Nigral glutathione deficiency is not specific for idiopathic Parkinson's disease

The consistent findings of decreased levels of the major antioxidant glutathione in substantia nigra of patients with idiopathic Parkinson's disease (PD) has provided most of the basis for the oxidative stress hypothesis of the etiology of PD. To establish whether a nigral glutathione deficiency is unique to PD, as is generally assumed, or is present in other Parkinsonian conditions associated with nigral damage, we compared levels of reduced glutathione (GSH) in postmortem brain of patients with PD to those with progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). As compared with the controls, nigral GSH levels were decreased in the PD and PSP patient groups (P < 0.05 for PD [-30%], PSP [-21%]), whereas a similar decrease in the MSA patient group did not reach statistical significance (P = 0.078, MSA [-20%]). GSH levels were normal in all examined normal and degenerating extra-nigral brain areas in PSP and MSA. A trend for decreased levels of uric acid (antioxidant and product of purine catabolism) also was observed in nigra of all patient groups (-19 to -30%). These data suggest that glutathione depletion, possibly consequent to overutilisation in oxidative stress reactions, could play a causal role in nigral degeneration in all nigrostriatal dopamine deficiency disorders, and that antioxidant therapeutic approaches should not be restricted to PD.     

Depression in Parkinson's disease: biogenic amines in CSF of "de novo" patients

INTRODUCTION: Etiology of depression in Parkinson's disease (PD) is associated with serotonergic dysfunction. Previous studies, supporting this hypothesis, were performed on patients treated with antiparkinsonian drugs. To eliminate the influence of parkinsonian drug therapy and to elucidate significance of different biochemical pathways in PD associated with depression we determined levels of biogenic amines in cerebrospinal fluid (CSF) of 26 untreated "de novo" Parkinsonian patients. MATERIAL AND METHODS: Patients were scored with the Hamilton depression scale (HD) and subdivided into groups with HD score > or = 18 and HD score < 18. Diagnosis of depression was made according to DSM III R. Both groups were matched for age and motor disability. RESULTS: In both groups no significant differences appeared between CSF levels of dopamine, noradrenaline, 3,4-dihydroxyphenylacetic acid, homovanillic acid, 3-methoxy-4-hydroxyphenylglycol and 5-hydroxyindole acetic acid, determined by high-performance liquid chromatography. DISCUSSION: In contrast to previous studies on treated Parkinsonian patients no sign of altered serotonin metabolism especially in context with severity of depression in early stages of PD was found. Due to our results, we suggest, that biochemical markers of depression in CSF of PD may be influenced by antiparkinsonian therapy and that depression in PD may respond to serotonin reuptake inhibitors mainly in later stages of PD.     

Reproductive and productive performance in Chios ewes mated in spring or in autumn

To determine whether specific antibodies are present in PD, we used an enzyme-linked immunosorbant assay (ELISA) that identifies increased immunoglobulin (IgG) levels towards a synthetic substrate prepared by incubating ovalbumin with dopamine and copper sulfate. Altered absorption spectrum and specific chemical detection demonstrated quinone modification of the ovalbumin. This modified protein was demonstrated to react with serial dilutions of PD sera. A threshold dilution of 1:500 was subsequently used to screen sera from patients with PD (n = 21), amyotrophic lateral sclerosis (n = 7), Alzheimer's disease (n = 7) and other neurological disease controls (n = 7). The assay produced a positive result in 7/21 PD patients and 0/21 disease controls (P < 0.02, Kruskal-Wallis test). Further testing of sera from untreated PD patients (n = 6) identified one positive sample. Thus, a subset of Parkinson's disease (PD) patients has immunoglobulin (IgG) to ovalbumin modified by dopamine oxidation. The presence of antibody reactivity to quinone-modified proteins could contribute to or amplify the inflammatory response in PD.     

