DOPA Levels Research Articles

B-HT 958 — An antagonist at α2-adrenoceptors and an agonist at dopamine autoreceptors in the brain

B-HT 958 (2-amino-6-(p-chlorobenzyl)-4H-5,6,7,8-tetrahydrothiazolo[5,4-d]azepine), a compound chemically related to clonidine-like drugs of the azepine type, was described previously as a mixed agonist-antagonist at peripheral α2-adrenoceptor sites. In the present experiments the actions B-HT 958 on brain noradrenergic and dopaminergic mechanisms were examined using behavioural, pharmacological and biochemical methods. (i) In the dog, intracisternally injected B-HT 958 (300 μg/kg) abolished the reflex bradycardia facilitated by the α2-agonist B-HT 920 (10 μg/kg i.ci.). (ii) In the whole mouse brain as well as in the rat hypothalamus and neocortex, but not in the hippocampus, amaygdala and nucleus accumbens B-HT 958 (5–20 mg/kg s.c.) accelerated the α-methyltyrosine (α-MT)-induced disappearance of noradrenaline. (iii) B-HT 958 decreased in a dose-dependent manner the exploratory activity of mice (ED50: 6.3 mg/kg s.c.) and slightly enhanced the motor activity of reserpine-treated mice only in high doses. (iv) B-HT 958 (20 mg/kg s.c.) lowered the level of homovanillic acid in the striatum and nucleus accumbens and dose dependently (1–20 mg/kg) slowed the α-MT-induced disappearance of dopamine in these 2 brain regions of the rat as well as in the whole mouse brain. (v) The γ-butyrolactone-induced increase in DOPA levels was effectively antagonized by B-HT 958 (1 and 5 mg/kg s.c.) in the rat striatum and nucleus accumbens. These behavioural, pharmacological and biochemical observations indicate that B-HT 958 possesses central α-adrenoceptor blocking activity and exerts a strong agonistic effect on brain dopamine autoreceptors.

An Assessment of the Potential of Vicia faba minor in the Storage of the L-Form of 3,4-Dihydroxyphenylalanine

The uncommon amino acid 3,4-dihydroxyphenylalanine (DOPA) was determined colorimetrically using isonicotinic acid hydrazide (IAH) in the crude extracts obtained from fresh material of Vicia faba minor. DOPA was found to accumulate at concentrations inconsistent with its solubility in water. Other orthodiphenols do not interfere in DOPA determination. The accumulated DOPA was only of the L-form. The DOPA content in the dry material of Vicia faba was significantly lower than that from the corresponding fresh material, suggesting some kind of DOPA oxidation during drying. Subsequent analyses designed to evaluate the actual potential of V. faba minor in the accumulation of DOPA were performed with fresh material. It was observed that the DOPA concentration in the tissues of V. faba minor is reproducible when expressed on a fresh matter weight basis. In young seedlings L-DOPA production is significantly enhanced by light via an increased fresh matter yield. The DOPA content was found to be increased in mature plants grown on media enriched with low concentrations of NaCl (up to 25 mM) that showed a positive effect on their growth. NaCl induced an overproduction of L-DOPA even when growth was restricted by ion excess. On the contrary, the DOPA level dropped in mature plants submitted to water stress. Nodulated plants were found to contain higher content of L-DOPA than the non-nodulated ones grown with NO(3)(-) and NH(4)(+). It is suggested that DOPA hyperproduction by Vicia faba minor might be optimized by growing plants in mild saline conditions and by inoculating them with efficient salt tolerant strains of R. leguminosarum.

Characterization of Melanogenesis in Mouse and Guinea Pig Hair by Chemical Analysis of Melanins and of Free and Bound Dopa and 5-S-Cysteinyldopa

This study examined how various genotypes of coat color in mice and guinea pigs are related to the type and content of melanin and to the levels of free and protein-bound dopa and 5-S-cysteinyldopa in hair. In analysis of black, yellow, and white areas of tortoiseshell guinea pigs, the melanogenesis type was in parallel to the type and content of melanin and was correlated fairly well with the levels of melanin precursors. In mouse hair, substitution of the brown allele (bb) for black (BB) reduced the eumelanin content to 1/2 to 1/3, while it significantly increased the dopa level. The dilution (dd) gene of mice reduced the eumelanin content only slightly, while the gene for pink-eyed dilution (pp) reduced the content of eumelanin and the level of dopa to as much as 1/10. From the eumelanin/pheomelanin ratio, the melanin of brown and dilute brown mice was found to be eumelanic, while the melanin of pink-eyed dilution mice appeared to be a mixed type because of an extremely low content of eumelanin. The levels of bound dopa and 5-S-cysteinyldopa in hair were found to largely reflect the tyrosinase activity.

