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PubMed1988

A pharmacological study of hibernation in rodents.

1. Hamsters and ground squirrels in deep hibernation were infused intra-arterially with drugs. 2. Norepinephrine and epinephrine sometimes caused arousal, sometimes transitory effects. 3. Adrenalectomy did not affect arousal. L-DOPA and amphetamine produced a slow arousal. 4. Arousal was blocked with alpha-methyltyrosine and the block was released with L-DOPA, DL- and L-threo-DOPS resulted in arousal and bromocriptine did not cause arousal, indicating that dopamine was not necessary for arousal. 5. Isoproterenol caused a transient increase in heart rate which was blocked by propranolol. 6. Phenylephrine caused vasoconstriction, but did not result in arousal. 7. No drug increased the sensitivity to peripheral stimuli during hibernation.

Adrenalectomy↗
PubMed1993

Preferential decarboxylation of L-threo-3,4-dihydroxyphenylserine in rat renal tissues.

1. Administration of L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS; 3, 10 and 30 mg/kg, i.p.) produced a dose-dependent increase in the tissue levels of both noradrenaline and its deaminated metabolite 3,4-dihydroxyphenylglycol (DOPEG) in the rat jejunum, liver and renal cortex, but not in the left ventricle. 2. The accumulation of noradrenaline and DOPEG after the administration of L-threo-DOPS (30 mg/kg, i.p.) was also found to be a time-dependent effect, reaching its maximum 15 min after the injection and then declining progressively. 3. The accumulation of noradrenaline and DOPEG after L-threo-DOPS (30 mg/kg, i.p.) was found to be similar in control and 6-OHDA treated rats and completely prevented by previous treatment with benserazide. 4. Administration of L-threo-DOPS (30 mg/kg) produced an increase in plasma levels of noradrenaline and DOPEG; this effect was maximum, for both noradrenaline (6.2-fold increase) and DOPEG (3.4-fold increase), at 30 min after the injection of L-threo-DOPS. 5. The results presented here support the view that most L-threo-DOPS is decarboxylated into noradrenaline by non-neuronal AAAD, a reaction occurring predominantly in renal tissues.

Animals↗
PubMed1994

Outflow of dopamine and noradrenaline originating from L-dopa and L-threo-DOPS in rat renal tissues.

1. The present study has examined the formation and outflow of newly-formed dopamine (DA) and noradrenaline (NA) in slices of the renal cortex of rats given L-beta-3,4-dihydroxyphenylalanine (L-DOPA) (10, 30 or 100 mg/kg i.p.) and L-threo-3-(3,4-dihydroxyphenyl)serine (L-DOPS) (10, 30 or 100 mg/kg i.p.), respectively. The outflow of 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylglycol (DOPEG), the deaminated metabolites of DA and NA, respectively, was also measured. 2. The accumulation of both newly-formed DA and DOPAC in renal tissues after the administration of L-DOPA was found to be dose dependent; after 30 or 100 mg/kg L-DOPA, the levels of both DA and DOPAC were, respectively, 3- and 20-fold those observed after the administration of 10 mg/kg L-DOPA. The outflow of DA and DOPAC in kidney slices of rats treated with L-DOPA was found to progressively decline with time and reflected the DA and DOPAC tissue contents. The rate constant (k) for DOPAC efflux (k = 0.0097) was higher (P < 0.01) than that for DA efflux (k = 0.0033) and did not depend on the dose of L-DOPA. DOPAC/DA perifusate ratios were 2-fold those occurring in the tissues. 3. The levels of NA in renal tissues of rats given 30 and 100 mg/kg L-DOPS were, respectively, 3- and 6-fold those observed after the administration of 10 mg/kg L-DOPS. The administration of L-DOPS was also found to be accompanied by the accumulation in renal tissues of DOPEG; this was, however, not dose dependent.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Determination of D,L-threo-3,4-dihydroxyphenylserine and of the D- and L-enantiomers in human plasma and urine.

DL-threo-3,4-Dihydroxyphenylserine (DOPS) is increasingly being investigated for treatment of disorders involving defects of the sympathetic nervous system, such as Parkinson's disease, Shy-Drager syndrome and congenital dopamine-beta-hydroxylase deficiency. Whilst L-DOPS is converted by aromatic L-amino acid decarboxylase into natural norepinephrine in vitro, D-DOPS inhibits this process. There are no data on the interaction between D- and L-DOPS in vivo because a reliable method for the measurement of the D- and L-enantiomers in plasma and urine is lacking. We describe here such a method based on reversed-phase chromatography after derivatization with o-phthaldialdehyde and N-acetyl-L-cysteine. Good separation was achieved with this procedure (resolution factor 2.33). Two simple and sensitive methods are also presented for total D,L-DOPS estimation, based on reversed-phase chromatography with electrochemical detection after either deproteinization (DP) or liquid-liquid extraction (LE) as sample preparation steps. The two methods gave identical results (regression line DOPS (DP) = 1.026 DOPS (LE) + 33.28; r = 0.997; n = 52). Excellent agreement was found between the sum of the D- and L-DOPS concentrations and the measured total D,L-DOPS concentration (regression line DOPS (D + L) = 0.955 DOPS (total, LE) + 116.65; r = 0.992; n = 100).