Cerebrospinal fluid levels of transition metals in patients with Parkinson's disease

We compared CSF and serum levels of iron, copper, manganese, and zinc, measured by atomic absorption spectrophotometry, in 37 patients with Parkinson's disease (PD) and 37 matched controls. The CSF levels of zinc were significantly decreased in PD patients as compared with controls (p < 0.05). The serum levels of zinc, and the CSF and serum levels of iron, copper, and manganese, did not differ significantly between PD-patient and control groups. There was no influence of antiparkinsonian therapy on CSF levels of none of these transition metals. These values were not correlated with age, age at onset, duration of the disease, scores of the Unified Parkinson Disease Rating Scale of the Hoehn and Yahr staging in the PD group, with the exception of CSF copper levels with the duration of the disease (r = 0.38, p < 0.05). These results suggest that low CSF zinc concentrations might be related with the risk for PD, although they could be related with oxidative stress processes.     

Relationships between plasma levels of type-II phospholipase A2, PAF-acetylhydrolase, leukotriene B4, complements, endothelin-1, and thrombomodulin in patients with sepsis

We determined the plasma levels of type-II phospholipase A2 (type II PLA2), platelet-activating factor acetylhydrolase (PAFAH) leukotriene B4 (LTB4) and of several complements (C3a, C4a, and C5a), which are considered to be among the cytokines and eicosanoids involved in vascular endothelial disorders and that vary in concentration during sepsis. We investigated the relationship between those levels and those of ET-1 and TM levels in plasma. Plasma levels of type II PLA2, PAFAH, LTB4, C3a, C4a, ET-1, and TM at the time that sepsis was diagnosed in 30 patients were 218.3 +/- 179.9 ng/ml, 23.92 +/- 9.66 nmol/min/ml, 90.35 +/- 31.49 pg/ml, 838.73 +/- 2.30 pg/ml, 1951.46 +/- 1697.78 pg/ml, 6.98 +/- 4.08 pg/ml and 7.80 +/- 3.34 ng/ml, respectively. The C5a plasma level was below the limit of detection in all cases. There were significant correlations between type II PLA2 and ET-1 plasma levels (r = 0.39, p = 0.032) and C3a and ET-1 plasma levels (r = 0.60, p = 0.03). There were also significant correlations between type II PLA2 and TM levels in plasma (r = 0.76, p = 0.0017), PAFAH and TM plasma levels (r = 0.53, p = 0.037), LTB4 and TM plasma levels (r = 0.46, p = 0.016) and C4a and TM plasma levels (r = 0.58, p = 0.037). Results suggest that the elevation of type II PLA2, PAFAH, LTB4 and complement in plasma is involved in vascular endothelial disorders in patients with sepsis.     

Force-frequency relations in the failing rabbit heart and responses to adrenergic stimulation

Yohimbine, an alpha 2 adrenoreceptor antagonist, enhances norepinephrine (NE) release and increases sympathetic activity. We examined the behavioral, peripheral sympathetic and adrenocortical responses to oral yohimbine in seven healthy controls and 11 patients diagnosed with agoraphobia with panic attacks (PD). Patients did not differ in baseline cardiovascular or neuroendocrine measures from controls despite significantly higher baseline anxiety ratings. Placebo caused no changes in baseline-corrected behavioral, cardiovascular or neurochemical responses in either group. Yohimbine induced a panic episode in six PD patients, but no controls. PD patients had significantly higher severity scores of autonomic anxiety symptoms. Yohimbine significantly raised systolic blood pressure (F = 3.07, P < 0.03), plasma NE levels (F = 12.11, P < 0.00) and cortisol levels (F = 4.82, P < 0.02), but had no effect on epinephrine levels. NE responses were similar in both groups, but patients had higher cortisol responses to yohimbine than controls (F = 7.14, P < 0.01). The correlational pattern between behavioral ratings and neuroendocrine responses in patients was opposite to that observed in controls. Despite similar increases in plasma NE levels between PD patients and healthy controls, PD patients had greater anxiogenic, cardiovascular and cortisol responses to yohimbine. Enhanced post-synaptic adrenoreceptor sensitivity may explain the noradrenergic dysregulation found in panic disorder.     