Olfactory bulb dopamine neurons survive deafferentation-induced loss of tyrosine hydroxylase

Peripheral deafferentation of the rodent olfactory bulb results in loss of dopamine content, tyrosine hydroxylase activity and immunocytochemical staining for tyrosine hydroxylase in juxtaglomerular dopamine neurons. Reinnervation of the bulb by afferent neurons results in the return of all parameters to control levels suggesting that the dopamine neurons did not degenerate but that the expression of tyrosine hydroxylase enzyme was transneuronally regulated in a static population of juxtaglomerular cells. To evaluate this possibility, we determined the activity and immunocytochemical localization of the second enzyme in the dopamine biosynthetic pathway, DOPA decar☐ylase. At a time when tyrosine hydroxylase activity was reduced to 25% of control values, DOPA decar☐ylase activity in the lesioned bulb was maintained at about 65% of that in the unlesioned bulb. Immunocytochemical staining with antibodies to both enzymes, performed sequentially in the same sections, demonstrated that in the unlesioned bulb tyrosine hydroxylase and DOPA decar☐ylase are co-localized in the same population of juxtaglomerular neurons. Similar results were obtained in adjacent sections each stained with one of the two antibodies. In contrast, in the deafferented bulb, about three times as many neurons were stained with DOPA decar☐ylase as with tyrosine hydroxylase antibodies. The DOPA decar☐ylase activity measurements and immunocytochemistry argue for the continued presence, in the lesioned olfactory bulb, of a population of tyrosine hydroxylase deficient dopamine neurons. The data suggest that olfactory receptor cell innervation transneuronally regulates the expression of tyrosine hydroxylase by mechanisms separate from those controlling the levels of DOPA decar☐ylase.

Combined use of benserazide and carbidopa in Parkinson's disease.

The pharmacokinetics of levodopa differs when it is combined with benserazide or carbidopa. Peak dopa levels are higher, occur sooner, but decline more rapidly with benserazide. Although many patients respond better to one drug than the other, we sought to exploit the differences in pharmacokinetics by giving both drugs to the same patient. Benserazide was combined with carbidopa in 38 patients who were experiencing a diminished response to carbidopa, including 22 patients with diurnal oscillations in performance, "wearing off" or on-off phenomena. Previous attempts to change the dose, sequence, or ratio of levodopa to carbidopa in these patients had been unrewarding. Ten of the patients improved on the combination of benserazide and carbidopa, with a 30% decline in disability. The mean dose of levodopa:carbidopa before benserazide was 910:100 (9 to 1 ratio); the mean dose of levodopa:benserazide was 355:90 (4 to 1 ratio). The mean dose of levodopa:carbidopa + benserazide was 925:155 (6 to 1 ratio). The combination of carbidopa with benserazide is useful in some parkinsonian patients.

Biogenic amines and DOPA in the central nervous system of decapod crustaceans

1. 1. The biogenic amines serotonin (5-HT), dopamine (DA), noradrenaline (NA), octopamine (OA) and the amino acid dihydroxyphenylalanine (DOPA) were identified and measured in the brain and the eyestalks of five decapod crustacean species using high pressure liquid chromatography (HPLC) with electrochemical detection. 2. 2. The amounts fall within 0.01–1.1 μg/g or 0.17–60 pmoles, and OA is the dominating amine in most species. 3. 3. The DOPA levels in many of the species varied considerably between different measurements. 4. 4. It is concluded that the biogenic amines and DOPA are ubiquitous in the central nervous system of decapod crustaceans and the presence of NA and DOPA increases the number of presumed neurotransmitter/modulator candidates in the crustacean nervous system.

