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PubMed1985

Effect of DL-erythro-dihydroxyphenylserine on the locomotor activity of the mouse.

Effect of dihydroxyphenylserine (DOPS) on the locomotor activity of mice pretreated with beta-phenylisopropylhydrazine was studied using an Animex activity meter. An intraperitoneal injection of DL-erythro-DOPS (200 mg/kg) suppressed significantly the locomotor stimulation by the MAO inhibitor, while DL-threo-DOPS (200 mg/kg) had no effect. Only slight suppression was observed after the administration of 100 mg/kg of DL-erythro-DOPS. Effect of DOPS on the concentrations of brain catecholamines and serotonin of mice pretreated with the MAO inhibitor was also analysed. The administration of DL-erythro-DOPS significantly increased the concentration of noradrenaline, while DL-threo-DOPS did not affect the contents of brain amines in the experimental condition. The suppressive effect of DL-erythro-DOPS on the locomotor stimulation by the MAO inhibitor was confirmed by a simultaneous administration of the amino acid and d-phenylisopropylmethylamine to mice. Based on these findings, the neural mechanisms of the locomotor activity and a clinical application of DL-erythro-DOPS to the manic syndrome were discussed.

Amino Acids↗
PubMed1986

The effect of L-erythro-dihydroxyphenylserine injected into the lateral ventricle and the hypothalamus on the locomotor activity.

The effect of dihydroxyphenylserine (DOPS) on locomotor activity was studied using the Animex activity meter. One microgram of L-erythro-DOPS, a precursor of d-noradrenaline, was injected into the lateral ventricle once a day for one week or into the anterior hypothalamic area (AHA) once. After the intraventricular injection, the total locomotor activity (from 8:00 p.m. to 8:00 a.m.) of the rats injected with DOPS was significantly less than that of the rats injected with an artificial cerebrospinal fluid (5-ion). Analysis of the locomotor activity in consecutive 2-hr periods showed that the activity of the DOPS group during the time intervals of 10 p.m.-12 a.m., 12 a.m.-2 a.m. and 2 a.m.-4 a.m. was significantly less than that of the control group. After injection of DOPS or 5-ion into AHA, the total activity of the DOPS group was significantly less than that of the control. Analysis of the activity of the DOPS group for each 2-hr period between 10 p.m.-4 a.m. was also significantly less than that of the control. On the basis of these findings, the effect of DOPS in the brain noradrenergic system are discussed.

Animals↗
PubMed1987

Studies on the central action of L-threo-3,4-dihydroxyphenyl-serine (L-threo-DOPS) in FLA-63-treated mice.

In order to clarify the central action of L-threo-DOPS, the effect of benserazide on behavioral and biochemical changes by L-threo-DOPS in FLA-63-treated mice was studied. L-threo-DOPS in combination with nialamide markedly increased both the locomotor activity and the concentrations of the brain, heart and kidney norepinephrine (NE) in the FLA-63-treated mice. Benserazide at low doses did not alter either the rise of the brain NE level or the increase in locomotor activity, whereas it significantly inhibited the rise of the heart and kidney NE levels. Benserazide at a high dose significantly inhibited all of them. These results suggested that the increase in locomotor activity might be mediated via activation of the central noradrenergic neurons system by L-threo-DOPS.

Animals↗
PubMed1990

Catecholamines and the initiation of sexual behavior in male rats without sexual experience.

The purpose of the present experiments was to investigate the effects of modified catecholaminergic neurotransmission upon sexual behavior in inexperienced males. Such males are critically dependent on stimuli from the female in order to initiate sexual behavior, and catecholamines are known to modulate interactions with environmental stimuli. It was found that D-amphetamine, 0.5 and 1 mg/kg, and amfonelic acid, 0.25 and 0.5 mg/kg, reduced mount and intromission latencies. Pimozide, in doses between 0.25 and 1 mg/kg, and cis(Z)-flupentixol, 0.5 mg/kg, reduced the proportion of animals displaying sexual behavior. The noradrenergic neurotoxin DSP4 (50 mg/kg one week before behavioral observation) shortened intromission latency while the noradrenaline precursor threo-dihydroxyphenylserine (10 mg/kg + carbidopa 50 mg/kg) increased mount and intromission latencies. In a test for social and exploratory behaviors it was found that amfonelic acid, in a dose of 0.5 mg/kg, augmented sniffing and rearing without affecting nonsexual interaction with a receptive female. Flupentixol (0.5 mg/kg) had a slight inhibitory effect on exploratory behavior and no effect on nonsexual interaction with a female. It is suggested that enhanced dopaminergic activity facilitates the initiation of sexual behavior due to an increased general arousal and not because of a specific effect on that behavior. The role of noradrenaline is less clear at present.

