A.M.L. Van Delft

Effect of metergoline, fenfluramine, and 8-OHDPAT on catalepsy induced by haloperidol or morphine

SummaryThe influences of the indirect serotonin agonist fenfluramine (5; 10 mg/kg s.c.), the serotonin antagonist metergoline (5; 10 mg/kg s.c.) and the 5-HT1A agonist 8-OHDPAT (0.1; 0.2; 0.46 mg/kg s. c.) on haloperidol-induced catalepsy in rats or mice and on morphine-induced catalepsy in rats were studied. Morphine-induced catalepsy was enhanced by fenfluramine and attenuated by metergoline, whereas neither fenfluramine nor metergoline had any effect on haloperidol-induced catalepsy. 8-OHDPAT strongly antagonised catalepsy induced by morphine or haloperidol. We conclude that serotonergic transmission plays a major role in effectuating morphine catalepsy but not in effectuating haloperidol catalepsy. The antagonistic effect of 8-OHDPAT suggests a secondary, modulating role for 5-HT1A receptor mediated events in both types of catalepsy.

Corticosterone, choline acetyltransferase and noradrenaline levels in olfactory bulbectomized rats in relation to changes in passive avoidance acquisition and open field activity

Consequences of olfactory bulbectomy in two behavioural situations, passive avoidance acquisition and activity in a brightly lit open field, were measured in the same animals for which data on four biochemical measures were also obtained. The biochemical measurements were on plasma corticosterone levels, noradrenaline (NA) levels in the midbrain and amygdala + pyriform cortex and the choline acetyltransferase (CAT) levels in the olfactory tubercle. Experimental variation in age groups of rats (7 weeks and 3 months) and in post-bulbectomy periods (1, 2 and 4 weeks) was made. The deficit in passive avoidance as a consequence of olfactory bulbectomy was evident in all groups of young animals and in older animals one and two weeks post-bulbectomy but not in older animals four weeks after bulbectomy. An increase in open field activity was similarly observed in all groups except in the older animals four weeks after bulbectomy. In contrast to reports by other investigators the basal plasma corticosterone levels were not increased in bulbectomized animals nor did we observe any diminution of NA levels in the amygdala (+ pyriform cortex). CAT levels were slightly increased in older animals two weeks after bulbectomy. The absence of a change in the plasma corticosterone level after bulbectomy is discussed in relation to the notion that the olfactory bulbectomized rat is in some way relevant as a test model for predicting efficacy of potential antidepressant drugs.

The effect of luteinizing hormone-releasing hormone analogue (LHRHa) in combination with different drugs with anti-dopamine and anti-serotonin properties on gonadotropin release and ovulation in the African catfish, Clarias gariepinus

Under hatchery conditions the reproduction of the African catfish depends on artificial induction of egg maturation and ovulation. In this study the effect of a number of potential psychotropic drugs with variable anti-dopamine and/or anti-serotonin properties in combination with LHRHa on gonadotropin release and ovulation was investigated. Drugs with a potent anti-dopaminergic character caused a preovulatory gonadotropin surge, which seems to be independent of their anti-serotonergic properties. One drug, however, did not follow this rule. Drugs exhibiting low interaction with dopamine and high interaction with serotonin receptors had no effect on the LHRHa-induced gonadotropin release.

A large scale, high resolution, automated system for rat sleep staging. I. Methodology and technical aspects

An automatic rat sleep classification system is described which records and analyses bioelectrical signals from 32 rats over extended periods of time. At present this system is used routinely for the screening of drug effects on sleep. The analysis is based on 3 signals, the parieto-occipital EEG, nuchal EMG and a movement indicator signal. The on-line analysis is done per epoch of 2 sec and involves power spectral analysis of the EEG and rectification and integration of the EMG and movement signals. The automatic sleep staging into 6 stages (active and quiet waking; quiet, deep, pre-REM and REM sleep) is performed off-line. Parameters derived from a discriminant analysis of visually scored tracings of individual rats constitute the basis for the automatic scoring procedure. The movement index is used to discriminate between active and quiet waking, while the use of the EMG level improves the separation of waking and REM sleep. After the construction of hypnograms from these computer scorings a set of parameters can be extracted which characterizes the sleep-waking behavior of each individual rat. These parameters are then used to compare statistically the 2-4 treatment groups which make up each experiment of 32 rats. Experimental validation of the system is reported in an accompanying paper.

Ovariectomy and subchronic estradiol-17β administration decrease dopamine D1 and D2 receptors in rat striatum

Ovariectomy and subchronic estradiol-17 beta cause a down-regulation of dopamine D1 and, to a lesser extent, D2 receptors in rat striatum. An intracellular mechanism mediates the DA receptor down-regulation, as various estrogens do not interact with membrane-bound DA receptors in vitro. A common denominator, e.g. enhanced DA turnover, is suggested to mediate the estradiol-induced DA receptor down-regulation. Ovarian factors other than estradiol are additionally proposed to be involved in the regulation of striatal DA receptors.