Plasma Catecholamines in the Chronically Cannulated Sheep Fetus: Predominance ofL-Dihydroxyphenylalanine*

Dihydroxyphenylalanine (Dopa) and catecholamines (CA) concentrations were determined in plasma collected from chronically cannulated fetal and maternal sheep from days 125-140 of gestation. Dopa was measured by a radioenzymatic assay, followed by ion exchange chromatography and high performance liquid chromatography. The assay was linear to 2.5 ng Dopa, and its sensitivity was 35-45 pg. Dopamine (DA), norepinephrine, and epinephrine were determined simultaneously by the same radioenzymatic incubation procedure, followed by solvent extraction and two-dimensional thin layer chromatography. The Dopa level in the fetal circulation was 10-25 times higher than that of DA, 5-10 times higher than that of norepinephrine, and 100 times higher than that of epinephrine. Furthermore, Dopa was the only CA that was significantly (P less than 0.05) higher in fetal (3.5-4.5 ng/ml) than in maternal plasma (1-1.5 ng/ml). The data indicate that Dopa is the predominant circulating CA in the sheep fetus. While the physiological importance of this observation is unknown at the present time, fetal Dopa might serve as the source of free DA in fetal urine and/or amniotic fluid.

Characterization of Structural Properties for Morphologic Differentiation of Melanosomes. III. Free and Protein-bound Dopa and 5-S-Cysteinyldopa in B16 and Harding-Passey Melanomas

This study analyzed the free and protein-bound forms of dopa, 5-S-cysteinyldopa (5-S-CD), and 5-S-glutathionedopa (5-S-GD) in B16 and Harding-Passey (HP) mouse melanomas to investigate the role of these catechols for melanogenesis and melanosome morphogenesis, inasmuch as these tumors produce melanosomes different in color and ultrastructure, i.e., eumelanosome type in B16 and pheomelanosome type in HP. Between B16 and HP mouse melanomas, however, we found (a) no significant difference in the level of free dopa and 5-S-CD in melanosomes and tumors, although the levels of these catechols reflected well the type of melanogenesis in control hair of normal mice, (b) a significant difference in free 5-S-GD level, which might, in part, reflect the observed difference in melanogenesis, and (c) no apparent difference in the level of bound dopa and 5-S-CD in either melanosomes or tumors. Thus, the striking difference in the color of melanosomes between B16 and HP melanomas seems to be related primarily to the content--not the type--of melanin pigments.

Abnormal tryptophan pyrrolase and amino acids related to melanogenesis in vitiligo

A comparison of the serum tyrosine, DOPA, tryptophan, tyrosinase and tryptophan pyrrolase levels of vitiliginous patients with those of normal subjects show abnormalities in all these parameters. As the clinical diagnosis of vitiligo may be made without difficulty, these parameters appear to be of little diagnostic value in vitiligo. But they may be considered as additional biochemical parameters in vitiligo.

Neurotensin interacts with dopaminergic neurons in rat brain

Neurotensin (NT) injected intracerebroventricularly in rat increases dopamine (DA) turnover in the corpus striatum and nucleus accumbens. Significant increases in 3,4-dihydroxyphenylacetic acid (DOPAC) levels occurred within 15 minutes after injection with peak levels at 60 minutes. The effect on NT on DOPAC and homovanillic acid (HVA) accumulation was dose-dependent at 3–100 μg. NT, like haloperidol, stimulated 3,4-dihydroxyphenylalanine (DOPA) accumulation in striatal neurons, in the presence of DOPA decarboxylase inhibitor, after injection of gamma-butyrolactone (GBL). NT had a similar stimulatory effect on DOPA levels in the accumbens while haloperidol (0.25 mg·kg −1) had no significant effect in this brain region. NT did not block the inhibitory effect of apomorphine on DOPA accumulation in both the striatum and accumbens, while haloperidol inhibited apomorphine effect in both regions. NT also failed to displace 3H-spiperone from DA receptors and the presence of NT in the binding assay did not alter the ability of DA to displace 3H-spiperone in either brain region. These experiments demonstrate that NT increases DA turnover in both the nigrostriatal and mesolimbic pathways.

Changes in electroretinogram and serum potassium during L-DOPA treatment in parkinsonism.

The relationship of L-DOPA plasma level, parameters of ERG and severity of extrapyramidal symptoms after a single dose of L-DOPA was investigated in 11 patients suffering from parkinsonism of idiopathic or arteriosclerotic origin. After a drug-free night, each patient received his/her usual morning dose of L-DOPA. In the subsequent 3 h, the ERG recordings, blood levels and clinical ratings of extrapyramidal symptoms significantly dropped after a delay of 60 min in relation to the occurrence of the peak plasma L DOPA level. The initial "b" wave amplitudes as well as initial serum potassium values were abnormally high. There was a statistically significant correlation between the decrease of "b" wave amplitude (delta "b") and the potassium "normalization index" (i.e. the ratio between the observed decrease of serum potassium and the pretreatment difference from the middle normal potassium value). A definite interpretation of the data cannot be provided until more knowledge about the origin of "b" wave of ERG is available. It can be concluded tentatively that dopaminergic processes influence electrophysiological reactivity of the retina.