Acetylcysteine↗
PubMed1996

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.

Administration, Oral↗
PubMed2006

Noradrenaline is necessary for the hedonic properties of addictive drugs.

To determine whether noradrenaline (NA) is an essential neurotransmitter for addictive and appetitive behaviors, we measured drug and food seeking in transgenic mice lacking dopamine beta-hydroxylase (Dbh), the enzyme responsible for synthesizing NA. Using the conditioned place preference test (CPP), we show that Dbh -/- mice do not exhibit rewarding behavior to morphine, cocaine, or the mixed reuptake inhibitor bupropion. In spite of their lack of preference for drugs, Dbh -/- mice had an unaltered preference for food. Drug seeking was induced when NA was restored to the central nervous system of Dbh -/- mice by administration of l-threo-3,4-dihydroxyphenylserine (DOPS) and carbidopa. When a NK1 receptor antagonist was co-administered with morphine or cocaine, it produced aversive behavior in Dbh -/- mice while it abolished place preference in the controls. NK1 antagonists alone did not have any rewarding or aversive effect in the CPP suggesting that substance P opposes some of the unpleasant effects of morphine and cocaine. Our results show that NAergic transmission is necessary for motivated behaviors, the dysregulation of which is a co-morbid factor of many depressive states. The reversibility of this phenomenon, by restoring NA, indicates that even when this behavioral deficit is genetically determined it can be reversed.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2002

Behavior of fluorinated analogs of L-(3,4-dihydroxyphenyl)alanine and L-threo-(3,4-dihydroxyphenyl)serine as substrates for Dopa decarboxylase.

We have determined the kinetic parameters for Dopa decarboxylase (DDC) of three ring-fluorinated analogs of 3,4-dihydroxyphenylalanine (Dopa). The rank order of catalytic efficiency of decarboxylation (k(cat)/K(m)) is Dopa>6-F-Dopa>2-F-Dopa>5-F-Dopa. This rank is consistent with previous in vivo and in vitro studies which indicate that, of the fluorinated analogs, 6-F-Dopa has pharmacokinetics that are most suited for positron emission tomographic (PET) evaluation of dopamine function. The effectiveness of PET as a diagnostic tool, the convenient half-life of (18)F (110 min) and the favorable pharmacokinetics of 6-[(18)F]FDOPA have combined to make this an extremely valuable reagent to study dopaminergic activity. The reactions of the related fluorinated DOPS analogs show that, while 6-F-threo-3,4-(dihydroxyphenyl)serine (DOPS) is decarboxylated at approximately the same rate as the non-fluorinated substrate, 2-F-threo-DOPS is not converted into the corresponding amine. In both cases a Pictet-Spengler condensation with the pyridoxal 5(')-phosphate (PLP) cofactor occurs to produce tetrahydroisoquinolines. Condensation of fluorinated catecholamines and catechol amino acids with endogenous aldehydes will be investigated as an approach to study possible mechanisms of L-Dopa-linked neurotoxicity.

Dihydroxyphenylalanine↗
PubMed2000

Increasing CNS norepinephrine levels by the precursor L-DOPS facilitates beam-walking recovery after sensorimotor cortex ablation in rats.

The present investigation was conducted to document a role of L-threo-3,4-dihydroxyphenylserine (L-DOPS), precursor of L-norepinephrine (NE), in the functional recovery from beam-walking performance deficits in rats after unilateral sensorimotor cortex ablation. L-DOPS was administered simultaneously with benserazide (BSZ; a peripheral aromatic amino acid decarboxylase inhibitor), and the regional contents of NE in the cerebral cortex, hippocampus, and cerebellum were assayed. Behavioral recovery was demonstrated by the rats treated with L-DOPS and BSZ, and the rate of recovery was significantly different from that of either BSZ-treated or vehicle-treated control rats. The NE tissue levels in the three discrete regions of the rat brain were significantly elevated in the experimental rats receiving both L-DOPS and BSZ. The present studies indicate that increasing NE levels by the precursor L-DOPS may be responsible for facilitating behavioral recovery from beam-walking performance deficits in rats, and further suggest that L-DOPS may become one of the candidate compounds for further clinical human trials promoting functional recovery after injuries to the cerebral cortex.

