Effects Of L-dihydroxyphenylalanine Research Articles

Spontaneous locomotor activity and L-DOPA-induced dyskinesia are not linked in 6-OHDA parkinsonian rats.

Bradykinesia (slowness of movement) and other characteristic motor manifestations of Parkinson’s disease (PD) are alleviated by treatment with L-dihydroxyphenylalanine (L-DOPA). Long-term L-DOPA treatment, however, is associated with complications such as motor fluctuations and dyskinesia that severely impair the quality of life. It is unclear whether the effect of L-DOPA on spontaneous motor activity and its dyskinesia-inducing effect share a common mechanism. To investigate the possible connection between these two effects, we analyzed the spontaneous locomotor activity of parkinsonian rats before surgery (unilateral injection of 6-OHDA in the right medial forebrain bundle), before treatment with L-DOPA, during L-DOPA treatment (the “ON” phase), and after the end of L-DOPA treatment (the “OFF” phase). We correlated the severity of dyskinesia (AIM scores) with locomotor responses in the ON/OFF phases of chronic L-DOPA treatment at two different doses. We treated three groups of parkinsonian animals with chronic injections of 8 mg/kg L-DOPA, 6 mg/kg L-DOPA, and saline solution and one group of non-lesioned animals with 8 mg/kg L-DOPA. At the end of the experiment, tyrosine hydroxylase (TH) immunoreactivity was analyzed in the striatum of all parkinsonian rats. We found no correlation between the severity of dyskinesia and spontaneous locomotor activity in the ON or OFF phase of L-DOPA treatment. The only observed correlation was between the pathological rotation induced by L-DOPA at the highest dose and locomotor activity in the ON phase of L-DOPA treatment. In addition, a L-DOPA withdrawal effect was observed, with worse motor performance in the OFF phase than before the start of L-DOPA treatment. These findings suggest that different neural mechanisms underlie the effect of L-DOPA on spontaneous motor activity and its dyskinesia-inducing effect, with a different dose-response relationship for each of these two effects.

The mechanism of the effect of apterous 56f mutation on the reproductive function of Drosophila melanogaster

The effects of L-dihydroxyphenylalanine (L-DOPA) and 20-hydroxyecdysone (20E) were studied with respect to the content of dopamine (DA), intensity of the juvenile hormone (JH) degradation, and fecundity of the wildtype flies (Canton S) and JH-deficient apterous56f mutants (in young females, carrying this mutation, the levels of DA and 20E production were strongly increased). Fly feeding with L-DOPA proved to increase the level of DA in a dose-dependent manner and reduce JH degradation in 2-day-old females of both strains. Feeding with 20E produced the same effect. Treating the wild-type flies with 2.5 mg L-DOPA caused a 24-h delay in beginning of oviposition and reduction in fecundity throughout the experiment. An L-DOPA dose of 1 mg caused no such changes. An experimental increase in 20E titer led to reduced fecundity of the wild-type flies, though no delay in oviposition was observed. In mutant flies, an increase in DA and 20E levels accelerated beginning of oviposition and increased fecundity of young females, though the latter parameter was reduced in mature individuals. Thus, an increase in endogenous DA and 20E characteristic of young apterous56f females is assumed to be a compensatory response that leads to a higher JH titer and induction of vitellogenesis.

Role of serotonergic neurons in L-DOPA-derived extracellular dopamine in the striatum of 6-OHDA-lesioned rats.

The effect of L-dihydroxyphenylalanine (L-DOPA) on extracellular dopamine (DA) in the striatum was determined by microdialysis in 6-hydroxydopamine (6-OHDA)-lesioned rats treated with and without the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). At the same time the intensity of L-DOPA-induced rotational behavior was assessed. In 6-OHDA-lesioned rats treated with 5,7-DHT, L-DOPA (50 mg/kg, i.p.) increased extracellular DA only to 20% of that measured in animals not treated with 5,7-DHT. Likewise, 6-OHDA-lesioned rats treated with 5,7-DHT exhibited a significantly lower number of L-DOPA-induced rotations. These results suggest that serotonergic terminals in the striatum can convert exogenously administered L-DOPA into DA that can be released into the extracellular space.

Alteration in L-DOPA evoked dopamine and DOPAC output under conditions of impaired vesicular dopamine storage.