Plasma levels of the beta-carbolines harman and norharman in Parkinson's disease

Several lines of evidence suggest that endogenous and exogenous toxins may play a major role in the pathogenesis of Parkinson's disease (PD). In vivo aromatic beta-carbolines, like harman or norharman, may easily be formed by cyclization of indoleamines with e.g. aldehydes. Because of the structural similarity to MPTP, beta-carbolines have been proposed as endogenous toxins. For further elucidation of the role of beta-carbolines in neurodegenerative disorders, harman and norharman plasma levels were measured in 36 patients with PD and compared to an age- and sex-matched control group. Plasma levels of norharman in PD were significantly higher compared to the control group. Harman in the plasma of Parkinsonian patients was also elevated compared to controls, but this difference was not significant. Correlation of beta-carbolines with plasma levels of L-dopa, oral doses of bromocriptine and selegiline in treated Parkinsonian patients showed no significant results. On the one hand these results may suggest a possible role of beta-carbolines in the pathophysiological processes initiating PD, by, e.g., inducing mitochondrial respiratory inhibition like MPP+. One may speculate, however, that elevated levels of norharman and harman are due to an endogenous upregulation caused by unknown metabolic processes.     

Locomotor activity in D2 dopamine receptor-deficient mice is determined by gene dosage, genetic background, and developmental adaptations

Locomotor activity is a polygenic trait that varies widely among inbred strains of mice (). To characterize the role of D2 dopamine receptors in locomotion, we generated F2 hybrid (129/Sv x C57BL/6) D2 dopamine receptor (D2R)-deficient mice by gene targeting and investigated the contribution of genetic background to open-field activity and rotarod performance. Horizontal activity of D2R-/- mice was approximately half that of drug-naive, strain-matched controls but was significantly greater than haloperidol-treated controls, which were markedly hypokinetic. Wild-type 129/SvEv and C57BL/6 mice with functional D2 receptors had greater interstrain differences in spontaneous activity than those among the F2 hybrid mutants. Incipient congenic strains of D2R-deficient mice demonstrated an orderly gene dosage reduction in locomotion superimposed on both extremes of parental background locomotor activity. In contrast, F2 hybrid D2R-/- mice had impaired motor coordination on the rotarod that was corrected in the congenic C57BL/6 background. Wild-type 129/SvEv mice had the poorest rotarod ability of all groups tested, suggesting that linked substrain 129 alleles, not the absence of D2 receptors per se, were largely responsible for the reduced function of the F2 hybrid D2R-/- and D2R+/- mice. Neurochemical and pharmacological studies revealed unexpectedly normal tissue striatal monoamine levels and no evidence for supersensitive D1, D3, or D4 dopamine receptors in the D2R-/- mice. However, after acute monoamine depletion, akinetic D2R+/- mice had a significantly greater synergistic restoration of locomotion in response to SKF38393 and quinpirole compared with any group of D2R+/+ controls. We conclude that D2R-deficient mice are not a model of Parkinson's disease. Our studies highlight the interaction of multiple genetic factors in the analysis of complex behaviors in gene knock-out mice.     

Effects of ageing on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxic effects on striatum and brainstem in the rat

In 3- and 18-month-old male Wistar rats, levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), ascorbic acid (AA), dehydroascorbic acid (DHAA), noradrenaline (NA), uric acid, glutathione (GSH) and 1-methyl-4-phenylpyridinium ion (MPP+) were determined by HPLC in the striatum and/or in the brainstem 24 h after single injections of MPTP (12-35 mg/kg i.p.). Aged rats had lower baseline levels of AA and GSH, compared to young rats. In aged rats, MPTP 35 mg/kg induced a 70% death rate and a decrease in striatal DOPAC/DA ratio which was significantly correlated to MPP+ concentrations (r = -0.840, P < 0.005); in addition, MPTP did not increase AA oxidation. In the brainstem, the MPTP-induced decrease in NA levels and increase in uric acid levels were significantly correlated to the MPP+ concentrations (r = -0.709, P < 0.05, and r = +0.888, P < 0.001, respectively). In conclusion, evidence is given of a mechanism of toxicity of MPTP involving oxidative stress produced by xanthine oxidase; in addition, in aged rats the neuronal antioxidant system (levels of AA and GSH) is considerably lower than in young rats and may play an enabling role in the MPTP age-related neurotoxic effects on striatum and brainstem.     