Effects of drugs interfering with dopamine and noradrenaline biosynthesis on the endogenous 3,4-dihydroxyphenylalanine levels in rat brain.

A chemical assay of 3,4-dihydroxyphenylalanine (DOPA) in nervous tissue is described. The method is based on a rapidly performed isolation of DOPA on small Sephadex G-10 columns, followed by reverse-phase HPLC with a trichloroacetic acid-containing eluent, in conjunction with a rotating disk electrochemical detector. The detection limit of the assay (about 100 pg/tissue sample) permits a detailed investigation of the regional distribution of endogenous DOPA levels in the rat brain. DOPA as well as dopamine (DA) could be quantified in the same chromatographic run. The assay was applied to a study of the effects of alpha-methyl-p-tyrosine, apomorphine, chlorpromazine, clonidine, gamma-butyrolactone, haloperidol, morphine, oxotremorine, pargyline, reserpine, and tyrosine methylester on the concentration of DOPA in the striatum, hypothalamus, frontal cortex, and cerebellum of the rat brain. Drugs known to interact with DA biosynthesis all caused characteristic changes of the DOPA content in the striatum and not in nondopaminergic brain areas. A close correlation existed between drug-induced changes in tyrosine hydroxylase activity and changes in the DOPA content in the striatum. Tyrosine methylester increased DOPA concentrations in all brain areas studied.

A semiautomated method for the rapid determination of dopa: Comparison of plasma and erythrocyte-dopa concentration in levodopa-treated patients

A rapid, sensitive, and reproducible method for the semiautomated determination of plasma dopa has been developed. Dopa in deproteinized plasma or tissue is isolated by cation—exchange column chromatography, and is then processed through a Technicon AutoAnalyzer and quantitated as its hydroxyindole derivative by fluorescence spectrometry. Plasma-dopa concentrations as low as 0.3 μ m can be readily determined. Plasma and erythrocyte levels in parkinsonian patients are routinely assayed by this method in our laboratory. A correlation coefficient of 0.995 was given by a comparison between this automated method and the manual method. Plasma and erythrocyte levels of dopa and 3- O-methyldopa (OMD) were measured in 14 randomly selected patients, and correlations were made between these concentrations and the dosage of levodopa.

Alternate day levodopa therapy in parkinsonism.

Chronic high dose levodopa therapy in Parkinson disease is associated with an apparent loss of efficacy and an increased prevalence of side effects which limit is effectiveness. The use of minimum dosage has therefore been recommended. We found that los-dose alternate-day levodopa provided adequate control of early but not late parkinsonism. Stable clinical responses occurred both on the day of drug administration and on the following day, although plasma dopa levels were negligible on the day when the drug was not given. Alternate-day therapy results in less cumulative dosage and may better preserve existing compensatory striatal activity, leading to more effective long-term treatment.

Identification and quantitative measurements of biogenic amines and DOPA in the central nervous system and haemolymph of the crayfish Pacif ast acus leniusculus (crustacea)

1. The biogenic amines dopamine (DA), noradrenaline (NA), octopamine (OA), serotonin (5-HT) and the amino acid dihydroxyphenylalanine (DOPA) have been identified and quantitatively measured in the crayfish nervous system and in haemolymph employing high performance liquid chromatography (HPLC). 2. The substances occurred in the nervous system in amounts ranging between 0.1 and 0.7 μg/g w/w. 3. The haemolymph contained very small amounts of NA, OA, 5-HT and DOPA. 4. No adrenaline (A) was present. 5. Prolonged handling of the animals caused dramatic changes in DOPA levels. 6. Depletion experiments using reserpine caused a pronounced decrease in the content of DA, NA, OA and 5-HT in the nervous system. DOPA, however, remained unaffected.