Animals↗
PubMed1992

Effects of L-threo- and erythro-3,4-dihydroxyphenylserine on learning performance and concentrations of brain noradrenaline and its metabolites in rats.

Effects of L-threo and L-erythro-3,4-dihydroxyphenylserine [DOPS, precursor amino acids for noradrenaline (NA)] on the learning performance in a maze paradigm designed to model on the water maze paradigm using a multicomputerized behavioral analysis system were studied. A marked facilitation of learning performance was observed in rats after an intraventricular injection of 5 micrograms L-threo-DOPS (the s-NA precursor), and this effect was inhibited by a simultaneous administration of 1 or 2 micrograms propranolol (a beta-adrenergic antagonist). As concentrations of brain NA, 3-methoxy-4-hydroxyphenylglycol, and normethanephrine were increased by the injection of 5 micrograms L-threo-DOPS, the effect seemed to be derived from activation of beta-adrenoceptors in the CNS by the formed s-NA. On the other hand, an intraventricular injection of 5 micrograms L-erythro-DOPS (the r-NA precursor) attenuated the learning performance, and this effect was probably caused by the formed r-NA from L-erythro-DOPS.

Animals↗
PubMed1982

The role of norepinephrine in feeding behavior.

When dopamine-beta-hydroxylase is inhibited with FLA-63 (10 mg/kg) free feeding behavior is disrupted in satiated rats. While the average number of meals taken was not different from vehicle injected controls, meal size was decreased 58% in the first 9 hr after treatment with FLA-63. In starved animals, FLA-63, when given alone, produced little effect on feeding behavior, even though norepinephrine depletion was in excess of 40%. When given in combination with RO4-1284 (5 mg/kg), a vesicular reuptake inhibitor, feeding was reduced to 16% of control intake and norepinephrine was specifically depleted 99%. Feeding was reliably reinstated in animals which received FLA-63 plus RO4-1284 with either dl-threo-DOPs, a metabolic precursor to NE, or direct intrahypothalamic injections of NE. These findings suggest that the feeding inhibition observed after treatment with FLA-63 plus RO4-1284 is due to disruption of transmission in brain NE systems. A non-anorectic dosage of L110-140 (3.73 mg/kg), a specific FLA-63. Taken collectively, these findings suggest that the primary role of NE in feeding is maintenance of the consummatory response and that these effects are expressed in relation to activity in other neurochemical systems.

2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-↗
PubMed1985

The effects of L-threo-dihydroxyphenylserine on norepinephrine metabolism in rat brain.

The effects of L-threo-3,4-dihydroxyphenylserine (DOPS), an artificial precursor of norepinephrine (NE), on NE metabolism in rat brain were investigated. DOPS administration resulted in a significant elevation in cerebral NE and 3-methoxy-4-hydroxyphenylglycol contents, while carbidopa pretreatment completely blocked these increases. After brain NE was depleted by either alpha-methyl-p-tyrosine (AMPT), fusaric acid, FLA-63, or reserpine, NE restoration by DOPS was observed in rats treated with either fusaric acid or chronic reserpine. No NE restoration was observed after pretreatment with AMPT, FLA-63, or acute reserpine. The results suggest that NE formed after DOPS administration is mainly localized in the brain capillaries. In some NE-depleting conditions, however, DOPS can penetrate the brain parenchyma.

Animals↗
PubMed1992

Effect of L-threo-3,4-dihydroxyphenylserine on muscle sympathetic nerve activity in humans.

To clarify the effect of L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS), a precursor of norepinephrine (NE), the effect of this drug on microneurographically recorded muscle sympathetic nerve activity (MSA) from the tibial nerve was analyzed in ten healthy male volunteers. A single dose of 600 mg of L-threo-DOPS was orally administered and the effect of this norepinephrine precursor on MSA at resting and at upright standing positions, as well as the MSA responsiveness to head-up tilting was examined by comparing the data obtained after administration of the drug with those obtained under control conditions. The plasma NE levels were determined in two subjects. The results were as follows: (1) resting MSA increased significantly 80 min after administration of L-threo-DOPS and was accompanied by an increase in plasma NE levels; (2) standing MSA when treated with the drug was not significantly different from values obtained under control conditions; and (3) MSA responsiveness to orthostasis was reduced after L-threo-DOPS. We conclude from the activation of MSA by L-threo-DOPS that this drug raised blood pressure not only through an increase in metabolized plasma NE levels, but also through the enhancement of MSA by activation of descending noradrenergic or adrenergic pathways proximal to the recording site of the sympathetic discharge.

