L-threo-3,4-dihydroxyphenylserine Research Articles

Effects of Manipulation of Noradrenergic Activities on the Expression of Dopaminergic Phenotypes in Aged Rat Brains.

This study investigated the effects of the pharmacological manipulation of noradrenergic activities on dopaminergic phenotypes in aged rats. Results showed that the administration of L-threo-3,4-dihydroxyphenylserine (L-DOPS) for 21 days significantly increased the expression of tyrosine hydroxylase (TH) and dopamine transporter (DAT) in the striatum and substantia nigra (SN) of 23-month-old rats. Furthermore, this treatment significantly increased norepinephrine/DA concentrations in the striatum and caused a deficit of sensorimotor gating as measured by prepulse inhibition (PPI). Next, old rats were injected with the α2-adrenoceptor antagonist 2-methoxy idazoxan or β2-adrenoceptor agonist salmeterol for 21 days. Both drugs produced similar changes of TH and DAT in the striatum and SN. Moreover, treatments with L-DOPS, 2-methoxy idazoxan, or salmeterol significantly increased the protein levels of phosphorylated Akt in rat striatum and SN. However, although a combination of 2-methoxy idazoxan and salmeterol resulted in a deficit of PPI in these rats, the administration of 2-methoxy idazoxan alone showed an opposite behavioral change. The in vitro experiments revealed that treatments with norepinephrine markedly increased mRNAs and proteins of ATF2 and CBP/p300 and reduced mRNA and proteins of HDAC2 and HDAC5 in MN9D cells. A ChIP assay showed that norepinephrine significantly increased CBP/p300 binding or reduced HDAC2 and HDAC5 binding on the TH promoter. The present results indicate that facilitating noradrenergic activity in the brain can improve the functions of dopaminergic neurons in aged animals. While this improvement may have biochemically therapeutic indication for the status involving the degeneration of dopaminergic neurons, it may not definitely include behavioral improvements, as indicated by using 2-methoxy idazoxan only.

Clinical presentation and long-term follow-up of dopamine beta hydroxylase deficiency.

Dopamine beta hydroxylase (DBH) deficiency is an extremely rare autosomal recessive disorder with severe orthostatic hypotension, that can be treated with L‐threo‐3,4‐dihydroxyphenylserine (L‐DOPS). We aimed to summarize clinical, biochemical, and genetic data of all world‐wide reported patients with DBH‐deficiency, and to present detailed new data on long‐term follow‐up of a relatively large Dutch cohort. We retrospectively describe 10 patients from a Dutch cohort and 15 additional patients from the literature. We identified 25 patients (15 females) from 20 families. Ten patients were diagnosed in the Netherlands. Duration of follow‐up of Dutch patients ranged from 1 to 21 years (median 13 years). All patients had severe orthostatic hypotension. Severely decreased or absent (nor)epinephrine, and increased dopamine plasma concentrations were found in 24/25 patients. Impaired kidney function and anemia were present in all Dutch patients, hypomagnesaemia in 5 out of 10. Clinically, all patients responded very well to L‐DOPS, with marked reduction of orthostatic complaints. However, orthostatic hypotension remained present, and kidney function, anemia, and hypomagnesaemia only partially improved. Plasma norepinephrine increased and became detectable, while epinephrine remained undetectable in most patients. We confirm the core clinical characteristics of DBH‐deficiency and the pathognomonic profile of catecholamines in body fluids. Impaired renal function, anemia, and hypomagnesaemia can be part of the clinical presentation. The subjective response to L‐DOPS treatment is excellent and sustained, although the neurotransmitter profile in plasma does not normalize completely. Furthermore, orthostatic hypotension as well as renal function, anemia, and hypomagnesaemia improve only partially.