Accumulation of 3,4-dihydroxyphenylglycolaldehyde, the neurotoxic monoamine oxidase A metabolite of norepinephrine, in locus ceruleus cell bodies in Alzheimer's disease: mechanism of neuron death

3,4-Dihydroxyphenylglycolaldehyde (DOPEGAL) is the neurotoxic monoamine oxidase A (MAO-A) metabolite of norepinephrine (NE). NE neurons in the locus ceruleus (LC) die in Alzheimer's disease (AD). To determine if DOPEGAL could contribute to NE neuron death in AD we measured levels of DOPEGAL, NE and their synthesizing enzymes in LC from AD and matched controls. We found 2.8- and 3.6-fold increases in DOPEGAL and MAO-A in AD LC neuronal cell bodies compared to controls. NE and dopamine beta-hydroxylase were increased by 3.8- and 10.7-fold, respectively. Implications for the mechanism of neuron death in AD are discussed.     

Catecholamine secretory vesicles. Augmented chromogranins and amines in secondary hypertension

Chromogranins A and B are major soluble proteins in chromaffin granules. Their adrenomedullary content is increased in the spontaneously (genetic) hypertensive rat. Is augmented catecholamine vesicular storage of the chromogranins a specific feature of genetic hypertension? To explore this question, we measured chromogranin A immunoreactivity, using a novel, synthetic peptide radioimmunoassay, in rat adrenal medullas 4-6 weeks after induction of the two-kidney, one clip Goldblatt model of renovascular hypertension and in unmanipulated control animals. We also measured messenger RNAs of chromogranins A and B and dopamine beta-hydroxylase by Northern blot. Immunoreactive adrenal chromogranin A was 3.3-fold higher (p < 0.01) in clipped rat adrenals. Adrenal catecholamine concentrations and phenylethanolamine-N-methyltransferase activity were also higher in clipped rats. Adrenal dopamine beta-hydroxylase activity (both membrane-bound and soluble forms) and corticosterone (glucocorticoid) concentration did not significantly differ between the groups. Adrenal medullary chromogranin A messenger RNA levels in clipped rats were 3.2-fold higher (p = 0.029) than those in the control group, and chromogranin B messenger RNA levels were 4.6-fold higher (p = 0.05). Dopamine beta-hydroxylase messenger RNA levels were 2.9-fold higher (p = 0.038). Thus, augmented synthesis and storage of adrenomedullary chromogranins A and B, catecholamines, and their biosynthetic enzymes appear to be characteristic of both acquired and genetic hypertension.     

Elevated 5-S-cysteinyldopamine/homovanillic acid ratio and reduced homovanillic acid in cerebrospinal fluid: possible markers for and potential insights into the pathoetiology of Parkinson's disease

High-performance liquid chromatography with electrochemical detection has been employed to analyze ultrafiltrates of cerebrospinal fluid of Parkinson's Disease (PD) patients and age-matched controls for the dopamine (DA) metabolites homovanillic acid (HVA) and 5-S-cysteinyldopamine (5-S-CyS-DA). The mean level of HVA in the CSF of PD patients, measured 5 days after withdrawal from L-DOPA therapy, was significantly lower than that measured in controls. By contrast, mean levels of 5-S-CyS-DA were not significantly different in the CSF of PD patients taking L-DOPA (PD-LT patients) the same patients 5 days after discontinuing this drug (PD-LW patients) or controls. However, the mean 5-S-CyS-DA/HVA concentration ratio was significantly (p < 0.05) higher in the CSF of PD-LW patients compared to controls. Although the PD patient population employed in this study had been diagnosed with the disease several years previously and had been treated with L-DOPA for prolonged periods of time the results of this study suggest that low CSF levels of HVA and a high 5-S-CyS-DA/HVA ratio together might represent useful markers for early diagnosis of PD. The high 5-S-CyS-DA/HVA ratio observed in the CSF of PD-LW patients also provides support for the hypothesis that the translocation of glutathione or L-cysteine into neuromelanin-pigmented dopaminergic cell bodies in the substantia nigra might represent an early event in the pathogenesis of PD.     

