Peter Moleman

CONGENITAL DOPAMINE-BETA-HYDROXYLASE DEFICIENCY: A Novel Orthostatic Syndrome

A woman was referred with severe orthostatic hypotension at the age of 21. Ptosis, skeletal muscle hypotonia, and recurrent hypoglycaemia had been noticed in early childhood. There was noradrenergic denervation and adrenomedullary failure but baroreflex afferents, cholinergic innervation, and adrenocortical function were intact. Noradrenaline and adrenaline were undetectable in plasma, urine, and cerebrospinal fluid (CSF), but dopamine was 7-fold to 12-fold normal in plasma, 4-fold normal in urine, and 20-fold normal in CSF. Measurements of catecholamine metabolites showed further evidence for impairment of noradrenaline and adrenaline biosynthesis due to deficient dopamine-beta-hydroxylation. Dopamine-beta-hydroxylase was undetectable in plasma and CSF. Physiological and pharmacological stimuli of sympathetic neurotransmitter release caused increases in plasma dopamine rather than plasma noradrenaline.

Characterization of stress reactions to the stroop color word test

Sympatho-adrenal activation induced by stress contributes to the development of pathological states such as hypertension and anxiety disorders. The Stroop Color Word Test (CWT) is evaluated as a test for the study of stress-induced sympathetic effects, on the basis of psychological, physiological and biochemical responses. The CWT induced increases in plasma and urinary adrenaline, heart rate, respiration rate, electrodermal activity, electromyography, feelings of anxiety, and decreased finger pulse amplitude.

SCHIZOPHRENIA-LIKE PSYCHOSIS CAUSED BY A METABOLIC DISORDER

Four patients with an intermittent psychosis closely resembling hallucinogenic drug-induced states were suspected of having a porphyric disease and were investigated for a possible relation between the metabolic dysfunctions of porphyria and the psychotic syndrome. Theoretically the link could be in a disturbance of serine and glycine metabolism. This theory was supported by disturbances in serine and glycine excretion found in all patients during psychotic episodes. In addition, loading with one low oral dose of serine produced psychotic symptoms 5 h later which lasted 3-6 h. One patient reacted to glycine in the same way. These findings suggest that disturbed serine-glycine metabolism may have a key role in certain schizophreniform psychotic syndromes.

A double-blind randomized study comparing imipramine with fluvoxamine in depressed inpatients

ObjectiveTo compare the efficacy of imipramine and fluvoxamine in inpatients from two centers suffering from a depressive disorder according to DSM IV criteria.MethodsThe study included 141 patients with a depressive disorder according to DSM IV criteria. After a drug-free and placebo run-in period of 1 week, patients were randomized to imipramine or fluvoxamine; doses of both drugs were adjusted to a predefined target blood level. Efficacy was evaluated 4 weeks after attaining predefined adequate plasma level.ResultsThe mean age of the study group (47 males, 94 females) was 51.8 (range 19–65) years. Of these 141 patients, 56 had episode duration longer than 1 year, 48 had mood congruent psychotic features, and 138 patients received medication. Seven patients did not complete the medication trial. The total number of patients using concurrent medication was 12/138 (8.6%). On the primary outcome criteria patients on imipramine improved significantly better on the change of illness severity score of the CGI (χ2 exact trend test=4.089, df=1, P=0.048). There was no significant difference in 50% or more reduction on the HRSD, the other primary outcome criterion. On the secondary outcome criteria the mean reduction of the HRSD scores was significantly larger in the imipramine group than in the fluvoxamine group (mean difference=3.1, standard error (SE)=1.4, t=2.15, df=136, P=0.033). There was no significant difference in the number of patients with an HRSD ≤7 at the final evaluation.ConclusionsIn depressed inpatients imipramine is more efficacious than fluvoxamine. Both drugs were well tolerated by all patients.