L-threo-3,4-dihydroxyphenylserine (L-DOPS) co-administered with entacapone improves freezing of gait in Parkinson’s disease

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a variety of motor symptoms including freezing of gait (FOG), in which walking is transiently halted as if the patient’s feet were ‘glued to the ground’. Treatment of FOG is still challenging. Although L-threo-3,4-dihydroxyphenylserine (L-DOPS), a precursor of noradrenaline, has been on the market in Japan because of its beneficial effect for FOG, clinical use of L-DOPS has been far from satisfying. However, the fact that there were some responders to L-DOPS encouraged us to hypothesize that the enhancement of L-DOPS concentration in the brain by the co-administration of L-DOPS and a catechol-O-methyl transferase (COMT) inhibitor, which is expected to interrupt L-DOPS metabolism in the peripheral circulation, would be beneficial for FOG.Based on our hypothesis, we conducted a preliminary study with a small number of participants with FOG. Of the 16 PD patients with FOG who completed this study, group 1 (n=6) received L-DOPS co-administered with entacapone, which is a COMT inhibitor used worldwide as an anti-parkinson drug, group 2 (n=5) received entacapone alone, and group 3 (n=5) received L-DOPS alone. Only the patients in group 1 showed a significant improvement in FOG. Moreover, the beneficial effect was observed only in patients with levodopa-resistant FOG. This result supports our hypothesis, at least in patients with levodopa-resistant FOG, and shows that the co-administration of L-DOPS and entacapone could be a new strategy for FOG treatment.

The noradrenaline precursor L-DOPS reduces pathology in a mouse model of Alzheimer's disease

Damage to noradrenergic neurons in the locus coeruleus (LC) is a hallmark of Alzheimer's disease (AD) and may contribute to disease progression. In 5xFAD transgenic mice, which accumulate amyloid burden at early ages, the LC undergoes stress as evidenced by increased astrocyte activation, neuronal hypertrophy, reduced levels of LC-enriched messenger RNAs (mRNAs), and increased inflammatory gene expression. Central nervous system (CNS) noradrenaline (NA) levels in 5-month-old male 5xFAD mice were increased using the NA precursor L-threo-3,4-dihydroxyphenylserine (L-DOPS). After 1 month, L-DOPS treatment improved learning in the Morris water maze test compared with vehicle-treated mice. L-DOPS increased CNS NA levels, and average latency times in the water maze test were inversely correlated to NA levels. L-DOPS reduced astrocyte activation and Thioflavin-S staining; increased mRNA levels of neprilysin and insulin degrading enzyme, and of several neurotrophins; and increased brain-derived neurotrophic factor protein levels. These data demonstrate the presence of LC stress in a robust mouse model of AD, and suggest that raising CNS NA levels could provide benefit in AD.

Effects of Carbidopa and Entacapone on the Metabolic Fate of the Norepinephrine Prodrug L-DOPS

L-threo-3,4-dihydroxyphenylserine (L-DOPS), a norepinephrine (NE) prodrug, is investigational for orthostatic hypotension, which occurs commonly in Parkinson's disease. Adjunctive anti-parkinsonian drugs might interact with L-DOPS. We tested whether L-aromatic amino-acid decarboxylase inhibition by carbidopa (CAR) attenuates L-DOPS conversion to NE and blocks the pressor effect of L-DOPS, whereas catechol-O-methyltransferase inhibition by entacapone (ENT) interferes with L-DOPS metabolism and augments the pressor effect. Twelve patients with autonomic failure took 400 mg of L-DOPS with 200 mg of placebo (PLA), CAR, or ENT on different days. Plasma L-DOPS, NE, and deaminated NE metabolites (dihydroxyphenylglycol [DHPG], dihydroxymandelic acid [DHMA]) were measured. L-DOPS+PLA and L-DOPS+ENT increased systolic pressure similarly (by 27 ± 8 and 24 ± 9 mm Hg at 3 hours). L-DOPS+CAR did not increase pressure. The peak increase in plasma NE (0.57 ± 0.11 nmol/L) averaged less than 1/15,000 th that in L-DOPS and less than 1/35th that in DHPG+DHMA. CAR prevented and ENT augmented responses of plasma DHPG and DHMA to L-DOPS. After L-DOPS administration plasma, NE levels do not increase sufficiently to increase blood pressure. Pressor responses to L-DOPS seem to reflect NE produced extraneuronally that escapes extensive enzymatic deamination and O-methylation and evokes vasoconstriction before reaching the systemic circulation.