Animals↗
PubMed1997

An L-DOPA-like depressor action of L-threo-dihydroxyphenyl-serine in the rat caudal ventrolateral medulla.

We have proposed that L-3,4-dihydroxyphenylalanine (L-DOPA) is a neurotransmitter and/or neuromodulator in the central nervous system (1). In this study, we investigated whether or not L-threo-dihydroxyphenylserine (L-threo-DOPS), a synthetic amino acid structurally related to L-DOPA, microinjected into the caudal ventrolateral medulla (CVLM) and the rostral ventrolateral medulla (RVLM) shows cardiovascular actions similar to those of L-DOPA in anesthetized rats. When L-threo-DOPS was microinjected into CVLM, it produced dose-dependent (0.01-3 ng) depressor and bradycardic responses. D-threo-DOPS (3 ng) produced no effect. The responses to L-threo-DOPS (1 ng) were almost completely blocked by L-DOPA methyl ester (1 microg), a competitive antagonist for L-DOPA, supporting the existence of an L-threo-DOPS-sensitive recognition site for L-DOPA in CVLM. Microinjection of L-threo-DOPS into RVLM, however, showed no effect (0.001-100 ng), which contrasted with the cardiopressor action of L-DOPA applied in RVLM. In RVLM, there may exist an L-threo-DOPS-insensitive recognition site for L-DOPA.

Animals↗
PubMed1997

Impaired maternal behavior in mice lacking norepinephrine and epinephrine.

The roles of norepinephrine (NE) and epinephrine in behavior were investigated by targeted disruption of the dopamine beta-hydroxylase (Dbh) gene, thereby eliminating these compounds in vivo. Most heterozygous pups born to Dbh-/- females died within several days of birth and were often found scattered within the bedding. Potential causes including deficits in olfaction and lactation were not apparent. A deficit in maternal behavior was confirmed by the lack of pup retrieval exhibited by Dbh-/- virgin females. Restoration of NE shortly before but not after birth induced females that previously abandoned their litters to act maternally. Our results suggest that NE is responsible for long-lasting changes that promote maternal behavior during both development and parturition in mice.

Animals↗
PubMed1987

Endogenous restoration of noradrenaline by precursor therapy in dopamine-beta-hydroxylase deficiency.

DL-dihydroxyphenylserine was given by mouth in a single-blind, placebo-controlled trial to two patients with orthostatic hypotension due to dopamine-beta-hydroxylase deficiency, in the hope of providing noradrenaline by endogenous decarboxylation. Dose-dependent increases in blood pressure were obtained over the range 150-600 mg. After 600 mg mean arterial pressure rose 33 and 19 mm Hg and these rises were tightly correlated with an increase in plasma noradrenaline (r = 0.995, p less than 0.001 and r = 0.88, p less than 0.05). Urinary noradrenaline increased from undetectable levels to 338 and 511 micrograms/24 h. Standing time (a correlate of functional capacity) also increased significantly in both patients. No side-effects were noted.

Adult↗
PubMed1987

Effect of unnatural noradrenaline precursor on sympathetic control and orthostatic hypotension in dopamine-beta-hydroxylase deficiency.

A patient with severe orthostatic hypotension due to dopamine-beta-hydroxylase deficiency was treated with the unnatural aminoacid D,L-threo-3,4-dihydroxyphenylserine (DOPS) in the hope that it would serve as a substrate of aromatic-L-aminoacid decarboxylase to produce (-)-noradrenaline. With a dose of 500 mg twice daily by mouth, blood pressure rose gradually from 100/55 to 145/85 mm Hg, and orthostatic hypotension disappeared. After 4 months' treatment the patient is free of symptoms and able to live a normal life. DOPS switched on the production of noradrenaline and reduced the excessive production of dopamine. During treatment plasma noradrenaline rose normally after standing and after infusion of tyramine, a biogenic amine that liberates stored neurotransmitter from sympathetic nerve terminals. These data demonstrate that in congenital dopamine-beta-hydroxylase deficiency dopamine instead of noradrenaline is released as the sympathetic neurotransmitter but that the integrity of the sympathetic neuron is otherwise intact.

Aromatic-L-Amino-Acid Decarboxylases↗
PubMed1997

Improved orthostatic tolerance in familial amyloidotic polyneuropathy with unnatural noradrenaline precursor L-threo-3,4-dihydroxyphenylserine.