EFFECTS OF LORAZEPAM ON CARDIAC VAGAL TONE DURING REST AND MENTAL STRESS - ASSESSMENT BY MEANS OF SPECTRAL-ANALYSIS

Dose-dependent effects of intravenously administered lorazepam on haemodynamic fluctuations were studied by means of spectral analysis, in order to elucidate sympathetic and parasympathetic components in cardiovascular control during situations of rest and mental stress after benzodiazepine administration. In a double-blind randomized cross-over study, nine male volunteers participated in two sessions: a placebo and lorazepam session. During these sessions, the subjects repeatedly performed a 10-min version of the Stroop Color Word Test (CWT), with 10 min of rest between the CWTs. Lorazepam was administered before each rest period in increasing doses of 0.0, 0.06, 0.13, 0.25 and 0.5 mg (total cumulative dose: 0.94 mg). During the placebo session the subjects received five placebo injections. For five of the nine subjects the lorazepam session was their first session. Heat rate (HR), blood pressure (BP) and respiration were recorded continuously. Power spectra were calculated per 2.5-min periods for HR, systolic (SBP) and diastolic BP (DBP). Spectral density was assessed for three frequency bands: low (LFB: 0.02–0.06 Hz), mid (MFB: 0.07–0.14 Hz) and high (HFB: 0.15–0.40 Hz). During the consecutive periods of rest, lorazepam induced a dose-dependent decrease in HR, and a dose-dependent increase in LFB, MFB and HFB power of HR, but lorazepam had no effect on BP. The effects were significant after 0.44 mg lorazepam for HR and HFB power, and after 0.94 mg lorazepam for the HR fluctuations in the LFB and MFB. Lorazepam did not influence the cardiovascular responses to the CWT. Our data underline that benzodiazepines can exert a specific influence on parasympathetic activity: lorazepam induced dose-dependent increases in cardiac vagal tone, resulting in decreased HR and increased HR variability, but only during periods of rest. The increase in vagal tone observed after low doses of lorazepam was not related to diminished sympathetic activity, altered respiration, or increased sedation.

Differential effect of morphine on dopaminergic neurons in frontal cortex and striatum of the rat.

Abstract Inhibition of dopamine synthesis by a single injection of α-methyl-para-tyrosine (200 mg/kg, i.p.) was complete from 30 to at least 300 min after administration. When morphine (20 mg/kg) was given intraperitonealy 30 min after α-MpT treatment an enhanced decline of dopamine was observed in frontal parts of the cortex but not in the striatum. These results indicate that morphine affects dopaminergic neurons in frontal parts of the cortex in a way differently from those in the striatum of the rat. This may be caused either by a difference in the properties of dopaminergic nerve endings in both structures or by an effect of morphine on the input to the cortical system which is lacking in the striatum.

Effects of alprazolam and lorazepam on catecholaminergic and cardiovascular activity during supine rest, mental load and orthostatic challenge

Abstract Effects of oral alprazolam (0.5 and 1 mg) and lorazepam (2 mg) on sympathetic adrenomedullary activity and sedation were studied during supine rest, mental load (Color Word Test, CWT) and active standing (OCT), in 12 male volunteers in a randomized double-blind placebo-controlled cross-over design. Compared to placebo, alprazolam significantly increased subjective sedation, reduced plasma adrenaline and noradrenaline concentrations and mean blood pressure (MBP) during supine rest, and attenuated plasma adrenaline responses during the CWT and the OCT; these effects during the CWT and OCT appeared to be dose-dependent. In comparison with lorazepam (2 mg), alprazolam (1 mg) showed reduced MBP levels during supine rest, whereas lorazepam showed a higher heart rate level during supine rest, a reduced plasma noradrenaline response to the OCT and a performance deterioration to the CWT. There were no differences between alprazolam (1 mg) and lorazepam regarding subjective sedation. Although the benzodiazepines were similar regarding their increase of sedation, alprazolam and loraze- pam induced differential effects on sympathetic adrenomedullary activity during rest and stress, whereby suppression of adrenomedullary activity may be specific for alprazolam.

Cardiovascular variability after clonidine challenge: assessment of dose-dependent temporal effects by means of spectral analysis.

Effects of four intravenous (i.v.) doses (0.25, 0.5, 1, and 2 μg/kg) of the α2-adrenoceptor agonist clonidine (CLO) were studied in 7 normotensive male volunteers in a placebo-controlled double-blind randomized design to evaluate the role of α2-adrenoceptors in spontaneous short-term cardiovascular fluctuations. Heart rate (HR), systolic and diastolic blood pressure (SBP, DBP; Finapres device), stroke volume (SV) and total peripheral resistance (TPR) were monitored for 1 h after infusion of CLO while the subjects rested in a semirecumbent position. For HR, SBP, and DBP, power spectra and variation coefficients were calculated for consecutive time segments of 2.5 min. Power density was assessed for three frequency bands: low (LFB, 0.02–0.06 Hz), mid (MFB, 0.07–0.14 Hz), and high (HFB, 0.15–0.40 Hz). Per time-segment, baroreflex sensitivity (BRS) was estimated as the gain (or modulus) in MFB between systolic pressure values and R-R interval times. Decreases in mean levels of SBP and DBP were observed within 15 min after infusion of ≥0.5 μg/kg CLO. HR first showed a slight increase 15 min after infusion of 0.5, 1, and 2 μg/kg CLO, but decreased subsequently as in all doses, including placebo. SV and TPR decreased after a dose of 2 μg/kg CLO. LFB and MFB power of HR were reduced after 2 μg/kg CLO, but only during the first 30 min after infusion; during this period, respiratory depth was also diminished, indicating that these effects may reflect a reduction in sympathetic outflow as well as a reduction in vagal outflow. Respiratory frequency did not change after CLO, nor did BRS. DBP MFB power was reduced after 2 μg/kg CLO during the entire postinfusion period, probably as a reflection of reduced sympathetic outflow. SBP HFB power was significantly increased after ≥0.5 μg/kg CLO, but only after 30 min of infusion, which could be a consequence of alterations in both vagal outflow and mechanical respiratory properties. Thus, in a dose range of 0.25–2 μg/kg CLO, significant effects were detected for SBP, DBP, and HR after ≥0.5 μg/kg, whereas spontaneous short-term fluctuations of HR and DBP were influenced only after a dose of 2 μg/kg. The effects were slight but could be detected within a postinfusion period of 1 h. Our data show that sequential spectral analysis of spontaneous hemodynamic fluctuations can be used to unravel time-dependent dynamics of sympathetic and vagal components in short-term cardiovascular control.