Local cerebral glucose uptake in anatomically defined structures of freely moving rats

Two limitations of the classical [14C]2-deoxyglucose (DG) method are the severe stress to which the restrained animals are exposed, and the difficulties with the anatomical analysis of the autoradiograms. The present study describes modifications which circumvent these limitations. Firstly, rats are provided with two chronic indwelling cannulas to allow blood sampling under unrestrained conditions. Absence of stress is demonstrated by low plasma corticosterone levels in the cannulated rats at the start of the experiment. The second modification concerns the image analysis system. The image of the autoradiogram is superimposed on the image of the identical histologically stained section in order to improve the accuracy of the structure identification. This approach enables the operator to delineate the anatomical brain structure in the histologically stained section and quantify the glucose uptake in the autoradiogram generated from this section. The reproducibility of the present quantitative measuring system is illustrated by glucose uptake measurements in different laminar zones of the various fields in the dorsal hippocampal formation. It is concluded that the present technical improvements of the classically applied [14C]2-deoxyglucose technique provide favourable conditions for the quantitative study on cerebral glucose uptake in normally behaving animals.

Effects of intra-arterial cannulation on blood platelet consumption in rats

Experimental arterial thrombosis has been induced by an indwelling cannula in the abdominal aorta of rats. The involvement of blood platelets was studied by the determination of the blood platelet count and the survival of 51Cr labeled platelets. Cannulation transformed the platelet disappearance patterns from linear to curvi linear and exponential curves. The blood platelet consumption rate increased 2–3 fold immediately after cannulation and remained at that level for at least 8 days. The consumption rate was higher when longer cannulae were used. Initially the increased blood platelet consumption was not compensated by an increase in platelet production, this resulted in a decreasing platelet count. After 3 to 7 days a long lasting steady state thrombocytopenia was achieved, under these circumstances the platelet turnover in cannulated and normal rats was the same. Withdrawal of the cannula normalized the platelet consumption within a few hours, leading to a linear disappearance pattern of the residual labeled platelets. The platelet count was readily restored to normal values via a rebound overshoot.

Facilitation of amphetamine-induced rotation by muscarinic antagonists is correlated with M2 receptor affinity

This study examined the relationship between the affinity of cholinergic drugs for muscarinic receptor subtypes and their potency in potentiating or inhibiting amphetamine-induced rotation. The ascending nigrostriatal dopaminergic pathway was unilaterally lesioned in male Wistar rats using 6-hydroxydopamine. In these rats, ipsiversive rotation induced by amphetamine sulphate (1 mg/kg, s.c.) was dose-dependently inhibited by the cholinergic agonists oxotremorine, RS86 and pilocarpine and by the acetylcholinesterase inhibitor physostigmine. In contrast the cholinergic antagonists scopolamine, secoverine and dicyclomine facilitated amphetamine-induced rotation. Agonist and antagonist potencies were then compared with M1 and M2 binding site affinities estimated by displacing [3H]pirenzepine from forebrain and [3H]QNB from brainstem homogenates. The data suggest a relationship between antagonist potency and M2 binding site affinity.

The pharmacological profile of Org 6906, a potential non-sedative antidepressant that combines monoamine uptake inhibition with alpha2-adrenolytic activity

(dl)-(5 alpha,8 alpha,9 alpha)-5,8,9,10-Tetrahydro-5,9- methanobenzocycloocten-8-amine hydrochloride (Org 6906) is a potential new antidepressant agent, with a neurochemical profile quite different from that of the classical tricyclic antidepressant drugs. The compound was found active in behavioural tests which are considered to be predictive for antidepressant activity, such as the muricidal test in the rat and the acquired immobility model. Neurochemical studies showed that Org 6906 was an inhibitor of the reuptake of monoamines both in vitro and ex-vivo without having appreciable anticholinergic, antihistaminergic or alpha 1-adrenolytic activity. The facilitatory effect on monoaminergic neurotransmission was confirmed by the reversal of hypothermia induced by reserpine. The drug Org 6906 appeared to have selective alpha 2-adrenolytic properties. It facilitated potassium-stimulated release of noradrenaline from slices of cortex, displaced [3H]rauwolscine and [3H]dihydroergocryptine from their binding sites but only weakly blocked alpha 1-adrenoceptors. The alpha 2-adrenolytic properties were also apparent in behavioural interaction models. The compound antagonized the sleep-inducing effects of clonidine in chicks and mice and it antagonized the mydriasis induced by clonidine in the rat. Finally, it was shown that the two enantiomers of Org 6906 contributed almost equally to the relevant neurochemical and behavioural properties.

Effects of Exogenous Pain Relieving Substances on Experimental Results

Pain or injury, as inflicted upon an animal in an experimental setting, will disturb its homeostatic balance and change its behaviour and its affective state. These 3 changes may have far reaching consequences upon the outcome of experiments and may require the application of proper analgesia. I will discuss these physiological consequences of injury and the effects of analgesia, while assuming that the investigator is not interested in nociception, pain or pain control in itself, but in other biological questions which apparently cannot be answered with the help of completely intact and undisturbed animals.