We examined the effect of L-dihydroxyphenylalanine (L-DOPA) infusion in vitro upon dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) output from superfused corpus striatum of vehicle and reserpine or tetrabenazine (TBZ) treated male rats. Specifically, we tested the effects of two 20-min infusions of L-DOPA (5 uM) upon DA and DOPAC output (pg/mg/min) in reserpine (5 mg/kg, i.p., 24 hours before sacrifice; n=11), TBZ (30 mg/kg, i.p. 1 hour before sacrifice; n=8) or vehicle (n=21) treated rats. There was an overall significantly higher L-DOPA evoked DA output from the vehicle (12.22+/-1.74) versus reserpine (4.39+/-2.40) (p < 0.05), but not TBZ (9.16+/-2.81) treated rats. In addition, the DA response to the second L-DOPA infusion was significantly increased over that of the first response in the vehicle (9.40+/-2.11 vs. 15.04+/-2.78) (p < 0.05), but not reserpine or TBZ treated rats. The overall DOPAC outputs did not achieve a statistically significant difference among all treatment groups. However, the DOPAC outputs following the second L-DOPA infusion were significantly reduced in reserpine (41.15+/-6.10 vs. 20.27+/-4.54) and TBZ (21.38+/-4.41 vs. 10.87+/-2.36) (both p < 0.05), but not vehicle (28.99+/-4.00 vs. 24.91+/-4.78) treated rats. We conclude that: 1) the storage capacity of DA neurons is one of the important elements involved in affecting L-DOPA's effects upon DA and DOPAC output, 2) the shunting of storage to metabolism may represent a common characteristic in impaired nigrostriatal dopaminergic system, and 3) TBZ may operate differently from reserpine in the nigrostriatal dopaminergic system.

The effects of L-dihydroxyphenylalanine on alertness and mood in α-methyl-para-tyrosine-treated healthy humans: Further evidence for the role of catecholamines in arousal and anxiety

Treatment with alpha-methyl-para-tyrosine (AMPT), a catecholamine synthesis inhibitor, has been shown to produce pronounced increases in sleepiness and mild increases in negative mood and anxiety when administered to healthy male adults. The present study was conducted to ascertain whether these effects of AMPT are secondary to decreases in brain catecholamines or whether they represent nonspecific drug effects. Forty-one healthy males were randomized to one of four treatment groups. (1) Treatment with AMPT alone (AMPT/placebo); (2) treatment with AMPT plus L-dopa/carbidopa (AMPT plus L-dopa/carbidopa); (3) treatment with L-dopa/carbidopa alone (placebo plus L-dopa/carbidopa); or (4) treatment with placebo alone (placebo plus placebo). Repeated measures of alertness, mood, and anxiety were obtained over a three-day period of drug treatment and following drug discontinuation. As before, AMPT treatment led to increased sleepines. In addition, AMPT treatment led to decreased calmness, increased tension and anger, and a trend for increased depression. Replacement of catecholamine stores with L-dopa reversed the effects of AMPT and was associated with a more rapid recovery from AMPT's effects. These findings indicate that AMPT's effects on alertness and anxiety are catecholamine-specific. Further, they provide additional evidence that catecholamines are involved in the regulation of normal states of arousal, and they are consistent with the view that brain catecholaminergic dysregulation is involved in pathological anxiety states.

The Effects of L-Dihydroxyphenylalanine on Alertness and Mood in α-Methyl-Para-Tyrosine-Treated Healthy Humans

Treatment with α-methyl-para-tyrosine (AMPT), a catecholamine synthesis inhibitor, has been shown to produce pronounced increases in sleepiness and mild increases in negative mood and anxiety when administered to healthy male adults. The present study was conducted to ascertain whether these effects of AMPT are secondary to decreases in brain catecholamines or whether they represent nonspecific drug effects. Forty-one healthy males were randomized to one of four treatment groups. (1) Treatment with AMPT alone (AMPT/placebo); (2) treatment with AMPT plus L-dopa/carbidopa (AMPT plus L-dopa/carbidopa); (3) treatment with L-dopa/carbidopa alone (placebo plus L-dopa/carbidopa); or (4) treatment with placebo alone (placebo plus placebo). Repeated measures of alertness, mood, and anxiety were obtained over a three-day period of drug treatment and following drug discontinuation. As before, AMPT treatment led to increased sleepiness. In addition, AMPT treatment led to decreased calmness, increased tension and anger, and a trend for increased depression. Replacement of catecholamine stores with L-dopa reversed the effects of AMPT and was associated with a more rapid recovery from AMPT's effects. These findings indicate that AMPT's effects on alertness and anxiety are catecholamine-specific. Further, they provide additional evidence that catecholamines are involved in the regulation of normal states of arousal, and they are consistent with the view that brain catecholaminergic dysregulation is involved in pathological anxiety states.

Effects of l-dihydroxyphenylalanine (l-Dopa) and d,l,5-hydroxytryptophan (d,l,5-HTP) on reserpine-induced amnesia

In a series of experiments the effects of reserpine, l-Dopa, and d,l,5-hydroxytryptophan (d,l,5-HTP) on retention of a passive avoidance training in mice were investigated. Reserpine (2.5 mg/kg) produced amnesia when given at 120 min before but not at 30 min before or at 0, 10, 30, or 90 min following training. This time-dependent reserpine effect did not appear to be due to either an alteration in footshock sensitivity during training or to the drug producing state-dependent learning. The amnesic effect of reserpine could be blocked when both l-Dopa and d,l,5-HTP were also administered up to 10 min but not at 30 or 90 min following training. The drugs, l-Dopa or d,l,5-HTP, given alone or in higher doses, could not at any time counteract the reserpine effect. The retrograde effects of the combined administration of these biogenic amine precursors on the reserpine-induced amnesia are discussed in terms of the possible role of biogenic amines in memory formation.

