Serotonergic function and late luteal phase dysphoric disorder

Thirty-eight subjects who met criteria for the DSM-III-R diagnosis late luteal phase dysphoric disorder (LLPDD) were compared with 18 controls in 5-HT uptake kinetics of the platelets in the premenstrual (day 26) as well as in the postmenstrual phase (day 4) of the cycle. Furthermore, 5-hydroxytryptophan (5-HTP) was administered to LLPDD patients and controls in both phases of the cycle, to investigate pituitary sensitivity for serotonin. Plasma samples for the measurement of cortisol and -endorphin were taken before and after oral administration of 200 mg 5-HTP, and considered as an index of pituitary-adrenal function. LLPDD was not associated with a lower platelet 5-HT uptake and content in the premenstrual phase of the cycle, compared with the postmenstrual phase. Patients appeared not to be different from controls in 5-HT uptake kinetics of platelets in the premenstrual phase of the cycle. No main differences were observed between LLPDD patients and controls in their ability to respond with secretion of cortisol and -endorphin to 5-HTP stimulation, either in the premenstrual, or in the postmenstrual phase. This observation could not be attributed to differences in 5-HTP metabolism. The findings of the present study do not support a specific role for 5-HT in the pathophysiology LLPDD.     

Increase in ω3 (Peripheral-Type Benzodiazepine) binding site densities in different types of human brain tumours

Summary The density of ₃ (peripheral type benzodiazepine) binding sites, a marker of reactive and tumoural cells, has been measured in different types of human brain tumours; ₃ sites were quantified autoradiographically in sections from biopsy or autopsy specimens labelled with the specific radioligand³H-PK 11195. Compared to normal brain parenchyma, up to 12-fold increase in ₃ site densities were found in appparently viable areas of high grade astrocytoma and glioblastoma specimens, whereas more limited increases (2 to 3-fold) in this marker were observed in areas of necrosis. Low grade gliomas (astrocytomas) and meningiomas exhibited only moderate increases (2 to 3-fold) in this autoradiographic marker. Metastases of lung or kidney origin were characterized by greatly elevated (up to 20-fold) ₃ site densities as compared to normal brain parenchyma. In every case, there was a good spatial correspondence between the histopathological limits of the tumour and the anatomical location of the increase in ₃ site densities. These results suggest that ₃ site densities in human brain tumours reflect their proliferative activity and point to a possible future usefulness of positron or gamma-ray emitting ₃ site ligands for the clinical investigation and detection of human brain proliferative diseases.     

Evaluation of cellular viability by quantitative autoradiographic study of myocardial uptake of a fatty acid analogue in isoproterenol-induced focal rat heart necrosis

Previous studies led us to hypothesize that a fatty acid analogue, 15-p-iodophenyl--methyl pentadecanoic acid (IMPPA or BMIPP), which is taken up but not quickly metabolized by heart cells, would be a more suitable tracer of cellular viability than thallium-201. Biodistribution studies of 1-¹⁴C-IMPPA in conscious, freely moving rats showed that the concentration ratio of radioactivity in the heart with respect to the blood was about 8 for at least 60 min after intravenous administration, permitting its use as a putative tracer in these conscious, freely moving rats. Thereafter, the myocardial uptake of¹⁴C-IMPPA was studied in isoproterenol-treated rats (daily treatment for 10 days in order to induce cardiac hypertrophy and necrotic foci) with respect to control ones. Comparison of myocardial localizations by quantitative autoradiography of the uptake of²⁰¹Tl and¹⁴C-IMPPA with that of triphenyltetrazolium chloride (TTC) staining enabled comparative evaluation of nutritional blood flow, localization and uptake of¹⁴C-IMPPA and necrotic foci size. Distributions of¹⁴C-IMPPA and²⁰¹1 T1 in control rats' hearts were homogeneous, like TTC staining. In infarcted hearts, areas of decreased¹⁴C-IMPPA uptake were nearly the same (100%±5%) as those unstained by TTC. These areas were larger than those showing a decrease in thallium uptake (about 70%±5% of the total scar size). Therefore, IMPPA seems to be a more accurate and sensitive indicator of necrosis localization compared with thallium. It may be a useful agent for assessment of myocardial viability by single photon emission tomography (SPET) imaging.     