Increasing CNS Noradrenaline Reduces EAE Severity

The endogenous neurotransmitter noradrenaline (NA) is known to exert potent anti-inflammatory effects in glial cells, as well as provide neuroprotection against excitatory and inflammatory stimuli. These properties raise the possibility that increasing levels of NA in the central nervous system (CNS) could provide benefit in neurological diseases and conditions containing an inflammatory component. In the current study, we tested this possibility by examining the consequences of selectively modulating CNS NA levels on the development of clinical signs in experimental autoimmune encephalomyelitis (EAE). In mice immunized with myelin oligodendrocyte glycoprotein peptide to develop a chronic disease, pretreatment to selectively deplete CNS NA levels exacerbated clinical scores. Elevation of NA levels using the selective NA reuptake inhibitor atomoxetine did not affect clinical scores, while treatment of immunized mice with the synthetic NA precursor L-threo-3,4-dihydroxyphenylserine (L-DOPS) prevented further worsening. In contrast, treatment of mice with a combination of atomoxetine and L-DOPS led to significant improvement in clinical scores as compared to the control group. The combined treatment reduced astrocyte activation in the molecular layer of the cerebellum as assessed by staining for glial fibrillary protein but did not affect Th1 or Th17 type cytokine production from splenic T cells. These data suggest that selective elevation of CNS NA levels could provide benefit in EAE and multiple sclerosis without influencing peripheral immune responses.

Midodrine Hydrochloride and l‐threo‐3,4‐dihydroxy‐Phenylserine Preserve Cerebral Blood Flow in Hemodialysis Patients With Orthostatic Hypotension

Orthostatic hypotension (OH) after hemodialysis (HD) is a serious complication, as it causes various neurological symptoms and even ischemic brain damage. The aim of the present study was to evaluate the effects of antihypotensive agents, midodrine hydrochloride (MID) and L-threo-3,4-dihydroxyphenylserine (L-DOPS), on OH after HD. We measured systolic blood pressure (SBP) and cerebral blood flow velocity in the middle cerebral artery (MCVm, by transcranial Doppler sonography), in patients with OH during a 5-min 60-degree head-up tilt test at both before and after 4-week treatment with MID at 4 mg/day (N = 6) or L-DOPS at 400 mg/day (N = 7). Both MID and L-DOPS did not significantly protect against falls in systolic BP (SBP) after passive head-up tilt. However, a significant improvement was achieved in MCVm-decrement in the MID group at 3 min and the L-DOPS group at 0, 1 and 3 min during head-up tilt. Although MID and L-DOPS did not prevent OH after HD in HD patients, both agents preserved cerebral blood flow during orthostasis in HD patients with OH.

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

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). 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. Plasma L-DOPS peaked at 1.9 microg/ml (9 micromol/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. 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.

Antidepressant Activity Requires Norepinephrine

Cryan et al. used mice deficient for the norepinephrine (and epinephrine) biosynthetic enzyme dopamine β-hydroxylase ( Dbh —/— ) to determine that the acute behavioral effects of different classes of antidepressants were dependent on norepinephrine and not only on changes in serotonergic or dopaminergic signaling. Drugs that were not selective but inhibited the reuptake or metabolism of serotonin, dopamine, and norepinephrine were effective in heterozygous littermates, but not in Dbh —/— mice, at decreasing immobility in the tail suspension test, an assay for the acute effects of antidepressant drugs. Two of the three drugs in the serotonin selective reuptake class were not effective in decreasing immobility in the tail suspension test in Dbh —/— mice. Only citalopram, which is the most selective and does not increase norepinephrine concentrations in vivo, was effective in the Dbh —/— mice. Restoration of norepinephrine by administration of the precursor L- threo -3,4-dihydroxyphenylserine (L-DOPS) restored responsiveness to norepinephrine selective reuptake inhibitors and the serotonin selective reuptake inhibitors. Thus, most antidepressants appear to have a requirement for noradrenergic signaling, with the exception of citalopram, which appears to bypass this requirement. J. F. Cryan, O. F. O'Leary, S.-H. Jin, J. C. Friedland, M. Ouyang, B. R. Hirsch, M. E. Page, A. Dalvi, S. A. Thomas, I. Lucki, Norepinephrine-deficient mice lack responses to antidepressant drugs, including serotonin reuptake inhibitors. Proc. Natl. Acad. Sci. U.S.A. 101 , 8186-8191 (2004). [Abstract] [Full Text]

Effects of L-Threo-3,4-Dihydroxyphenylserine on Orthostatic Hypotension in Hemodialysis Patients