Catecholamines in honey bee ( Apis mellifera L.) and various vespid (Hymenoptera) venoms

—Liquid chromatography with electrochemical detection was used to separate, identify and quantitate the levels of dopamine (DA) and noradrenaline (NA) present in the venoms of honey bees of known ages and of DA and 5-hydroxytryptamine (5-HT) in various species of vespid wasps. Fluorescence histochemistry corroborated the presence of amines in honey bee venom glands and reservoirs and supported the quantitative results. The results show: (i) There is an age dependent variation in DA and NA levels in honey bee venom and there may be a similar variation in DA and 5-HT in the venom of queen Dolichovespula arenaria. (ii) There appears to be a seasonal variation in the quantities of DA and NA present in honey bee venom. Such a seasonal variation may be one of the factors involved in the variation in the levels of amine components present in the various vespid wasp venom samples. (iii) 5-HT is present in much greater quantities than DA in vespid venoms. Low levels of NA and DOPA are present in vespid venoms.

Renal handling of dopa, dopamine, norepinephrine, and epinephrine in the dog.

The uptake and excretion of endogenous dopa, dopamine, norepinephrine, and epinephrine by the kidney were studied. Blood samples were taken from the aorta at the origin of the renal artery and from the renal vein during a timed urine collection in each of six anesthetised greyhound dogs. Arterial plasma dopa (1,043 +/- 129 pg/ml) and epinephrine (218 +/- 96 pg/ml) were consistently higher than venous levels of dopa (591 +/- 80) and epinephrine (54 +/- 16 pg/ml), showing extraction of these by the kidney, whereas arterial plasma norepinephrine (329 +/- 89 pg/ml) and dopamine (64 +/- 9 pg/ml) were lower than the venous levels of norepinephrine (695 +/- 161 pg/ml) and dopamine (239 +/- 45 pg/ml), indicating secretion of these catecholamines into the circulation. The dopa extracted did not appear in the urine. Norepinephrine (7.2 +/- 1.7 ng/min), epinephrine (4.5 +/- 1.7 ng/min), and dopamine (3.2 +/- 0.7 ng/min) were excreted in the urine. These rates of urinary excretion could be accounted for by glomerular filtration and tubular secretion of the three catecholamines. The kidney extracts circulating dopa. It extracts and excretes epinephrine, norepinephrine, and dopamine, and, in addition, secretes both dopamine and norepinephrine into the circulation. These observations emphasize the important relationship between renal function and the peripheral sympathetic nervous system.

Dopamine release in rat striatum after administration of l-DOPA as studied with in vivo electrochemistry

The time-course of changes in dopamine (DA) release induced by systemic administration of L-DOPA was studied in the rat striatum using electrochemistry in vivo. Recordings were obtained from anesthetized animals in which carbon past microelectrodes were implanted stereotaxically into the striatum. Chronoamperometric measurements were made by applying 0.8 V for 1 sec, with an interval of 5 min between measurements; in some experiments, the potential was scanned every 5 min from 0 to 1.0 V. Administration of L-DOPA (50 mg/kg) after pretreatment with an inhibitor of peripheral aromatic amino acid decarboxylase (AAAD) produced a large rise in chronoamperometric currents, lasting for about 6 h. Different approaches were used to determined whether DOPA, DA or DA metabolites (all of which are oxidized at the potential chosen) were responsible for these DOPA-induced increases. (1) Rats were killed at different times after L-DOPA administration, and their striatal were analyzed biochemically for DOPA, DA, and DA metabolites. Comparison of time-courses indicated that the rise in chronoamperometric responses correlated with elevations in striatal 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels rather than with those of DOPA or DA, suggesting that DA metabolites contribute significantly to the increases in chronoamperometric responses observed after administration of L-DOPA. (2) Administration of L-DOPA after pretreatment with an inhibitor of central AAAD, a treatment that results in large increases in striatal DOPA levels but abolishes L-DO DA, suggesting that DA metabolites contribute significantly to the increases in chronoamperometric responses observed after administration of L-DOPA. (2) Administration of L-DOPA after pretreatment with an inhibitor of central AAAD, a treatment that results in large increases in striatal DOPA levels but abolishes L-DO DA, suggesting that DA metabolites contribute significantly to the increases in chronoamperometric responses observed after administration of L-DOPA. (2) Administration of L-DOPA after pretreatment with an inhibitor of central AAAD, a treatment that results in large increases in striatal DOPA levels but abolishes L-DOPA-induced formation of DA and DA metabolites (measured biochemically), failed to increase chronoamperometric responses. This finding indicates that exogenous L-DOPA entering the striatum is not detected with this technique and that it must be decarboxylated to produce the elevations of currents. (3) In animals pretreated with an inhibitor of monoamine oxidase to abolish formation of DOPAC and HVA, L-DOPA administration produced only a small and short lasting increase in chronomaperometric responses, despite sustained and large increases in striatal DA concentrations. By using the potential-scanning technique we showed that these increase in electrochemical responses occur at a potential at which DA but not methylated catechols are oxidized...

