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PubMed1987

Behavioral and biochemical evidence for a different effect of repeated administration of L-dopa and bromocriptine on denervated versus non-denervated striatal dopamine receptors.

The effect of repeated administration of bromocriptine and L-3,4-dihydroxyphenylalanine (L-DOPA) was studied behaviorally and biochemically in rats with a unilateral lesion of the nigrostriatal pathway. Groups of rats injected eight times with bromocriptine or L-DOPA significantly increased their contraversive circling. Rats receiving only two injections of bromocriptine did not. Animals receiving two injections of L-DOPA showed a slight but significant increase in circling. The affinity of the binding of [3H]spiperone to the dopamine receptors was unchanged by the lesion or the treatments, while the density of the binding was significantly modified. Chronic treatment with bromocriptine induced a significant decrease in the density of D2 dopamine receptors in the intact striata, while on the lesioned side, it remained unchanged. By contrast, chronic administration of L-DOPA induced a significant increase in density of the striatal dopamine receptors in the lesioned striata in addition to that caused by denervation, while the decrease on the intact side was not significant. It seems that contrary to the intact striatum, the lesioned side had a defective down-regulation mechanism in response to chronic treatment with a dopamine agonist. The results also show that L-DOPA was more potent than bromocriptine in inducing agonist supersensitivity in a denervated striatum. This may explain why chronic treatment with bromocriptine has a lesser tendency to induce dyskinesia in patients with Parkinson's disease.

Animals↗
PubMed1976

The significance of dopamine, versus other catecholamines, for L-dopa induced facilitation of sexual behavior in the castrated male rat.

The effects of a wide dose range of L-DOPA on male rat sexual behavior were investigated. The animals were castrated as adults and supplied with small amounts of testosterone propionate. It was found that doses of L-DOPA up to 2.5 mg/kg facilitated, while higher doses inhibited, sexual behavior in animals pretreated with pargyline, 20 mg/kg, + MK486, 50 mg/kg. The effects of L-DOPA on sexual behavior were not restricted to the copulatory act, but included elements preceding the copulatory act as well. Most of the facilitatory effects of L-DOPA 2.5 mg/kg were prevented by the dopamine receptor blocker pimozide; 0.10 mg/kg. It is concluded that dopamine is the catecholamine of major importance in mediating the L-DOPA induced facilitation of sexual behavior in the castrated male rat. However, some elements of the copulatory act appear to be modified by noradrenaline and/or adrenaline as well.

Animals↗
PubMed1981

Potentiation by deprenil of 1-dopa induced circling in nigral-lesioned rats.

1-Deprenil, a potent inhibitor of type B monoamine oxidase, was a weak inhibitor of 3H-dopamine uptake as well as a weak releasing agent for previously accumulated 3H-dopamine in rat neostriatal tissue slices. In similar experiments d-amphetamine as approximately 100 times as potent as 1-deprenil as a releasing agent. When deprenil (20 mg/kg IP) was given to rats with a unilateral 6-hydroxydopamine lesion of the substantia nigra, it brought about a moderate but long-lasting ipsilateral rotational behavior. 1-Dopa (20-40 mg/kg, IP) by itself caused a considerably stronger rotation in the opposite direction (contralateral). When 1-dopa was given to rats 1 hr after 1-deprenil, there was a considerably greater contralateral rotation than after 1-dopa alone. Clorgyline, a type A monoamine oxidase inhibitor, which by itself at 20 mg/kg caused no rotation, also potentiated the contralateral rotation seen after 1-dopa (5-20 mg/kg). In contrast, d-amphetamine, which by itself caused ipsilateral rotation, failed to potentiate the rotation after 1-dopa. Possible mechanisms for these observations will be discussed.

Animals↗
PubMed1992

Parkinson's disease-like effects of S-adenosyl-L-methionine: effects of L-dopa.