Adult↗
PubMed1995

Total norepinephrine spillover, muscle sympathetic nerve activity and heart-rate spectral analysis in a patient with dopamine beta-hydroxylase deficiency.

Dopamine-beta-hydroxylase (D beta H) is the enzyme responsible for intraneural conversion of dopamine to norepinephrine. Its deficiency results in failure of norepinephrine synthesis, excessive dopamine release and orthostatic hypotension. We studied a young patient with this deficiency using the currently available methods to assess sympathetic function namely measurement of norepinephrine kinetics, microneurography to assess muscle sympathetic nerve activity (MSNA), and heart-rate spectral analysis. We compared these findings with those in 24 young healthy controls, and 4 patients with peripheral autonomic failure (PAF). Recordings were made in our subject before and after 5 months of treatment with L-threo-3,4-dihydroxyphenylserine (DOPS) (which is converted directly into L-norepinephrine bypassing the D beta H enzymatic step); measurements were made at rest in the supine position and after 15 min of 30 degrees head-up tilt. Our subject with D beta H deficiency had a high resting nerve firing rate (40.3 bursts/min) compared with the mean value in normal controls (19.3 bursts/min), and an appropriate increase in nerve firing rate during tilt. Total body norepinephrine spillover at rest was very low, 38 ng/min, compared with age-matched normals (519 +/- 43.3 ng/min, mean +/- SEM), and epinephrine secretion was undetectable. Conversely, the plasma concentrations of dopamine, DOPAC, HVA and DOPA were raised. At rest, low-frequency heart-rate variability (0.1 Hz) was absent with preservation of the respiratory-related high-frequency peak. In contrast, the PAF subjects had no detectable muscle sympathetic nerve activity, very low levels of norepinephrine spillover and epinephrine secretion and a reduction in heart rate variability at all frequencies. After 5 months treatment with L-threo-3,4-dihydroxyphenylserine (DOPS) in the D beta H deficiency patient there was a dramatic clinical improvement with resolution of the orthostatic symptoms, dramatic reduction in MSNA activity at rest, and return of plasma norepinephrine, norepinephrine spillover, DHPG and MHPG to within the normal range, indicating intraneuronal production of norepinephrine.

Adolescent↗
PubMed1987

The effect of L-threo-DOPS on synaptic transmission to soleus motoneuron in normal subjects and patients with Parkinson's disease.

The effect of L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS) on synaptic transmission to the soleus motoneurons was studied using the H-reflex method in 12 normal subjects and in 4 patients with Parkinson's disease. A long-lasting depression of the test H-reflex, which was evoked by a conditioning group I volley in the homonymous tibial nerve with an onset latency of ca. 30 ms and a duration of more than 1 s and was regarded to represent the transmitter depletion caused by a preceding volley, diminished significantly after the oral administration of L-threo-DOPS both in the normal subjects and in the patients. On the other hand, no change was recognized in the slow depression which was caused by a group I volley of the heteronymous common peroneal nerve and was regarded as the presynaptic inhibition. The findings suggest that L-threo-DOPS influences the reduction of transmitter depletion.

Adult↗
PubMed1993

Regulation of nerve growth factor secretion in L-M cells by catechol derivatives.

We investigated the mechanism responsible for the stimulation of nerve growth factor (NGF) secretion by catechol derivatives in L-M cells, using L-threo-3,4-dihydroxyphenylserine (L-DOPS). Treatment of the cells with L-DOPS increased the NGF content in the L-M cell medium by approximately 3-fold. This stimulatory effect was not blocked by a decarboxylase inhibitor, or by alpha- or beta-adrenergic blockers. Intracellular cAMP levels were not changed by exposure to L-DOPS. The antioxidants, ascorbic acid and sodium pyrosulfite, completely prevented the stimulatory effect of L-DOPS, and radical scavengers (superoxide dismutase plus catalase) caused a significant partial inhibition of the response to L-DOPS. Quinone derivatives (adrenochrome, 4-n-propyl-1,2-benzoquinone), which are the oxidative products of the catechol derivatives, increased the NGF content in the medium, and their potency was greater than that of the catechol derivatives themselves. These findings suggest that L-DOPS and other catechol derivatives might be oxidized in the medium to form quinone derivatives, and that it is these which predominantly express a stimulatory effect on NGF secretion by a novel cAMP-independent mechanism in L-M cells.