In vivo studies on striatal dopamine D1 and D2 site binding in L-dopa-treated Parkinson's disease patients with and without dyskinesias

Dyskinesias are usually seen in Parkinson's disease (PD) patients after several years of L-dopa therapy. Their presence has been attributed to supersensitivity of striatal D1 and D2 receptors. We have used PET to assess striatal D2 receptor binding in untreated PD patients and striatal D1 and D2 binding in L-dopa-treated PD patients. Untreated patients showed a 14% increase in mean D2 receptor binding in the putamen contralateral to the more affected limbs (p < 0.02). Treated patients were segregated into subgroups according to the presence or absence of dyskinesias. There were no differences in mean caudate and putamen D1 and D2 binding between dyskinetic and nondyskinetic patients, matched for duration of clinical disease. Both dyskinetic and nondyskinetic PD subgroups showed a similar 16% reduction of mean caudate D2 binding (p < 0.01) with normal D2 binding in putamen. Mean caudate and putamen D1 binding potentials of both subgroups were reduced by 10% compared with those of controls, though this trend did not reach significance. Putamen D1 binding, however, showed a negative correlation with duration and L-dopa treatment (p < 0.03). These findings suggest that, while exposure of PD patients to L-dopa may be associated with reductions in caudate D2 and caudate and putamen D1 receptor, dyskinesias are unlikely to result from alterations in striatal dopamine receptor binding.     

Decreased pain threshold and tolerance in patients with chronic tension headache

Nociceptive processing was studied in 40 patients with chronic tension-type headache and in 40 healthy controls. We found that pericranial tenderness recorded by manual palpation was considerably higher in patients than in controls (p < or = 0.0002). Pressure pain detection and tolerance thresholds recorded in the finger, by means of a pressure algometer, were significantly lower in patients than in controls (p < or = 0.0009), and a non-significant similar trend was observed in the temple (p < or = 0.12). Detection and tolerance thresholds were decreased to a similar degree in patients compared with controls, and pain thresholds recorded in the finger and in the temple were highly correlated (r = 0.84, p < 0.0001). The electrical pain threshold at the labial commissure, by means of an electrical stimulator, was significantly decreased in patients compared with controls (p = 0.03). All of the examined pain thresholds were significantly correlated to the pericranial tenderness recorded by palpation (r = -0.35 to -0.53, p < or = 0.03). We conclude that the present finding of a general hypersensitivity to pain stimuli in chronic tension-type headache indicates that central factors play an important role in the pathogenesis of this disorder.     

Effect of weak electromagnetic fields on the amplitude of the pattern reversal VEP response in Parkinson's disease

Visual evoked potential (VEP) studies are widely used for the diagnosis of multiple sclerosis (MS) and are also useful in monitoring the effects of various therapeutic modalities in the disease. Prolongation of the VEP latencies has been demonstrated in patients with MS and in other neurodegenerative disorders including Parkinson's disease (PD), a disorder characterized by deficient cerebral dopamine (DA) functions. Pharmacological and biochemical studies have demonstrated a positive correlation between the amplitude of the VEP response and cerebral DA levels. Since brief, extracerebral applications of picotesla (pT) range flux intensity electromagnetic fields (EMFs) of low frequency have been shown to produce rapid improvement in motor and cognitive symptoms in PD, it is expected that application these EMFs would lead also to an increase in the amplitude of VEP response. This report documents three randomly selected PD patients who, following two successive brief extracerebral applications of pT range EMFs, showed an almost 3-fold increase of the mean pretreatment amplitude of the pattern reversal VEP in response to monocular stimulation. One patient underwent also a placebo EMF treatment which did not result in a significant change in the posttreatment amplitude. The study demonstrates that in Parkinsonian patients extracerebral application of these EMFs rapidly increases in amplitude of the VEP response and, by inference, cerebral DA levels presumably by increasing DA release.     