Untersuchungen zur beziehung zwischen vinylchlorid (VCM)-aufnahme und metabolitenausscheidung bei 15 VCM-exponierten

Summary Fifteen workers employed in a PVC producing plant were investigated concerning their individual vinyl chloride (VCM) exposure and the urinary excretion of the VCM metabolite thiodiglycolic acid (TdGA). The urine concentrations found were in the range 0.94–20.4 g/ml. These could be compared with exposure data calculated from VCM air analyses performed by personal air sampling and corrected with respect to the exposure times of the workers. The amounts of TdGA excreted within 24 h were correlated with the effective VCM body concentrations calculated from the exposure data as mean values for 12 h periods (Spearman coefficient P=<0.005). This correlation resembles a function of the Michaelis-Menten type. It could be shown that during short exposure periods of less than 5 min, the metabolite formation in relation to the exposure data was lower than during longer periods of exposure although, as would be expected, there were some fluctuations of the exposure level. Therefore, the VCM body concentrations could not normally reach steady state values.

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Untersuchungen zur beziehung zwischen vinylchlorid (VCM)-aufnahme und metabolitenausscheidung bei 15 VCM-exponiertenII. Messungen zur ausscheidung des VCM-metaboliten thiodiglykolsaure im harn

Zusammenfassung In einer Feldstudie an 15 Beschäftigten eines PVC-produzierenden Betriebes wurde der Zusammenhang zwischen der Höhe der Exposition gegenüber monomerem Vinylchlorid (VCM) und der Ausscheidung des VCM-Harnmetaboliten Thiodiglykolsäure (TdGA) untersucht. Die ermittelten Harnkonzentrationen, die sich zwischen 0,94 und 20,4 g/ml bewegten, konnten mit Expositionsdaten verglichen werden, die durch personal air sampling unter Berücksichtigung der Aufenthaltszeiten im Expositionsbereich gewonnen werden waren.Aus den mit Personendosimetern gewonnenen Analysedaten wurden unter Berücksichtigung pharmakokinetischer Gesetzmäßigkeiten die effektiven VCM-Körperkonzentrationen als 12-h-Mittelwerte kalkuliert. Mit diesen waren die im 24-h-Harn ausgeschiedenen Mengen an TdGA deutlich korreliert (P=<0,005; Spearman-Koeffizient). Die Korrelation entspricht in guter Näherung einer Funktion vom Michaelis-Mengen-Typ. Unter Berücksichtigung der Arbeitsprotokolle konnte aus den Meßdaten abgeleitet werden, daß bei Ansteigen der VCM-Luftkonzentration für Zeiträume von weniger als 5 min die Metabolitenausscheidung relativ zur kalkulierten mittleren Körper-konzentration geringer ansteigt als bei längerfristigen Expositions schwankungen. Offenbar schwankte die VCM-Raumluftkonzentration derart, daß die VCM-Körperkonzentrationen den Gleichgewichtswert in der Regel nicht erreichten.

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Abkürzungen VCM Vinylchlorid Monomer - TdGA Thiodiglykolsäure - p.a.s. personal air sampling Mit Unterstützung der Berufsgenossenschaft der Chemischen Industrie     

Excitatory and depressant effects of Δ 9-tetrahydrocannabinol and cannabidiol on cortical evoked responses in the conscious rat

The influences of ⁹-tetrahydrocannabinol (THC) and cannabidiol on electrically evoked cortical potentials of conscious rats with chronically implanted electrodes were investigated. Specifically, the cannabinoids' effects on a transcallosal evoked response were compared with those of ethosuximide, phenytoin, and pentylenetetrazol. THC produced dose-related opposite effects: Low doses increased the amplitude of the response, whereas higher doses reduced the response. Other drugs that can cause or exacerbate seizures, i. e., phenytoin and pentylenetetrazol, also increased the amplitude of the cortical response. In contrast, cannabidiol, over a wide dosage range, caused only depression. Ethosuximide, like cannabidiol, elicited a depressant effect. The data indicate that under the conditions of the present investigation, cannabidiol shares electrophysiological properties with ethosuximide but not with phenytoin, and that cannabidiol is a relatively selective, centrally acting drug. In addition, our findings support the suggestion that augmentation of neurotransmission in central pathways may contribute to the convulsant actions of THC, and the cannabinoids' depressant effects may, at least partially, account for their anticonvulsant actions.     

