J.M. van Rossum

Effects of chemical stimulation of the mesolimbic dopamine system upon locomotor activity.

The effects of local injections of drugs into terminal areas of the mesolimbic dopamine system were investigated. Bilateral administration of dopamine, but not of noradrenaline and serotonin, into the nucleus accumbens of non-pretreated rats resulted in stimulation of locomotor activity. No clear or only minor effects were seen after injections of the dopamine metabolites 3-methoxytyramine, DOPAC and HVA and after injections of media with different pH and osmolality. d-Amphetamine proved more effective than dopamine in producing locomotor stimulation, whereas both stimulant and depressant effects were observed following injection of apomorphine into the nucleus accumbens. ET 495 and the noradrenaline agonists clonidine, phenylephrine and isoprenaline did not enhance locomotor activity, but theophylline was effective. Pretreatment with haloperidol, but not with clozapine, significantly reduced the effects of dopamine and theophylline. Locomotor stimulation was also found following bilateral administration of dopamine, d-amphetamine and apomorphine into the tuberculum olfactorium, whereas noradrenaline, serotonin and ET 495 produced no, or rather depressant effects. These results provide further evidence for an important role of the mesolimbic dopamine system with respect to locomotor activity.

Stimulation of locomotor activity following injection of dopamine into the nucleus accumbens

Recently we have observed that bilateral injection of ergometrine into the nucleus accumbens of rats results in a strong and long-lasting enhancement of locomotor activity (Pijnenburg, Woodruff & van Rossum, 1973). This effect was antagonized by low doses of haloperidol and pimozide. The hypothesis was proposed that this enhanced locomotor activity was elicited by a stimulation of dopamine receptors in the nucleus accumbens. We now report that administration of dopamine directly into the nucleus accumbens of nialamide-pretreated rats produces a pattern of enhanced locomotor activity similar to that seen after ergometrine. Seven male Wistar rats (200-220 g) were implanted with double barrelled cannulas in each side of the nucleus accumbens (coordinates A 9.4, L 1.2 and H -0.6 according to the atlas of Konig & Klippel, 1963). These animals were used for all experiments with 5-8 days between experiments. The animals were subsequently killed and brains were sectioned to determine the position of the cannulas. For details of the experimental procedure see Pijnenburg & others (1973). Injections were made by means of a 5 pl Hamilton syringe with a 31 gauge needle. The injection volume was 0.5 pl. Dopamine HCl and (-)-noradrenaline (-)-hydrogen tartrate were dissolved in saline. Locomotor activity was measured in activity cages, equipped with photoelectric cells and recorded on a cumulative recorder. The rats were always pretreated with the monoamine oxidase inhibitor nialamide (100 mg kg-l i.p.) 18 h before administration of saline, dopamine or noradrenaline. Injection of dopamine ( 5 pg) to each side of the nucleus produced a strong enhancement of locomotor activity, which started in 5 animals within 10 min of injection and lasted for up to 4 h, reaching a peak at about 1 h returning to 0 over the next 3 h with the most rapid decline over the last 30 min. In two rats, in which the injection site was found to be at the border of the nucleus accumbens, stimulation of locomotor activity started after 20 and 30 min respectively and failed to reach the level seen in the other rats. This is probably the reason for the large variability in the results (see Table 1). Injection of noradrenaline (5.0 pg) into each side of the nucleus accumbens of the same rats produced enhanced locomotor activity in 5 of the 7 animals but this was

Excitation-mediating and inhibition-mediating dopamine-receptors: A new concept towards a better understanding of electrophysiological, biochemical, pharmacological, functional and clinical data

A great number of earlier reported experimental data dealing with the role of dopamine in dopamine-loaded structures within the mammalian brain have raised questions concerning the concept of dopamine as an inhibitory agent acting on one type of receptor. A critical review of the anatomical, histochemical, electrophysiological, pharmacological and functional studies reveals that the dopamine-loaded structures are marked by an internal differentiation at various levels. It is attempted to demonstrate that this is due to a heterogeneous distribution of two distinct types of dopamine-receptors, each characterized by their own properties: DAe- and DAi-receptors. Furthermore, the experimental and clinical. implications are discussed in view of the hypothesis that balance between both types of receptors is essential for normal psychomotor functioning.