A procedure to measure the specific activities of dopamine and its metabolites in rat striatum, based on HPLC, electrochemical detection and liquid scintillation counting

A procedure to determine the specific activities (s.a.) of the putative neurotransmitter dopamine (DA) and its metabolites in rat striatum is described. For this purpose 200 mu Ci L-[3,5-3H]tyrosine was injected via a jugular vein cannula into freely moving rats. Contents and radioactivity of striatal tyrosine, DA, 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT) and homovanillic acid (HVA) were determined by means of HPLC, electrochemical detection (ECD) and liquid scintillation counting. In the phase system applied DA, DOPAC, 3-MT and HVA can be separated in a single run after direct injection of striatal supernatants. The selectivity of the phase system was sufficient to analyse the supernatant of two rat striata over a 150 X 4.6 mm column, even when DA turnover was strongly stimulated. Tyrosine levels and radioactivity were measured by re-analysis of the front peak with divergent mobile phase parameters. In order to demonstrate the applicability of the present procedure, the s.a. of DA and its metabolites, as found 20 min after [3H]tyrosine administration, and the effect of haloperidol thereupon, are presented.

Haloperidol inhibits the disappearance of acidic dopamine metabolites from rat striatum.

1 Administration of neuroleptic drugs to laboratory animals results in increased dopamine turnover. This has been shown by use of diverse techniques, like conversion of radioactive tyrosine to dopamine (Nyback & Sedvall, 1969; Zivkovic, Guidotti & others, 1975), dopamine loss after synthesis inhibition with a-methylp-tyrosine (r-MT) (Anden, Corrodi & others, 1971 ; Waldmeier & Maitre, 1976) and accumulation of the acidic dopamine metabolites homovanillic acid (HVA) and 3,4-dihydroxyphenyl acetic acid (DOPAC) (AndCn, ~ o o s & Werdinius, 1964; Westerink & Korf, 1976b). The latter method has also been used extensively to compare quantatively the effects of different neuroleptics in striatal and mesolimbic brain structures (Stawarz, Hill & others, 1975; Wiesel & Sedvall, 1975; Wilk, Watson & Stanley, 1975; Waldmeier & Maitre, 1976; Westerink & Korf, 1976b). A basic assumption in such studies is, that alterations in metabolite concentrations reflect alterations in functional activity of dopaminergic neurons. In the maintainance of normal metabolite concentrations, however, at least two processes are rate-limiting, i.e. the formation of the metabolites and their removal from the brain. The fact that considerable amounts of acidic metabolites are present in normal brain tissue may indicate that the removal from the brain is indeed a rate-limiting process. I t seems reasonable to assume that the rate of formation of acidic metabolites is related to the activity of dopaminergic neurons. The concentrations of these metabolites, however, are not only determined by the rate of formation, but also by the rate of transport from the brain. Drug-induced alterations of metabolite concentrations, therefore, cannot be taken as a reflection of the activity of dopaminergic neurons, when the transport of metabolites is also affected by the same drug. To test whether the increase in the acidic metabolites HVA and DOPAC by haloperidol (Andkn, Roos & Werdinius, 1964; Westerink & Korf, 1976b) was a t least in part the result of an inhibition of the transport of these metabolites, we inhibited the formation of acidic metabolites with pargyline after which the effect of haloperidol on the metabolite concentrations was studied. Since the formation of acidic metabolites will be inhibited by pargyline, an alteration in metabolite concentrations by haloperidol can only be ascribed to an alteration in the rate of transport (or conjugation). Similarly the effect of the dopamine agonist apomorphine was studied.