Background: Orthostatic hypotension (OH) is a serious complication observed in hemodialysis (HD) patients after HD as well as during the interdialytic period. L-Threo-3,4-dihydroxyphenylserine (L-DOPS) is a nonphysiological neutral amino acid that is directly converted to the neurotransmitter norepinephrine by aromatic L-amino acid decarboxylase. Methods: A placebo-controlled double-blind study for 4 consecutive weeks and a long-term study (24–52 weeks) were conducted to evaluate the efficacy of L-DOPS for OH after HD. The drug was administered orally 30 min before the start of each HD period in both studies. Doses of 400 mg of L-DOPS or placebo were given to HD patients with OH (45 and 41 patients, respectively) in the double-blind study, and doses of 200 or 400 mg of L-DOPS were given to 74 HD patients in the long-term study. Results: In the double-blind study, L-DOPS significantly ameliorated subjective symptoms related to OH, including dizziness/light-headed feeling, and malaise, throughout the interdialytic period. For 19 patients with delayed-type OH, hypotension with the lowest blood pressure recorded 10 min after standing, the decrease in blood pressure was suppressed significantly after L-DOPS treatment (10 patients) as compared with the placebo-treated group (9 patients). In the long-term study, the efficacy of L-DOPS was not attenuated, and the marked fluctuations in the plasma L-DOPS and norepinephrine levels were not noted after long-term use, without increases in incidence or severity of adverse reactions. Conclusions: These results indicate that L-DOPS is effective for improving OH-related interdialytic subjective symptoms in HD patients after short-term as well as after long-term administration.

Clinical Effects of L-Threo-3,4-Dihydroxyphenylserine on Orthostatic Hypotension in Hemodialysis Patients

Orthostatic hypotension is one of the major factors interfering with everyday activities in hemodialysis patients, but there has been no effective agent for treating it. In order to clarify the clinical effects of L-threo-3,4-dihydroxyphenylserine (L-DOPS) on orthostatic hypotension of hemodialysis patients, we conducted a randomized, double-blind comparative trial. 149 regular hemodialysis patients with orthostatic hypotension were randomly allocated to three groups and L-DOPS at doses of 400 mg, 200 mg or placebo was orally administrated to each group 30 min before starting every hemodialysis for 4 weeks. Changes of blood pressure (BP) in orthostatic hypotension immediately after completion of hemodialysis and symptoms related to orthostatic hypotension were compared between the three groups. In the 400-mg group, systolic and diastolic BP after standing increased significantly and the drop of mean BP after standing was also reduced compared with pretreatment levels. No such changes were observed in the placebo group. Fatiguability, malaise/weakness, dizziness and light-headed feeling, the interdialytic symptoms commonly observed in hemodialysis patients who developed orthostatic hypotension, were improved to a significant extent in the L-DOPS group compared with the placebo group. In particular, the improvement was more remarkable for the L-DOPS 400-mg group than the placebo group in patients with diabetic nephropathy, lower systolic BP after standing, and the long duration type of orthostatic hypotension. The incidence of adverse events was comparable between the three groups, and all recovered after discontinuation of L-DOPS or concomitantly administered drugs, or without any treatment. These findings indicate that L-DOPS taken before hemodialysis prevents orthostatic hypotension in patients undergoing hemodialysis, and is also effective for the interdialytic symptoms related to orthostatic hypotension.

The norepinephrine precursor L-threo-3, 4- dihydroxyphenylserine facilitates motor recoveryin chronic stroke patients

L-threo-3, 4-dihydroxyphenylserine (L-DOPS) is a precursor of norepinephrine. We reported that administration of L-DOPS to rats with ablation of the right sensorimotor cortex results in functional recovery from deficits in beam-walking performance. We al so reported that improvement in Fugl-Meyer Score (FMS) was significantly higher in an L-DOPS-treated group of chronic neurologically stable stroke patients than in a control group for 2 days. In the present study, 27 patients who had suffered from stroke more than one month previously and had exhibited no improvement in neurological deficits for at least one week were administered 300mg/day L-DOPS for 28 days with rehabilitation. FMS improved by 4.4 points (P< 0.001), 10m gait time was shortened by 16% (P< 0.001) and the cerebral blood flow of the lesion was increased (P< 0.03), after 28 days of drug administration. These findings suggest that L-DOPS is effective in restoring neurological deficit, which does not usually recover when only treated with rehabilitation therapy.