Inhibition of d-amphetamine-induced locomotor activity by injection of haloperidol into the nucleus accumbens of the rat

The effect of intracerebral administration of antagonists of dopamine and noradrenaline upon the locomotor stimulation induced by intraperitoneal injection of d-amphetamine sulfate in rats was investigated. Injection of low doses of the dopamine antagonist haloperidol (2.5 Μg and 5 Μg) bilaterally into the nucleus accumbens antagonized the locomotor stimulation following d-amphetamine. No significant inhibition was observed following administration of the alpha-adrenergic antagonist phentolamine or the beta-adrenergic antagonist propranolol into the nucleus accumbens. Injection of the same doses of haloperidol into the caudate nucleus did not inhibit the d-amphetamine induced locomotor activity, in contrast to the effects seen following injection into the nucleus accumbens.The results confirm the significance of dopaminergic mechanisms for the locomotor stimulant effect of d-amphetamine and indicate that the mesolimbic dopamine system plays an important role in this respect.

Effects of antagonists upon locomotor stimulation induced by injection of dopamine and Noradrenaline into the nucleus accumbens of nialamide-pretreated rats.

The effects of injections of monoamines, alone and in combination with different antagonists, bilaterally into the nucleus accumbens of nialamide-pretreated rats were investigated.Dopamine was found to produce a stronger stimulation of locomotor activity than noradrenaline, whereas serotonin was effective only in a small number of animals, in which the duration of locomotor stimulation was shorter than after dopamine or noradrenaline. The effects of both dopamine and noradrenaline were completely antagonized by administration of a small dose of the dopamine antagonist haloperidol, administered bilaterally 15 min after the catecholamines. The α-adrenergic antagonist phentolamine did not inhibit the effect of noradrenaline but, on the contrary, potentiated and considerably prolonged the duration of locomotor stimulation. Also, the effect of dopamine was potentiated and prolonged by phentolamine. Bilateral injection of phentolamine alone had no influence upon locomotor activity. The effect of noradrenaline was not clearly inhibited nor potentiated by the Β-adrenergic antagonist propranolol. It is suggested that the stimulation of locomotor activity induced by injection of noradrenaline into the nucleus accumbens of nialamide-pretreated rats is brought about via dopaminergic mechanisms.

Ergometrine induced locomotor activity following intracerebral injection into the nucleus accumbens

Abstract Ergometrine was injected in rats intraperitoneally or intravenously and also directly into different parts of the brain. After peripheral injection the animals showed a characteristics crawling behaviour. This behaviour was reversed by apomorphine. Following bilateral injection of ergometrine into the nucleus accumbens, the rats showed a biphasic response. After a period, during which sedation and ptosis predominated, their followed a strong and long-lasting locomotor stimulation, which started and finished in most cases rather abruptly. When the doses of ergometrine were lowered the locomotor activity remained at a constant high level, but the duration was shorter. Bilateral injection of ergometrine into the caudate nucleus or into the septum had only little or no stimulant effect on locomotor activity. The strong locomotor stimulation following injection of ergometrine into the nucleus accumbens was inhibited by low doses of haloperidol and pimozide given intraperitoneally. Pretreatment with α-methyl-p-tyrosine had no influence on this motor activity. Ergometrine injected unilaterally into the nucleus accumbens and into the caudate nucleus caused only a slight enhanced locomotor activity and turning to the contralateral side. The possible mode of action of ergometrine is discussed.

Mechanism of action of cocaine and amphetamine in the brain

Die Ähnlichkeit der zentral stimulierenden Wirkung des Kokains und des Benzedrins wurde besprochen und weiter untersucht. An mit Reserpin vorbehandelten Mäusen wurde die Wirkung des Benzedrins nicht geändert; die Wirkung des Kokains aber wurde völlig blockiert. Aus diesen Befunden wurde geschlossen, dass die psychomotorischen Stimulantien oder Weckamine in zwei Klassen eingeteilt werden können. Klasse I: Substanzen mit einem direkten arterenergischen Wirkungsmechanismus, das heisst Mimetika der Katecholamine (zum Beispiel Benzedrin und Pervitin); Klasse II: Substanzen mit einem indirekten arterenergischen Wirkungsmechanismus, das heisst Wirkung durch Freisetzung der Katecholamine (zum Beispiel Kokain und N-Benzyl-Benzedrin).

