal O-methylation of DHPG, and that NE turnover is more greatly increased by SART stress than by continuous cold stress. Plasma levels of DOPA, dopamine, dihydroxyphenylacetic acid and homovanillic acid also increased after either SART or continuous cold stress for 1 day and 5 days. Adrenal TH activities were significantly increased in rats exposed to SART or continuous cold stress for 1 day and 5 days, but in brown fat TH activity was elevated only in rats exposed to 5 days of continuous cold. Both SART and continuous cold stress are selective and potent stimuli for activation of the sympathoneural system, apparently without significant adrenomedullary EPI release. The increase of TH activity in the brown fat pad as well as of plasma NE and its metabolites is probably a result of adaptation to cold. It appears that even short intervals of return to a normal environmental temperature, as in SART, are sufficient to diminish sympathetic adaptation to cold.     

Cyanide-induced increases in plasma catecholamines: relationship to acute toxicity.

Cyanide is known to initiate release of catecholamines from chromaffin cells and isolated adrenals but the effect of cyanide on plasma catecholamine levels has not been reported. The present study demonstrates that cyanide produces marked elevation of plasma catecholamines in mice. A sublethal dose of KCN (5 mg/kg, sc) significantly increased plasma norepinephrine (NE) and epinephrine (EPI) at 5 min after administration, and the elevated levels returned to normal at 15 min. At a dose of 10 mg/kg, NE and EPI plasma levels remained elevated over a 15 min period. Multiple exposures to sublethal doses of KCN (5 mg/kg, sc, 4 doses at 15 min intervals) produced a steep, sustained rise in plasma NE and EPI. Administration of KCN (15.6 micrograms) directly into the lateral ventricles of the brain caused convulsions and respiratory depression, but did not affect plasma catecholamine levels. Pretreatment with pargyline did not alter the magnitude of the response to KCN. Adrenalectomy prevented the increase in plasma EPI and had no influence on plasma NE levels, indicating cyanide acts directly on the adrenals to stimulate EPI release. It is proposed that KCN directly stimulates the sympathoadrenal axis to increase plasma catecholamine levels.     

Clinical pharmacokinetics of the norepinephrine precursor L-threo-DOPS in primary chronic autonomic failure

Abstract Background Oral L-threo-3,4-dihydroxyphenylserine (L-DOPS), a synthetic catechol amino acid, increases standing blood pressure and improves standing ability in patients with neurogenic orthostatic hypotension, by conversion of L-DOPS to norepinephrine (NE) outside the brain. This study assessed the pharmacokinetics of L-DOPS, NE, and dihydroxyphenylglycol (DHPG), the main neuronal metabolite of NE, in patients with primary chronic autonomic failure from pure autonomic failure (PAF) or multiple system atrophy (MSA). Methods In 5 MSA and 4 PAF patients, antecubital venous blood was drawn during supine rest and plasma levels of catechols measured at various times for 48 hours after a single oral dose of 400 mg of L-DOPS. Results Plasma L-DOPS peaked at 1.9 µg/ml (9 µmol/L) about 3 hours after drug administration, followed by a monoexponential decline with a half-time of 2–3 hours in both patient groups. Plasma NE and DHPG also peaked at about 3 hours, but at much lower concentrations (4 and 42 nmol/L). Compared to the MSA group, the PAF group had a smaller calculated volume of distribution of L-DOPS and up to 10-fold lower plasma NE levels at all time points. Plasma NE was above baseline in MSA even at 48 hours after L-DOPS. Conclusions The relatively long half-time for disappearance of L-DOPS compared to that of NE explains their very different attained plasma concentrations. The similar NE and DHPG responses in PAF and MSA suggests production of NE from LDOPS mainly in non-neuronal cells. Persistent elevation of plasma NE in MSA suggests residual release of NE from sympathetic nerves.     

Noradrenergic responses to clonidine in acute and remitted depressed male patients.

To investigate noradrenergic function in depression, plasma 3-methoxy-4-hydroxyphenylglycol (MHPG), plasma norepinephrine (NE), mean arterial pressure (MAP), and heart rate responses to intravenous clonidine (2 micrograms/kg), an alpha 2-adrenergic agonist, were measured in 27 acutely depressed patients, 18 remitted depressed patients, and 27 normal control subjects; a placebo infusion was administered to a subgroup. Clonidine compared with placebo, over a 150-minute time course, decreased plasma NE, MAP, and heart rate, but not plasma MHPG, in the control subjects. Plasma MHPG, plasma NE, MAP, and heart rate at baseline or in response to clonidine and placebo over 150 minutes did not indicate any group differences. The only significant plasma MHPG response to clonidine in the normal control subjects occurred 60 minutes after the infusion. A significantly diminished plasma MHPG response to clonidine at 60 minutes was found in the acutely depressed group compared with the normal control subjects. These results suggest that peripheral inhibitory noradrenergic responses to clonidine are normal in depressed patients, while plasma MHPG responses to clonidine, which have a limited central contribution, appear to be a weak reflection of central noradrenergic function and appear insufficiently robust for a meaningful evaluation of hypothetical group differences in central inhibitory alpha 2-adrenergic activity in this population.