Renovascular interaction of epinephrine, dopamine, and intraperitoneal sepsis

OBJECTIVE: To determine the effect of intraperitoneal sepsis on the systemic and renal actions of the continous infusion of epinephrine or dopamine, and during the concurrent administration of both drugs. DESIGN: Prospective, randomized study. SETTING: Laboratory at a university hospital. SUBJECTS: Seven conscious, chronically catheterized, adult merino sheep. INTERVENTIONS: Epinephrine at 40 micrograms/min or dopamine at 2 micrograms/kg/min, or both drugs concurrently were infused for 4 hrs on separate study days in healthy sheep. This protocol was then repeated following the induction of sepsis after the intraperitoneal injection of 10(11) Escherichia coli, 10(12) Bacteroides fragilis, and bran. MEASUREMENTS AND MAIN RESULTS: Systemic oxygen delivery (DO2) and consumption were measured using thermodilution cardiac output and measured oxygen content. Renal blood flow was measured using an electromagnetic flow transducer, and creatinine clearance was calculated as the quotient of renal blood flow and the renal extraction ratio of creatinine. Infusion of epinephrine augmented systemic DO2 and mean arterial pressure (MAP) during both healthy and septic studies. Systemic oxygen consumption was only increased during epinephrine infusion in the septic study. During the healthy animal study, renal blood flow was initially decreased during epinephrine infusion, but increased to 36% above baseline (p = .003). However, creatinine clearance remained unchanged. During the experimental sepsis study, the infusion of epinephrine had less marked effects on renal blood flow (unchanged from baseline), while an initial reduction (15 mins) in creatinine clearance (p = .04) was not sustained and had returned to baseline by 3 hrs. Dopamine alone produced no change in systemic oxygen variables or MAP during the studies on healthy or septic animals. Although dopamine produced renal vasodilation and an increase in renal blood flow in the healthy state, these results were not found during the septic state. In addition, concurrent infusion of dopamine with epinephrine did not alter the systemic or renal effects of epinephrine during the healthy or septic states. CONCLUSIONS: These results do not support the routine use of low-dose dopamine, and demonstrate a change in renovascular responses to catecholamines during intraperitoneal sepsis. The infusion of epinephrine at 40 micrograms/min had few deleterious effects on the kidney, and augmented both MAP and systemic DO2. Its role as a catecholamine in the management of sepsis may need to be reconsidered.     

Conservation of baculovirus inhibitor of apoptosis repeat proteins (BIRPs) in viruses, nematodes, vertebrates and yeasts

The purpose of this study was to compare striatal D2 dopamine receptor occupancy of various typical neuroleptics and clozapine in relation to the occurrence of extrapyramidal side effects (EPS). Forty-four inpatients with schizophrenia, including 12 patients with schizodominant schizoaffective disorder, were evaluated using 123I-iodobenzamide (IBZM) and single photon emission computed tomography. Striatal D2 dopamine receptor occupancy was estimated by use of a striatal/frontal cortex ratio (ST/FC) of IBZM binding. Fourteen patients were neuroleptic-free and served as controls. Six patients were treated with clozapine and 24 patients were treated with various typical neuroleptics. ST/FC ratios in patients taking typical neuroleptics were significantly lower than those who were neuroleptic free or treated with clozapine. Patients with EPS had lower ST/FC ratios than those without EPS. A significant linear relationship between ST/FC ratios and severity of EPS estimated by the Simpson-Angus-Scale was established (r=-0.51, p=0.041).     