Multiple receptors for brain dopamine in behavior regulation: Concept of dopamine-e and dopamine-i receptors

Abstract From current knowledge, it is possible to substantiate the original concept of DAe and DAi receptors including the predicted correlation with the anatomical, histochemical, biochemical and functional features of the distinct neuronal structures, in which they occur; labelling them as neostriatal DAe receptors and mesolimbic DAi receptors appears to be justified. Available data warrant a revision of currently employed behavior and pharmacological tests. When revised in terms of the DAe-DAi concept, assessment of such tests reveals that agents such as (-)NPA, 6, 7ADTN and certain ergot alkaloids like lergotrile, lisuride and, to a less degree, CB-154 are weak DAe agonists and strong DAi antagonists (Table I). The discovery that mesolimbic α-like NE receptors which regulate the DA activity at the level of the mesolimbic DAi, but not neostriatal DAe, receptors show adaptational changes following priming or subacute treatments with apomorphine or haloperidol, opens new perspectives for understanding phenomena such as the development of hypersensitivity to apomorphine etc. Presynaptic DA receptors located within the DA synaps and DA receptors located at DA cell-bodies resemble closely the DAe receptors, although absence of linkage to the enzyme adenylyl cyclase hints at some distinction. It is possible that the distinct classes of DA receptors identified by behavior and pharmacological studies in mice correspond with the DAe and DAi receptors in snails, rats and cats. There is no evidence to suggest that DAe and DAi receptors are directly related to a) so-called DA1 and DA2 receptors which are coupled and uncoupled respectively to the enzyme adenylyl cyclase, or to b) any of the DA-specific binding sites identified with radiolabelled DA agonists or antagonists. Nonetheless, it cannot be excluded that DAe receptors may correspond with DA-specific binding sites identified with tritiated DA and/or haloperidol, and DAi receptors with a particular subclass of DA-specific binding sites identified within certain mesolimbic structures with radiolabelled spiperone. Thus, future work is still required to relate DAe and DAi receptors to particular, molecular entities within the brain.

Hypothalamic alpha adrenergic receptors in cardiovascular regulation

Abstract Stereotaxic injection of noradrenaline (3–100 nmol) into the anterior hypothalamicpreoptic region of pentobarbital anaesthetized rats induced a fall in blood pressure and heart rate. The size of the effect was related to the size of the dose. Phenylephrine (70 nmol) and clonidine (1.5–100 nmol), two typical alpha adrenergic receptor stimulating agents, mimicked the noradrenaline induced depressor effects. Local pretreatment with phentolamine (106 nmol) abolished the fall in blood pressure and heart rate induced by noradrenaline (40 nmol) or clonidine (15 and 40 nmol). Noradrenaline (40 nmol) and clonidine (15 nmol) injected into the brain ventricles also caused a fall of both blood pressure and heart rate, but the size of these effects was significantly smaller than that after direct intrahypothalamic injection of the same amounts of these drugs. These results suggest that stimulation of alpha adrenergic receptors in the anterior hypothalamic-preoptic region of rats causes a fall in blood pressure and heart rate. The relevance of these data is discussed in view of the role of alpha adrenergic receptors in the hypothalamus in both cardiovascular regulation and thermoregulation.

Gas chromatographic determination of chloral hydrate, trichloroethanol and trichloroacetic acid in blood and in urine employing head-space analysis

Abstract A specific and sensitive gas chromatographic method for the quantitative determination of chloral hydrate and its metabolites trichloroethanol, trichloroethanol glucuronide and trichloroacetic acid in blood and urine is described. Use is made of the relative volatility of trichloroacetaldehyde, trichloroethanol and trichloroacetic acid methyl ester, which offers the possibility of head-space analysis. A known volume of the head-space gas, in equilibrium with its liquid phase (blood or urine), is directly injected into the gas chromatograph, which is equipped with an electron capture detector. Samples are divided in two portions: 1.0 ml for the determination of unconjugated trichloroethanol and 2.0 ml+1.0 ml of concentrated sulphuric acid for the determination of chloral hydrate, trichloroethanol (conjugated+unconjugated) and trichloroacetic acid after esterification with dimethyl sulphate. Detection limits for chloral hydrate and trichloroethanol are 0.5 μg/ml in blood or urine and for trichloroacetic acid 0.1 μg/ml. Some preliminary pharmacokinetic studies on chloral hydrate and its metabolites in dogs and humans are reported.