L-DOPS-Accelerated recovery of locomotor function in rats subjected to sensorimotor cortex ablation injury: pharmacobehavioral studies.

Central norepinephrine (NE) has been shown to play a beneficial role in amphetamine-facilitated recovery of behavior. To give insight into understanding the mechanism, the present studies were conducted to examine (a) the effects of L-threo-3,4-dihydroxyphenylserine (L-DOPS) combined with benserazide (BSZ; a peripheral aromatic amino acid decarboxylase inhibitor) and L-3,4-dihydroxyphenylalanine (L-DOPA), precursors of NE and dopamine (DA), respectively, on the recovery from beam-walking performance deficits in rats subjected to unilateral sensorimotor cortex ablation injury, and (b) the relationships between the behavioral recovery and the frequency of postoperative training and the size of ablation injury. It was found that the combined treatments with L-DOPS and BSZ promoted the recovery of locomotor function as early as 24 hours after injury. L-DOPA alone, however, did not facilitate behavioral recovery. The results of assay for the tissue levels of NE and its major metabolite (3-methoxy-4-hydoxyphenylethylene glycol; MHPG) in the brain using high-pressure liquid chromotography showed MHPG, but not NE, significantly increased in the cerebellum and the hippocampus. The behavioral recovery was also significantly correlated with the frequency of training subsequent to injury, but inversely with the size of cortex ablation. These results suggest that NE is likely to modulate functional recovery in this rodent model.

Result of Long-Term Administration of L-Threo-3,4-Dihydroxyphenylserine in Patients With Pure Akinesia as an Early Symptom of Progressive Supranuclear Palsy

Results of long-term administration of L-threo-3,4-dihydroxyphenylserine (L-DOPS), a synthetic precursor of noradrenaline, in a patient with freezing gait and pure akinesia are reported. Effects were temporal and disappeared during a 16-month treatment period. It was recognized that pure akinesia is an early symptom of progressive supranuclear palsy (PSP). Previously, we reported results of short-term (4 weeks) administration of L-DOPS in this patient. We present the further clinical course of the patient, along with results of long-term (16 months) administration of L-DOPS.

Analgesic effect of l- threo-3,4-dihydroxyphenylserine (L-DOPS) in patients with chronic pain

Previous pharmacological studies using animals indicated that a systemic administration of l- threo-3,4-dihydroxy-phenylserine (L-DOPS), a precursor of noradrenaline, induces an antinociceptive effect and an increase in the CNS level of noradrenaline which serves an inhibitory role at the spinal dorsal horn and the supraspinal pain afferent system. The aim of the present study was to investigate the analgesic effect of L-DOPS in patients with chronic pain. We selected 18 patients with various kinds of pain. In nine patients, L-DOPS (tablets) was orally administered and pain was assessed by the visual analogue scale (VAS) before and after the L-DOPS administration. Administration of L-DOPS resulted in dose-dependent analgesia. The maximum analgesia (VAS change: from 10 to 4.1 ± 0.9) was observed 60 min after an administration of 100 mg and it lasted for 2–5 h depending on the patient. In the other nine patients, oral administration of placebo tablets produced only a slight analgesia (VAS change: from 10 to 9.2 ± 0.3). The difference between the L-DOPS-induced effect and the placebo-induced one was statistically significant. After repeated administration of L-DOPS for 4–5 weeks, neither tolerance nor side effects were observed.