Endogenous dopa in rat brain. Occurrence, distribution and relationship to changes i catecholamine synthesis.

Dopa was isolated from rat brain by cation exchange chromatography and determined by a radioenzymatic method using catechol-O-methyl-transferase and [3H]-S-adenosyl-methionine as cofactor. The product [3H]-methoxytyrosine was purified by cation and anion exchange chromatography. For identification of presumed endogenous dopa isolated from rat brain and rat blood plasma the [3H]-labelled product was purified further by thin-layer chromatography. In the brain of rats killed by decapitation, dopa in a concentration of 7 ng/g was identified. When unstressed rats were killed by focussed microwave irradiation at 2.450 MHz and 8 kW for 1.3 s dopa levels as high as 20 ng/g were measured. The regional distribution of dopa in brain or rats killed by microwaves was similar to the distribution of catecholamines, dopa levels being highest in c. striatum and lowest in cerebellum. Inhibition of tyrosine hydroxylase with alpha-methyl-p-tyrosine methylester HCl, 250 mg/kg i.p. 90 min before death did not change the brain dopa levels in rats killed by decapitation or in rats killed by microwaves. Compounds, such as haloperidol, chlorpromazine, apomorphine and pentobarbital which are known to increase or decrease catecholamine synthesis did not change the basal level of dopa. The data indicate that in rat brain, the main portion of dopa is associated with catecholamine-containing nerve terminals and that this portion is present in a pool which is only slowly metabolized. A second very small pool of dopa must exist, which is serving as precursor pool for catecholamines and which is turned over at a higher rate. It can be concluded that the basal dopa level cannot be used as an indicator of catecholamine synthesis.

Chronic L-DOPA treatment of mice: a behavioural and biochemical study.

Mice were pretreated once daily with L-DOPA (200 mg/kg) plus benserazide (B) (50 mg/kg) for ten days and challenged with various doses of L-DOPA + B on the first, fourth or sixteenth days of withdrawal. L-DOPA + B-pretreated mice were more sensitive the locomotor stimulant effect of L-DOPA + B challenge one and four days, but not sixteen days after withdrawal. The enhanced response was most marked on the first day of withdrawal. Other mice, pretreated once daily with B (50 mg/kg), responded one day after the tenth dose with a slightly enhanced response to L-DOPA + B challenge compared to the response to vehicle-pretreated animals. Moreover, vehicle-pretreated mice challenged with B alone, were significantly less active than those challenged with vehicle. On the first day of withdrawal, the L-DOPA + B-pretreated animals were supersensitive to locomotor stimulant effects of apomorphine but subsensitive to dexamphetamine (Bailey et al., 1979). On the fourth day of withdrawal, there were no differences in the responses of the L-DOPA + B-pretreated mice compared to the vehicle-pretreated mice, to apomorphine or apomorphine plus clonidine, but L-DOPA + B-pretreated mice were still subsensitive to the locomotor stimulant effects of dexamphetamine. Clonidine produced a dose-dependent, but similar, degree of hypothermia in both pretreatment groups. On the first and fourth days of withdrawal L-DOPA + B-pretreated mice exhibited higher brain levels of dopamine (DA) and DOPA than vehicle-pretreated mice in response to an acute dose of L-DOPA + B. The biochemical results suggest that the enhanced locomotor response to L-DOPA + B in L-DOPA + B-pretreated mice is probably dependent on changes in the amount of L-DOPA (and DA) available in the brain. Moreover, it is not ruled out that some of the effects of L-DOPA + B pretreatment were due to the B alone. Some of the enhanced response to L-DOPA + B on the first day of withdrawal may have been dependent on the same mechanism as that underlying the apparent supersensitivity to apomorphine. The subsensitive response to dexamphetamine would appear to be independent of changes in post-synaptic DA and alpha-adrenergic receptor sensitivity.