Noradrenergic and dopaminergic interactions in escape behavior: Analysis of uncontrollable stress effects

The effects of norepinephrine receptor blockade on the deficits of escape behavior induced by haloperidol and by inescapable shock were evaluated. Phenoxybenzamine, the -norepinephrine receptor blocker, was found to enhance escape behavior and to eliminate the disruptive effects of both inescapable shock and haloperidol. In contrast, the -norepinephrine receptor antagonist, propranolol, was without effect on behavior under any of these conditions, while the dopamine--hydroxylase inhibitor, FLA-63, disrupted performance. Like phenoxybenzamine, the norepinephrine receptor stimulant, clonidine, was found to eliminate the behavioral disruption produced by haloperidol. These somewhat paradoxical findings were discussed in terms of the contribution of DA-NE interactions in determining behavioral change in aversive paradigms.     

Haemodynamic response to graded exercise during chronic beta-adrenergic blockade with bunitrolol,an agent with intrinsic sympathomimetic activity

Summary The effect of chronic beta blockade on the haemodynamic response to graded exercise was studied in 18 hypertensive patients treated with bunitrolol, which has partial agonist activity. The patients first received a placebo for 5 to 12 days, then bunitrolol 30 mg daily for one week and subsequently the dose was doubled weekly as necessary upto 240 mg daily. At rest haemodynamic changes after beta blockade were only minor; heart rate decreased by 8% and no significant change was observed in stroke index, cardiac index, (a-v)O₂ difference and VO₂. The hypotensive effect was not significant and no significant change in mean pulmonary arterial and wedge pressure was observed. Maximal exercise capacity remained unchanged, because of haemodynamic responses. The maximal exercise heart rate was reduced by 25% during beta blockade, which was compensated by a 34% elevation in stroke index, whereas maximal cardiac index and (a-v)O₂ difference remained unchanged. There was no consistent change in mean pulmonary artery pressure during maximal exercise, but the mean brachial artery pressure fell by 12%.     

Effects of theβ-adrenoceptor antagonists acebutolol and metoprolol on sleep pattern in normal subjects

Summary The effects of acute introduction and withdrawal of 2 new -adrenergic blockers, acebutolol and metoprolol, on sleep in normal subjects were investigated. Both the subjective effects of the drug and EEG sleep variables were determined during a baseline period with placebo and in relation to the drug. The results showed that neither drug had a significant effect on sleep pattern in normal subjects. However, a transient effect on certain sleep parameters was seen on the first night of drug administration, with complete return to baseline, on the following night without any evidence of rebound. Possible mechanisms to explain the central actions of -adrenergic blockers are briefly discussed.     

Characteristics of pentobarbital discrimination in the gerbil: Transfer and antagonism

Experiment 1. Gerbils were trained in a T-shaped maze to discriminate the effects produced by pentobarbital (P-barb. 15 mg/kg, i.p.) and the effects of saline. The response, a left or right turn in the maze, was thus contingent upon the prevailing training condition (P-barb. or saline). The criterion of performing 8 correct first trial choices in 10 consecutive sessions was reached within 20 training sessions. Tests with descending doses of P-barb. yielded an ED₅₀ of 9 mg/kg. Tests with phenobarbital (40 mg/kg) or diazepam (2 and 4 mg/kg) solely maintained the drug response. P-barb. discrimination was reversed by megimide (ED₅₀: 8.5–9.6 mg/kg) and metrazol (ED₅₀: 24.9–27.9 mg/kg). Thus megimide was approximately 3 times more effective than metrazol. Metrazol (40 and 80 mg/kg) also counteracted the phenobarbital and diazepam response. Picrotoxin (2.5 and 5 mg/kg) was less effective whereas caffeine (100 mg/kg) and piracetam (100–1000 mg/kg) did not upset P-barb. discrimination. Experiment 2. Naive gerbils had to discriminate mixtures of P-barb. (15 mg/kg) plus either 40 or 80 mg/kg of metrazol from saline already at the start of the discriminative training. The drug combinations produced discriminable effects since most gerbils reached the acquisition criterion (8/10), although more slowly than gerbils trained with P-barb. solely. Gerbils trained without a drug stimulus (saline vs. saline) never attained the criterion during 60 consecutive sessions. In conclusion, reversal of established discrimination (Expt. 1) does not necessarily mean that the same drug combination lacks discriminable effects as demonstrated in Experiment 2.