Treatment of dialysis-induced hypotension with L-threo-3,4-dihydroxyphenylserine

L-threo-3,4-dihydroxyphenylserine (L-DOPS), a precursor of noradrenaline (norepinephrine), which is converted into noradrenaline when orally administered, was given orally to haemodialysed patients exhibiting dialysis-induced hypotension. In five patients given 300 mg L-DOPS plasma concentrations reached a peak of 1.43 +/- 0.59 micrograms/ml 6 h after administration and decreased slowly to disappear after 36 h. Plasma noradrenaline concentrations showed a significant increase (P < 0.05), reaching a peak of 1.28 +/- 0.64 ng/ml after 24 h and declined to 0.75 +/- 0.47 ng/ml by 48 h. Administration of L-DOPS to six patients during dialysis for 6 consecutive weeks showed no accumulation in the blood. Oral administration of 200-400 mg L-DOPS to 34 patients 1 h before dialysis prevented dialysis-induced hypotension and decreased the number of concurrent treatments required for hypotension. The signs and symptoms of hypotension were improved in 73.5% of the patients and persisted after dialysis in 64.7%. The preventive effect of L-DOPS was significantly more prominent in patients with predialysis systolic blood pressure less than 100 mmHg and in patients with non-diabetic nephropathy. L-DOPS appeared to be an effective and well-tolerated treatment for the prevention of dialysis-induced hypotension.

Determination of l-threo-3,4-Dihydroxyphenylserine and L-α-Methyldopa in Rat Serum by High Performance Liquid Chromatography with Fluorescence Detection

A highly sensitive method for the determination of L-threo-3,4-dihydroxyphenylserine (L-DOPs) and l-α-methyldopa in rat serum is described. The method uses high performance liquid chromatography with fluorescence detection. l-DOPs and l-α-methyldopa (analyte and internal standard, respectively, and vice versa) in serum, after cleanup with a cation exchanger cartridge (Toyopak IC-SP S), are converted into the corresponding fluorescent compounds by reaction with me.so-1,2-diphenylethylenediamine. The derivatives are separated by reversed phase chromatography on a TSK gel ODS-120T column. The detection limits (S/N—3) for L-DOPs and L-a-methyldopa are 6 and 9 fmol for an injection volume of 100 μl.

L-threo-3,4-dihydroxyphenylserine treatment for gait apraxia in parkinsonian patients.

L-threo-3,4-dihydroxyphenylserine (L-DOPS) was administered to six parkinsonian patients for the treatment of gait related akinesia which was refractile to L-DOPA treatment. One responded with marked improvement and one with only mild improvement. Although number of patients who respond markedly to this noradrenaline precursor, L-DOPS, is limited, L-DOPS was felt to be the most effective treatment modality for L-DOPA refractile gait related akinesia and L-DOPA related orthostatic hypotension.

Increase in the blood pressure and decrease in the norepinephrine release in the ventrolateral medulla during intraventricular administration of hypertonic NaCl.

Norepinephrine (NE) release in the ventrolateral medulla (VLM) was serially measured in anesthetized male Wistar rats during the rise in the blood pressure (BP) produced by acute intraventricular (ICV) administration of hypertonic (1.5 M) NaCl. Catecholamine release was determined by a brain microdialysis method using high performance liquid chromatography and electrochemical detector. The release of NE in the VLM was significantly decreased after ICV 1.5 M NaCl. In another set of rats, the pressor response to acute ICV 1.5 M NaCl was attenuated by selective administration of NE to the VLM using the microdialysis method. Chronic and continuous ICV infusion of 1.5 M NaCl to conscious rats caused an increase in BP on day 10 which was associated with a decrease in NE release in the VLM; concomitant ICV infusion of NE or of a synthetic NE precursor, L-threo-3,4-dihydroxyphenylserine (L-DOPS) prevented the rise in BP as well as the reduction in NE release. These results suggest that a decrease in the NE release of the VLM may contribute to the change in BP induced by ICV infusion of hypertonic saline.

Effect of L-threo-3,4-dihydroxyphenylserine (L-DOPS) on catecholamine levels in plasma and cerebrospinal fluid (CSF) in anesthetized rats.

The effect of L-threo-3,4-dihydroxyphenylserine (L-DOPS) on norepinephrine (NE) levels in plasma and CSF was examined in urethane-anesthetized rats. Intravenous injection of L-DOPS (0.5, 1, and 10 mg/100 g body wt) raised plasma NE levels in a dose-related manner whereas CSF NE levels were significantly increased only by the largest dose of L-DOPS. Intracerebroventricular injection of L-DOPS (50 and 250 micrograms/rat) dose-relatedly raised CSF NE levels whereas plasma NE levels were slightly increased by a larger dose of L-DOPS. These findings may indicate that L-DOPS stimulates central noradrenergic mechanisms in the rat although a large dose of L-DOPS is required for peripheral administration.