The major symptoms of Parkinson's disease (PD) are due to degeneration of the nigrostriatal pathway and depletion of dopamine (DA). Tyrosine hydroxylase (TH), norepinephrine (NE), serotonin (5-HT), and melanin pigments are also decreased and acetylcholinergic activity increased. Biochemically, increased methylation can cause the depletion of DA, NE, 5-HT, and melanin pigments and also an increase of acetylcholine; thus, increased methylation can present a biochemical picture that resembles the biochemical changes that occur in PD. During the therapy of PD with L-dopa, it is well known that L-dopa reacts avidly with S-adenosyl-L-methionine (SAM), the biologic methyl donor, to produce 3-O-methyl-dopa. Correspondingly, L-dopa has been shown to deplete the concentration of SAM, and SAM has been found to induce PD-like motor impairments in rodents; therefore, an excess of SAM-dependent methylation may be associated with Parkinsonism. To further study the effects of methylation, SAM was injected into the lateral ventricle of rats. SAM caused tremors, rigidity, abnormal posture, and dose-related hypokinesia. Doses of 9.38, 50, and 400 nM/rat caused 61.9, 73.4, and 94.8% reduction, respectively, of motor activity. A 200-mg/kg IP dose of L-dopa, given before 50 nM SAM, blocked the SAM-induced hypokinesia. SAM also caused a decrease in TH immunoreactivity, apparent degeneration of TH-containing fibers, loss of neurons, and the accumulation of phagocytic cells in the substantia nigra. These results showed that excess SAM in the brain, probably due to its ability to increase methylation, can induce symptoms that resemble some of the changes that occur in PD.

Animals↗
PubMed1991

Striatal dopamine release in vitro from immature male rats shows enhanced responsiveness to pulsatile, but not continuous, infusions of L-dopa.

In the present experiment we compared the effects of continuous versus pulsed infusions of L-beta-3,4,dihydroxyphenylalanine (L-DOPA) upon dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) release in vitro from superfused corpus striatal tissue fragments of immature (25-32 day) and adult (90-120 day) male rats. In response to two pulse infusions of L-DOPA (5 microM) a significantly greater amount of dopamine and DOPAC was released from the striatal fragments of immature vs adult males. In contrast, when L-DOPA was infused continuously throughout the superfusion virtually identical amounts of dopamine and DOPAC were obtained for immature and adult male rats. No differences in postsuperfusion dopamine tissue content were obtained between adult and immature rats following the two pulses or continuous infusion of L-DOPA. These results suggest that the corpus striatum of the immature rat has an enhanced capacity to convert and release dopamine in response to a submaximal pulsatile infusion of L-DOPA.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

Noradrenergic alpha-1 and alpha-2 antagonists block L-dopa-induced air-stepping in neonatal rats.

Five-day-old rat pups suspended in air and administered L-3,4-dihydroxyphenylalanine (L-DOPA) engage in a highly stereotyped and coordinated locomotor behavior termed air-stepping. L-DOPA is a precursor for dopamine and noradrenaline and one or both of these neurotransmitters could play a role in L-DOPA-induced air-stepping. The role of noradrenaline was investigated by assessing the abilities of the alpha-1 noradrenergic receptor antagonist prazosin and the alpha-2 noradrenergic receptor antagonist idazoxan to block L-DOPA-induced air-stepping in 5-day-old rats. Both antagonists decreased the duration of air-stepping. In addition, prazosin altered the topography of air-stepping by interfering with coordination of the hindlimbs. The results suggest that alpha-1 and alpha-2 noradrenergic receptor subtypes are involved in L-DOPA-induced air-stepping.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1996

An aromatic L-amino acid decarboxylase inhibitor blocks L-dopa-induced air-stepping in neonatal rats.

Rat pups suspended in air and administered L-DOPA engage in a locomotor behavior termed air-stepping. The role of L-DOPA itself was investigated by administering several doses of an aromatic L-amino acid decarboxylase inhibitor, NSD 1015, prior to 100 mg/kg L-DOPA to 5-day-old rats. NSD 1015 dose-dependently increased the latency to onset and decreased the duration of L-DOPA-induced air-stepping. Thus L-DOPA induces air-stepping only after its conversion to dopamine and/or noradrenaline.

Animals↗
PubMed1995

Effects of L-DOPA on fusimotor control of triceps surae muscle spindles in the cat.

The experiments were performed on lightly alpha-chloralose anaesthetised and spinalized cats. Alterations in fusimotor activity were assessed by recordings from single spindle afferents (90 primary and 12 secondary) from the triceps surae muscle, before and after i.v. administration of L-beta-3,4-dihydroxyphenylalanine (L-DOPA). The effects of L-DOPA on fusimotor reflexes from ipsi- and contralateral hind limb afferents were investigated by using extensions of the intact contralateral hind limb and tonic stretches of the ipsilateral posterior biceps and semitendinosus muscles as reflex stimuli. Prior to injection of L-DOPA, a low reflex responsiveness was found to both the ipsi- and the contralateral stimulation. After administration of L-DOPA, the reflex responsiveness as well as the resting activity of the muscle spindle afferents were increased as a result of enhanced activity in mainly dynamic fusimotor neurones. The results indicate that changes in fusimotor activity elicited after administration of L-DOPA are caused by release of transmission in interneuronal pathways mediating ipsi- and contralateral reflexes to mainly dynamic fusimotor neurones. The possible role of monoaminergic descending control of fusimotor neurones in the regulation of muscle tone, tremor and rigidity is discussed.