Animals↗
PubMed1994

Strychnine-induced seizures in mice: the role of noradrenaline.

1. The effects of some noradrenergic agents on seizures induced by strychnine were investigated in mice. 2. Strychnine (0.5-4 mg/kg, i.p.) dose-dependently produced tonic seizures. 3. DOPS (4-8 mg/kg, i.p.) significantly shortened the latency of seizures elicited by strychnine (2 mg/kg, i.p.). Similarly, DOPS (4 mg/kg, i.p.) effectively increased the incidence and significantly shortened the latency of seizures induced by strychnine (1 mg/kg, i.p.). 4. Imipramine (20-40 mg/kg, i.p.) and pargyline (200 mg/kg, i.p.) significantly shortened the latency of strychnine (2 mg/kg, i.p.)-induced seizures. 5. Phentolamine (5-20 mg/kg, i.p.) effectively antagonised the seizures elicited by strychnine (2 mg/kg, i.p.). Furthermore, phentolamine (10 mg/kg, i.p.) attenuated the seizure-potentiating effect of DOPS (4 mg/kg, i.p.). 6. Propranolol (0.5-2 mg/kg, i.p.) and prazosin (1-2 mg/kg, i.p.) reduced the incidence and significantly delayed the latency of seizures induced by strychnine (2 mg/kg, i.p.). 7. Reserpine (5-10 mg/kg, i.p.) significantly prolonged the latency of strychnine (2 mg/kg, i.p.)-induced seizures. 8. Clonidine (0.25-1 mg/kg, i.p.) dose-dependently and significantly antagonised strychnine (2 mg/kg, i.p.)-induced seizures. 9. Idazoxan (1-4 mg/kg, i.p.) in a dose related manner significantly shortened the latency of seizures induced by strychnine (2 mg/kg, i.p.). Similarly, idazoxan (2 mg/kg, i.p.) profoundly potentiated seizures elicited by strychnine (1 mg/kg, i.p.). Idazoxan (4 mg/kg, i.p.) significantly antagonised the protective effect of clonidine (1 mg/kg, i.p.) against strychnine (2 mg/kg, i.p.)-induced seizures. 10. Disulfiram (3 x 25 - 3 x 100 mg/kg, i.p.) significantly attenuated strychnine (2 mg/kg, i.p.)-induced seizures. DOPS (4 mg/kg, i.p.) significantly potentiated strychnine seizures in disulfiram (3 x 100 mg/kg, i.p.)-pretreated animals. 11. These results indicate that enhancement of noradrenergic neurotransmission potentiates strychnine seizures in mice.

Adrenergic alpha-Antagonists↗
PubMed1983

The simultaneous determination of 3,4-dihydroxyphenyl-ethylene glycol, 3,4-dihydroxyphenylacetic acid and catecholamines in brain tissue by high performance liquid chromatography with electrochemical detection.

An assay is described for the simultaneous determination of the deaminated metabolites 3,4-dihydroxyphenylethylene glycol (DHPG) and 3,4-dihydroxyphenylacetic acid (DOPAC), together with noradrenaline, dopamine and adrenaline in brain using high performance liquid chromatography with electrochemical detection. The procedure is simple, specific, and has a limit of detection for each catechol of 5 pg. It offers the advantage of measuring the major monoamine oxidase metabolites of both noradrenaline (i.e. DHPG) and dopamine (i.e. DOPAC), which in some circumstances may reflect neuronal activity, simultaneously with their catecholamine neurotransmitter precursors.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Effect of a synthetic norepinephrine precursor, L-threo-3,4- dihydroxyphenylserine on the total norepinephrine concentration in the cerebrospinal fluid of parkinsonian patients.