Effect of 1-dihydroxyphenylalanine (l-dopa), anesthesia and surgical stress on the secretion of growth hormone in the dog.

A radioimmunoassay for canine growth hormone (cGH) is described utilizing a sensitive and specific 125I-double antibody system. The assay is capable of detecting concentrations of GH as low as 0.7 ng/ml. Resting venous concentrations were 3.8 ± 0.3 ng/ml. Pentobarbital anesthesia and surgical stress failed to cause a significant increase in these values. However, the administration of L-dopa in a dose of 50 mg/kg iv caused a rapid rise in plasma GH from 1.2 to 21.6 ng/ml within 10 min, with a peak of 25.7 ng/ml at 20 min, and a slow decrease to base line values by 90 min. Continuous administration of L-dopa (a stat intravenous dose of 50 mg/kg followed by a constant infusion of 1 mg/kg/min for 2 hr) resulted in a transient rise in plasma GH concentration. After hypophysectomy, plasma GH concentration fell to less than 2 ng/ml. Thus, L-dopa is a potent stimulus for the secretion of GH in the dog, as it is in man. (Endocrinology 95: 1317, 1974)

Effect of l-dihydroxyphenylalanine upon serum growth hormone concentrations in children and adolescents

Serum growth hormone levels were measured serially in 26 children and adolescents, two adult males, and four patients with Parkinson's disease after oral administration of 0.5 Gm. of l -dihydroxyphenylalanine ( l -dopa); the results were compared to those obtained after administration of arginine and insulin. In 22 children without pituitary disease the mean maximum growth hormone concentration (8.9±1.5 [S.E.M.] mμg per milliliter) was recorded 60 minutes after l -dopa ingestion. The mean peak growth hormone concentrations was 11.2±1.4 mμg per milliliter; the mean increment was 10.1±1.4 mμg per milliliter. During a combined arginine-insulin tolerance test (N=19) the mean peak growth hormone value was 13.4±1.3 mμg per milliliter; the mean increment was 11.9±1.2 mμg per milliliter. Growth hormone levels did not increase in four patients with hypopituitarism following administration of l -dopa, arginine, or insulin. Growth hormone concentrations increased in both adult males and in one of four patients with Parkinson's disease after administration of l -dopa. Variable changes in blood glucose and insulin concentrations followed l -dopa ingestion. l -dopa stimulates the release of growth hormone in young subjects without pituitary disease.

Effect of l-dihydroxyphenylalanine on methylation of 3H-norepinephrine and 3H-histamine

Acute administration of l-dihydroxyphenylalanine ( l-dopa) to mice produced a dose-dependent decrease in O-methylation of 3H-norepinephrine. It was maximal 35 min after l-dopa and was still apparent for up to 2 hr. It was not reversed by concomitant administration of methionine and presumably is a consequence of competitive inhibition of O-methylation of norepinephrine by the administered l-dopa. Formation of N-methylhistamine from histamine was also partly inhibited by l-dopa. This effect was short in duration; it terminated within 1 hr. It was partially reversed by methionine but not by leucine administration. The unchanged 3H-norepinephrine was the same in both control and l-dopa-treated mice. 3H-histamine retention was significantly higher in the l-dopa-treated animals than n control mice. The results are discussed in terms of specific and nonspecific effects of l-dopa on methylation processes.

Inhibitory effect of L-dihydroxyphenylalanine on the venous 17-hydroxycorticosteroid response to surgical stress in dogs.

The effect of intravenous L-dihydroxyphenylalanine (L-dopa) on the adrenal venous 17-hydroxycorticosteroid (17OHCS) output in response to laparotomy and intestinal manipulation was studied in pentobarbital-anesthetized dogs. L-Dopa, 50 mg/kg but not 10 nag/kg, markedly decreased the 17OHCS response to surgical stress. The catecholamines, norepinephrine and dopamine, administered intravenously, did not have this inhibitory effect on 17OHCS output. The effect of L-dopa in inhibiting the 17OHCS response to stress was not dependent on the increase in blood pressure that it produced, since prior treatment of dogs with the α-adrenergic blocking agent, phenoxybenzamine, prevented the pressor response to L-dopa without altering the effect on 17OHCS output. The minimum effective dose of L-dopa that inhibited the 17OHCS response to stress was decreased by the monoamine oxidase inhibitor, pargyline, and increased by the catecholamine synthesis inhibitor, α-methyl-ptyrosine. These data support the hypothesis of a cen...

Effect of catecholamines precursors on insulin secretion.

The effect of L-dihydroxyphenylalanine (DOPA) administration on blood glucose, serum insulin levels, pancreatic dopamine concentration and β-cell fluorescence was studied in normal rats. It was possible to demonstrate that DOPA injection was followed both by a significant rise in the pancreatic dopamine concentration and by the appearance of fluorescence within the β-cells of the islets of Langerhans. However, no changes could be detected in the blood glucose and serum insulin levels after the above-mentioned treatment. Similar results were obtained in vitro with the incubation of slices of pancreas technique. These results therefore failed to demonstrate a correlation between dopamine pancreatic levels and serum insulin secretion. (Endocrinology 87: 823, 1970)