Afferent Pathways↗
PubMed1987

In vivo release of dopamine and its metabolites following a direct infusion of L-dopa into the caudate nucleus of awake, freely behaving rats using a push-pull cannula.

In vivo release of dopamine (DA) and its metabolites were determined following a direct infusion of 3,4-dihydroxyphenylalanine (L-DOPA) through a push-pull cannula in the caudate nucleus of unanesthetized, freely behaving rats. L-DOPA infusions increased the release of DA and dihydroxyphenylacetic acid (DOPAC) beginning with 10(-5) M L-DOPA, while homovanillic acid (HVA) was released consistently only following 10(-3) M L-DOPA. Maximal release of DA preceded that of DOPAC which preceded that of HVA. No salient changes in 5-hydroxyindoleacetic acid or behavior were observed following any L-DOPA dose.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1995

Loss of tonic neuronal activity to release L-DOPA in the caudal ventrolateral medulla of spontaneously hypertensive rats.

Experiments were designed to clarify whether a tonic L-DOPA system is altered in the caudal ventrolateral medulla (CVLM) of adult spontaneously hypertensive rats (SHR), compared to age-matched Wistar-Kyoto rats (WKY). By microdialysis in CVLM, basal L-DOPA release was constantly detectable and was lower in SHR than that in WKY. This release was reduced by tetrodotoxin perfusion (1 microM) in WKY to a basal level in SHR, whereas no modification occurred with tetrodotoxin in SHR. No difference of tyrosine hydroxylase and DOPA decarboxylase activities in the CVLM region was seen between the two strains. By microinjections into depressor sites of CVLM, L-DOPA (10-300 ng) or L-glutamate (3-300 ng) elicited dose-dependent depressor and bradycardic responses and greater depressor responses to both amino acids were seen at high doses in SHR, compared to WKY. Tonic neuronal activity to release L-DOPA is lost in the CVLM of adult SHR and this loss may contribute to maintenance of hypertension in SHR.

Animals↗
PubMed1984

Enzymatic 5-hydroxylation of L-dopa by a tyrosinase isolated from the sea anemone Metridium senile.

A particulate tyrosinase has been extracted and purified from tentacles of the sea anemone Metridium senile. The purified enzyme had properties in common with both mushroom and vertebrate tyrosinase and catalyzed three different reactions: oxidation of catechols, hydroxylation of L-tyrosine with L-dopa as cofactor and 5-hydroxylation of L-dopa. 5-Hydroxylation of L-dopa by an animal tyrosinase has not been reported earlier. The reaction could be analyzed under reducing conditions when the much faster oxidation of L-dopa to dopaquinone was inhibited. The conditions required for the accumulation of L-dopa and 5-hydroxydopa observed in vivo in tentacles of Metridium are discussed.

Animals↗
PubMed1991

The effect of L-dopa and carbidopa treatment on the survival of rat fetal dopamine grafts assessed by tyrosine hydroxylase immunohistochemistry and [3H]mazindol autoradiography.

The effect of treatment with L-3,4-dihydroxyphenylalanine (L-DOPA) and carbidopa for five weeks on the survival of rat fetal dopaminergic ventral mesencephalon cells implanted into the denervated striatum of rats with unilateral 6-hydroxydopamine nigrostriatal lesions was assessed. Rats receiving unilateral nigral 6-hydroxydopamine lesions followed by sham striatal grafts (Groups A and B) showed no recovery of (+)-amphetamine- or apomorphine-induced motor asymmetry. Rats in Group B (receiving treatment with L-DOPA and carbidopa) showed an increase in apomorphine-induced contralateral rotation and stereotypy. Animals receiving unilateral nigral 6-hydroxydopamine lesions followed by fetal striatal dopamine grafts (Groups C and D) showed complete recovery of (+)-amphetamine-induced rotation and a decrease of apomorphine-induced contralateral rotation. Treatment of animals in Groups B and D with L-DOPA (200 mg/kg per 24 h) and carbidopa (25 mg/kg per 24 h) by mouth for five weeks had no effect on the behavioural response to (+)-amphetamine. In the 6-hydroxydopamine-lesioned animals there was loss of tyrosine hydroxylase-immunoreactive cells in substantia nigra and ventral tegmental area of greater than 97% and to 66%, respectively, compared to the intact side. The number and morphology of tyrosine hydroxylase-immunoreactive cells in the intact substantia nigra and ventral tegmental area was not altered by treatment with L-DOPA and carbidopa. In the 6-hydroxydopamine-lesioned striatum of rats receiving a sham graft (Group A) or a sham graft and treatment with L-DOPA and carbidopa (Group B) there were no tyrosine hydroxylase-positive cells or fibres visible.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Effect of the adenosine A2A receptor antagonist 8-(3-chlorostyryl)caffeine on L-DOPA biotransformation in rat striatum.