Disabling orthostatic hypotension, due to insufficiency of the autonomic nervous system, is a common complication of type I familial amyloidotic polyneuropathy (FAP). We investigated whether oral treatment with L-threo-3,4-dihydroxyphenylserine (L-threo-Dops), a noradrenaline precursor, might be of therapeutical benefit. In twenty untreated FAP patients, aged 33 to 44 years, who, because of severe orthostatic hypotension, were bedridden or constrained to a sitting life, supine and erect blood pressure (BP), plasma noradrenaline and tilting time, defined as the interval (s) between the beginning of a 60 degrees head-up tilt and the occurrence of orthostatic symptoms (dizziness, blurred vision or near syncope) were determined before and at repeated intervals during oral treatment with L-threo-Dops, 100 mg bid, for 6 months. Before treatment supine mean BP was 80 (76-85) mmHg (mean and 95% CI), supine plasma noradrenaline was low, 59 (41-77) pg/ml and tilting time ranged from 38 to 118 s. In response to tilt, mean BP immediately fell by 36 (31-41) mmHg, whereas plasma noradrenaline increased by only 11 (0-21) pg/ml (p = 0.05). After 3 to 5 days of treatment with L-threo-Dops all patients experienced marked improvement of their orthostatic tolerance as reflected by their ability to walk freely around. This effect sustained throughout the six months of treatment. Plasma noradrenaline increased moderately by 37 (11-63) pg/ml (p = 0.02) and supine mean BP increased by 8.6 (5.8-12.4) mmHg (p < 0.001) during chronic treatment. Supine or nocturnal hypertension did not develop, the fall in mean BP in response to tilt diminished by 12.5 (6.5-17.3) mmHg (p < 0.001) and tilting time became longer than 600 s in all patients. Because of its efficacy, its sustained duration of action and the lack of side effects, L-threo-Dops is advocated to improve orthostatic tolerance in patients with autonomic insufficiency due to FAP.

Adult↗
PubMed1998

Visceral orthostatic hypotension in patients with severe autonomic dysfunction.

Although changes in the blood flow of the cerebral vessels and the peripheral vessels in the extremities after changing body postures have been well examined in patients with orthostatic hypotension (OH), such changes in visceral vessels have not been well investigated. To elucidate the effect of autonomic dysfunctions on changes in the abdominal blood flow, the blood flow velocity of the portal vein was measured by Doppler ultrasonography in 11 patients with familial amyloidotic polyneuropathy (FAP) (Met30), 3 with pandysautonomia, 1 with Shy-Drager syndrome, and 10 healthy controls, in the supine and at the upright position. Among the 15 patients with the above-mentioned autonomic disorders, 5 of the patients showed a marked decrease in blood flow after standing, and one of these 5 patients exhibited transient hepatic and intestinal ischemia during intensive rehabilitation because of a severe decrease in visceral blood flow. Another 7 patients exhibited moderate decreases in the blood flow after standing. In contrast, no such change was observed in the 10 healthy controls. The FAP patients with L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS) administration showed no significant correlation between the degree of OH and the decrease in the blood flow of the portal vein, and the patients without the drug exhibited a weak correlation. On the contrary, the pandysautonomia and Shy-Drager syndrome patients exhibited a linear positive correlation. These results suggest that FAP is a disease for which this kind of ultrasonographic examination should be applied, and that Doppler ultrasonography may be a helpful tool to evaluate visceral OH.

Adult↗
PubMed1996

Enhancement of mRNA expression of tissue-type plasminogen activator by L-threo-3,4-dihydroxyphenylserine in association with ocular dominance plasticity.

Tissue-type plasminogen activator (tPA) plays important roles in the regulation of synaptic plasticity in the hippocampus and cerebellum. We found that the expression of tPA mRNA in the visual cortex was increased significantly by the peripheral administration of L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS; 100 mg/kg, i.p.), which we had previously shown to have a promotive effect on ocular dominance (OD) plasticity. When plasminogen activator inhibitor-1 (PAI-1; 100 muM in an osmotic minipump) was infused into the kitten visual cortex, OD plasticity was suppressed; i.e. a significantly large number of binocular cells was recorded in the PAI-1 infused cortex following monocular deprivation. These results, therefore, suggest that the PA system is involved in the promotive effect of L-threo-DOPS in OD plasticity.

Animals↗
PubMed1985

Rett syndrome--an early catecholamine and indolamine deficient disorder?

The results of clinical and polysomnographical examinations on 11 Japanese Rett syndrome cases were summarized to substantiate further our previous results regarding the pathophysiology of the disease. It was concluded that the disease starts early in infancy and takes a progressive course. Each characteristic symptom appears in an orderly sequence which is thought to reflect the sequential systemic involvement of certain neuronal systems. Based on the characteristic symptoms and signs, and polysomnographical studies, we speculated that the initial lesion was the locus coeruleus with a hypoactive noradrenergic system combined with other hypoactive monoaminergic systems, including those of serotonin and dopamine, occurring along with the early developmental course. In later stages, hyperfunction possibly due to postsynaptic supersensitivity of the dopamine system causes the characteristic symptoms of the Rett syndrome.

5-Hydroxytryptophan↗