We studied the effect of a synthetic norepinephrine precursor, L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS) on the total (conjugated and unconjugated) norepinephrine concentrations in the cerebrospinal fluid (CSF) of 6 parkinsonian patients with freezing phenomenon. The total norepinephrine concentrations in the CSF increased from 5- to 75-fold after treatment with L-threo-DOPS. The degree of increase in the norepinephrine (NE) concentrations was closely correlated to the dosage of L-threo-DOPS. The freezing phenomenon improved in 3 out of 6 patients.

Carbidopa↗
PubMed1992

L-threo-3,4-dihydroxyphenylserine enhanced ocular dominance plasticity in adult cats.

We studied whether ocular dominance plasticity can be restored to the aplastic visual cortex of the adult cat by peripheral administration of L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS), an exogenous precursor of L-noradrenaline (NA). We found that NA output in the visuocortical dialysate was significantly increased by a single administration of L-threo-DOPS (200 mg or 1 g, i.p.). Single unit recordings revealed a significant reduction of binocular cells (binocularity = 0.30) in juvenile cats (7-8 months of age) that had been monocularly deprived for one month in combination with L-threo-DOPS (200 mg/day, per os). These results suggest that peripheral administration of L-threo-DOPS enhances ocular dominance plasticity, presumably through activation of the central noradrenergic system.

Animals↗
PubMed1984

Influence of levodopa, apomorphine and 3,4-dihydroxyphenylserine (DOPS) on strychnine-induced seizures in mice.

The effects of levodopa, apomorphine and 3,4-dihydroxyphenylserine (DOPS) on tonic seizures elicited by strychnine were investigated in mice. Levodopa (6.25-100 mg/kg), apomorphine (0.2-0.8 mg/kg) and FLA-63 (12.5 mg/kg) profoundly delayed the onset and reduced the incidence of strychnine seizures. In addition, these drugs decreased strychnine-induced mortality. DOPS (1-16 mg/kg) apparently shortened the onset of strychnine seizures and altered strychnine-induced mortality in a dose-dependent manner; low doses (1-2 mg/kg) enhanced while moderate doses (4-8 mg/kg) reduced the mortality rate. FLA-63 (12.5 mg/kg) potentiated the anticonvulsant effect of low doses of levodopa (6.25-12.5 mg/kg) while it had no significant influence on the anticonvulsant effect of higher doses (25-100 mg/kg) of levodopa. In addition, the onset of strychnine seizure was further delayed by FLA-63. Haloperidol (0.5 mg/kg) potentiated the convulsant effect of strychnine (1 mg/kg) as well as strychnine-induced mortality. It also antagonised the protective effect of levodopa (12.5 and 100 mg/kg) against strychnine (1 mg/kg). Phentolamine (5 mg/kg) and +/- propranolol (1 mg/kg) antagonised strychnine seizures. Strychnine-induced mortality was also reduced by these drugs. In addition, the effects of DOPS (2 mg/kg) on strychnine seizures were antagonised by phentolamine and propranolol. These results indicate that enhancement of dopaminergic and noradrenergic neurotransmission respectively attenuate and potentiate strychnine seizures in mice.

Animals↗
PubMed1988

Effects of L-threo-dihydroxyphenylserine on spinal reflexes and decerebrate rigidity in rats.

1. The effects of a noradrenaline precursor, L-threo-3,4-dihydroxyphenylserine (L-DOPS), on spinal mono-(MSR) and polysynaptic reflexes (PSR) and decerebrate rigidity, were studied. 2. Although a low dose of L-DOPS (10 mg/kg, i.v.) did not affect MSR or PSR in C1 spinal rats, high doses of L-DOPS (50 and 100 mg/kg, i.v.) moderately enhanced the amplitudes of both MSR and PSR. 3. Clorgyline-HCl (1 mg/kg, i.v.), an MAO inhibitor, enhanced the excitatory effects of low-dose L-DOPS (10 mg/kg, i.v.) on both reflexes. 4. Benserazide-HCl (1 mg/kg, i.v.), an L-aromatic amino acid decarboxylase inhibitor, decreased the pressor effect, but not the stimulatory effects, of L-DOPS (100 mg/kg, i.v.) on MSR and PSR. 5. L-DOPS (300 mg/kg, i.p. or i.d.) did not affect the muscle tone of rigid hindlimbs caused by radio frequency lesioning of the midbrain. 6. These results suggest that the moderate enhancing effects of L-DOPS on MSR and PSR are due to conversion of L-DOPS to noradrenaline in the spinal cord.

Animals↗