In the present study, we investigated effects of the new selective adenosine A2A receptor antagonist 8-(3-chlorostyryl)caffeine (CSC) on L-DOPA-induced dopamine (DA) release in the striatum of intact and reserpine-treated rats. CSC given in a pharmacologically effective dose of 5 mg/kg i.p. significantly increased striatal DA release after joint administration of L-DOPA (100 mg/kg, i.p.) and benserazide (50 mg/kg, i.p.) to intact and reserpine (2.5 mg/kg, s.c.)-injected rats. CSC did not change the elevated level of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in intact rats, but raised it in DA-depleted animals. The availability of exogenous L-DOPA in the extracellular space was similar and equally increased by CSC in both intact and reserpinized rats. Our results suggest that the observed effects may be mediated by striatal adenosine A2A receptors, and are probably related to the CSC action on DA metabolism and the increased transport of exogenous L-DOPA into the brain. These observations might be of relevance, considering the use of selective A2A antagonists as potential supplements to L-DOPA therapy of Parkinson's disease.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2004

Detection of UDP-glucose:cyclo-DOPA 5-O-glucosyltransferase activity in four o'clocks (Mirabilis jalapa L.).

Although a pathway for betacyanin biosynthesis has been postulated, most of the catalytic steps have not yet been identified or demonstrated with biochemical evidence. In the postulated pathway, the glucose moiety of betanin is conjugated to the aglycone, betanidin, because the glucosyltransferase (GT) activity that produces betanin has been reported and its cDNA isolated. However, another pathway for betacyanin biosynthesis is proposed in which betanin is formed by GT acting at the 5,6-dihydroxyindoline-2-carboxylic acid (cyclo-DOPA) step, followed by condensation of the product with betalamic acid. Here, we show that GT activity acts upon cyclo-DOPA in the betacyanin synthetic pathway. A crude extract from the petals of four o'clocks (Mirabilis jalapa L.) was mixed with cyclo-DOPA and UDP-glucose. After the reaction was stopped with phosphoric acid, the product was chemically reacted with betalamic acid. In the final reaction mixture, betanin formation was confirmed by HPLC analysis, demonstrating cyclo-DOPA 5-O-glucosyltransferase activity. This activity was correlated with the accumulation of betanin during the development of four o'clock flowers and was detected in another five species of Centrospermae. These results indicate that the glucose moiety of betanin is introduced at the cyclo-DOPA step, which is followed by condensation with betalamic acid, and not at the betanidin aglycone step.

Chromatography, High Pressure Liquid↗
PubMed2005

Detection of levodopa, dopamine and its metabolites in rat striatum dialysates following peripheral administration of L-DOPA prodrugs by mean of HPLC-EC.

A high performance liquid chromatography (HPLC) method was developed to detected simultaneously L-dihydroxyphenylalanine (L-DOPA), dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in rat striatum dilaysates following oral administration of L-DOPA or its prodrugs. The chromatographic system uses a reversed-phase C18 column with electrochemical detection at +0.30 V. Mobile phase consisted of 0.05 M citric acid, sodium EDTA 50 microM, sodium octylsulphonate 0.4 nM at pH of 2.9 and 8% methanol (v/v) at a flow rate of 1 ml/min. The calibration curves were linear over the concentration range of 10nm to 100 microM and the lower limits of detections were 125 fmol for L-DOPA, 50 fmol for DOPAC, 250 fmol for DA and 150 fmol for HVA at signal noise to ratio of 3. The repeatability (or intra-day precision), expressed by the relative standard deviation, were better than 4%. The construction of microdialysis probes has been described. The in vitro relative recoveries of each microdialysis probe were evaluated and the results show that they are similar and reproducible for all the analytes with CVs from 1 to 4%. The HPLC-EC method was applied to detect the extracellular levels of L-DOPA, DA, DOPAC and HVA in the striatum dialysates of freely moving rats after oral administration of six new potential L-DOPA prodrugs.