Neural dynamics of short and medium-term motor control effects of levodopa therapy in Parkinson's disease

A neural network model of movement control in normal and Parkinson's disease (PD) conditions is proposed to simulate the time-varying dose-response relationship underlying the effects of levodopa on movement amplitude and movement duration in PD patients. Short and long-term dynamics of cell activations and neurotransmitter mechanisms underlying the differential expression of neuropeptide messenger RNA within the basal ganglia striatum are modeled to provide a mechanistic account for the effects of levodopa medication on motor performance (e.g. the pharmacodynamics). Experimental and neural network simulation data suggest that levodopa therapy in Parkinson's disease has differential effects on cell activities, striatal neuropeptides, and motor behavior. In particular, it is shown how dopamine depletion in the striatum may modulate differentially the level of substance P and enkephalin messenger RNA in the direct and indirect basal ganglia pathways. This dissociation in the magnitude and timing of peptide expression causes an imbalance in the opponently organized basal ganglia pathways which results in Parkinsonian motor deficits. The model is validated with experimental data obtained from handwriting movements performed by PD subjects before and after medication intake. The results suggest that fine motor control analysis and network modeling of the effects of dopamine in motor control are useful tools in drug development and in the optimization of pharmacological therapy in PD patients.     

A multicenter trial of ropinirole as adjunct treatment for Parkinson's disease. Ropinirole Study Group

OBJECTIVE: To evaluate the nonergot dopamine agonist ropinirole as an adjunct to L-dopa in a randomized, double-blind trial in PD patients with motor fluctuations. BACKGROUND: L-dopa in the treatment of PD is associated with motor fluctuations, dyskinesia, and other adverse effects. The use of dopamine agonists in the treatment of PD delays recourse to L-dopa and thus delays the possibility of adverse effect onset. METHODS: Ropinirole (n = 95) or placebo (n = 54) was added to L-dopa, and L-dopa was then reduced in a planned manner during the 6-month trial. RESULTS: A significantly greater number of ropinirole patients were able to achieve a 20% or greater reduction in both L-dopa dose and in percent time spent "off" compared with placebo (35.0% versus 13.0%; p = 0.003). The mean daily L-dopa dose was reduced significantly with ropinirole treatment (242 mg versus 51 mg; p < 0.001) as was the percent awake time spent "off" (11.7% versus 5.1%; p = 0.039). There was no difference in the percent of patients who withdrew because of adverse effects (15.8% on ropinirole versus 16.7% on placebo). CONCLUSIONS: Ropinirole permits a reduction in L-dopa dose with enhanced clinical benefit for PD patients with motor fluctuations.     

Gestational exposure to cocaine or pharmacologically related compounds: effects on behavior and striatal dopamine receptors

Gestational cocaine (COC) exposure has been reported to alter behavior and possibly dopamine (DA) receptors. In this paper, we further examined the effects of prenatal COC (40 mg/kg, s.c.) on DA receptor binding and the behavioral response to quinpirole, a DA D2 receptor agonist. In an attempt to elucidate possible mechanisms of such effects, we exposed pregnant dams to specific reuptake blockers; fluoxetine 12.5 mg/kg, a serotonin reuptake blocker; desipramine 10 mg/kg, a norepinephrine reuptake blocker; GBR-12909 10 mg/kg, a DA reuptake blocker; or to a local anesthetic, lidocaine 40 mg/kg. Drugs were administered once daily over gestational days 8-20. Control dams were injected with saline (SAL) or pair-fed to the COC group. Quinpirole challenge was performed in the offspring on post natal day 19. Two pups per litter were injected (s.c.) with 0.03 or 0.09 mg/kg quinpirole-HCl on post-natal day 19. The remaining pups in each litter were sacrificed for analysis of striatal DA receptors. Results showed that only COC exposure altered the behavioral response to the quinpirole challenge by increasing quinpirole-induced stereotypy and motor activity relative to SAL controls. DA receptor analysis showed no alteration in K(D) or B(MAX) for striatal D1 or D2 sites in any group. These results suggest that prenatal COC exposure produces alterations in function of the D2 receptor complex which are not reflected in K(D) or B(MAX) and that these effects are not fully mimicked by exposure to specific monoamine reuptake blockers or a local anesthetic.