Animals↗
PubMed2005

Distribution kinetics of 18F-DOPA in weaver mutant mice.

Distribution kinetics of 18F-fluoro-dihydroxy phenylalanine (18F-DOPA) were studied with high-resolution micro-positron emission tomography (microPET) imaging and conventional methods in control wild-type mice, heterozygous weaver mutant mice, and homozygous weaver mutant mice. 18F-DOPA uptake was significantly increased in the CNS within 60 min in all the genotypes examined. Homozygous weaver mutant mice exhibited significantly reduced 18F-DOPA uptake in the region of interest (striatum) as compared to heterozygous weaver mutant mice and control wild-type mice. 18F-DOPA was de-localized in the kidneys of homozygous weaver mutant mice. The radioactivity was localized primarily in the liver and kidneys within 2 h and in the urinary bladder within 4 h. After 8 h, it could be detected neither by conventional nor by microPET imaging. Distribution kinetics of 18F-DOPA with microPET imaging correlated and confirmed the conventional observations. These data are interpreted to suggest that microPET imaging may provide an efficient, noninvasive, cost-effective procedure to study distribution kinetics of PET radiopharmaceuticals in rare genetically altered animals. Furthermore, this unique and noninvasive approach may expedite quality control and drug development for human applications.

Animals↗
PubMed2006

Effect of L-DOPA on nitric oxide production in striatum of freely mobile mice.

In Parkinson's disease, nitric oxide (NO) and other free radicals are thought to be involved in neuronal degeneration. Furthermore, L-DOPA is suggested to have a cytotoxic action on dopaminergic neurons. We studied 24-h NO production and the effect of L-DOPA on this in freely mobile mice using in vivo microdialysis. A microdialysis probe was implanted into the right striatum 12 h before the experiment. This dialysis probe was perfused with Ringer solution for 100 min, then with 20, 50, or 100 nM L-DOPA for 20 min, and finally with Ringer solution. Dialysate fractions were collected every 20 min for 4 h. Production of nitrite and total NO were significantly higher during daytime than during nighttime. Nitrate production was increased significantly by L-DOPA. NO production in the striatum appears to exhibit a diurnal rhythm and to increase with exposure to L-DOPA.

Analysis of Variance↗
PubMed2004

Rasagiline enhances L-DOPA-induced contralateral turning in the unilateral 6-hydroxydopamine-lesioned guinea-pig.

The modification of L-3,4-dihydrooxyphenylalanine- (L-DOPA-) induced turning response by the new selective monoamine oxidase type B (MAO-B) inhibitor rasagiline was studied in guinea-pigs bearing a unilateral 6-hydroxydopamine-induced lesion in the substantia nigra. In an initial experiment, it was established that contralateral turning is induced in lesioned guinea-pigs in response to apomorphine (18 mg/kg i.p.) and L-DOPA/carbidopa (15/3.5 mg/kg i.p.), while ipsilateral turning is induced by S(+)-methamphetamine (7 mg/kg i.p.). The effect of rasagiline was studied in a chronic treatment regimen, in which animals were treated with rasagiline (0.05 mg/kg s.c.) or saline s.c. daily commencing 2 weeks after lesioning, and L-DOPA/carbidopa (4:1 mg/kg) was administered once daily for 21 days. Only guinea-pigs with 95% or more depletion of striatal dopamine were included in this study. Guinea-pigs treated with rasagiline had a significantly increased intensity and duration of turning in response to L-DOPA (P <0.05 by repeated measures ANOVA) over the 21-day period. On day 21, turning averaged 806+/-105 (n=10) vs 442+/-123 (n=11) turns per 180 min for rasagiline and vehicle treated animals, respectively (P <0.05); turning duration half-time averaged 81+/-15.4 (n=10) as opposed to 33+/-7.6 (n=11) min for rasagiline and vehicle treatments (P <0.01). Concentration of dopamine in intact striatum was significantly increased (69.3+/-2.1 and 60.3+/-2.4 pmol/mg tissue for rasagiline and vehicle, P <0.05) and levels of dihydroxyphenylacetic acid and homovanillic acid were decreased by the rasagiline treatment. Activity of brain MAO-B was 8.6+/-2.9% and MAO-A was 71+/-1.5% that of control in rasagiline-treated animals. Chronic, selective inhibition of MAO-B by rasagiline potentiated L-DOPA-induced turning in this rodent model.

3,4-Dihydroxyphenylacetic Acid↗