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A R Cools

Publications and source records attributed to A R Cools.

At least 181 records · Page 10Linked to original sources
PubMed1989

Are antagonists of dopamine D1 receptors drugs that attenuate both positive and negative symptoms of schizophrenia? A pilot study in Java monkeys.

Amphetamine is known to elicit stereotyped behavior in various species. For a long time, this effect was considered to be an animal model for the positive symptoms of schizophrenia. In addition, amphetamine is known to induce a strong social isolation in socially living monkeys. Both on symptomatologic and pharmacologic grounds, this amphetamine-induced social isolation has been suggested to represent an animal model for the negative symptoms of schizophrenia. To date no effective treatment has been found for these negative symptoms. We now report that the selective D1 dopamine antagonist SCH 23390 is very effective in antagonizing both the stereotyped behavior and the social isolation in Java monkeys induced by amphetamine. Moreover, SCH 23390 is able to reinstate normal behavior in these animals. These results may have important consequences for our understanding of the functional significance of the D1 receptor as well as for the clinical treatment of the positive and negative symptoms of schizophrenia.

Animals↗
PubMed1988

Differential effects of the selective D2-antagonist raclopride in the nucleus accumbens of the rat on spontaneous and d-amphetamine-induced activity.

The effect of the D2-antagonist raclopride was investigated in two test situations, which are presumed to involve dopamine (DA) transmission within the nucleus accumbens of the rat. Local injection of d-amphetamine sulphate (10 micrograms/0.5 microliter) produced a marked increase in motor activity, measured as motility, locomotion, and rearing, which was dose- and time-dependently antagonised by local injection of raclopride (0.05-5.0 micrograms/0.5 microliter). After an initial decrease, at low doses (0.05-0.25 microgram/0.5 microliter) an apparent enhancement of the d-amphetamine-induced motor activity appeared, which was most clearly seen with rearing. These lower doses, however, did not induce any clear changes in the exploratory activity in a novel environment (i.e., the second test situation). Only the higher doses used (1.0-5.0 micrograms/0.5 microliter) decreased exploratory activity during the first 5-10 min, also measured as motility, locomotion, and rearing. These data are discussed with respect to the role of D2-receptors within the nucleus accumbens of rats in the motor activity induced by a novel environment and d-amphetamine. Overall, the data underline previous notions that raclopride is a potent antagonist of DA-mediated behaviour.

Animals↗
PubMed1988

The nucleus accumbens and forelimb muscular rigidity in rats.

The present set of experiments were performed to evaluate the role of the nucleus accumbens in the regulation of forelimb muscle tone. Rats were chronically implanted with cannulae aimed at the nucleus accumbens or the neostriatum and with EMG electrodes in the triceps or the gastrocnemius soleus muscle. The experiments were all performed in non-anaesthetised freely moving animals. The results show that haloperidol induced an increase in triceps muscle tone when injected into the nucleus accumbens but not when injected into the neostriatum. Likewise it was found that haloperidol induced an increase in gastrocnemius soleus muscle tone when injected into the neostriatum but not when injected into the nucleus accumbens. The increase in triceps muscle tone seen after intra-accumbens haloperidol was only briefly attenuated by apomorphine, whereas phenylephrine produced a more long lasting antagonism. The present data show that in addition to the cortex, subcortical structures also appear to possess a certain topography, with forelimb rigidity being mediated, at least in part, by the nucleus accumbens, and hindlimb rigidity, at least in part by the neostriatum. In addition it appears that the effects of haloperidol in the nucleus accumbens on triceps muscle tone are primarily mediated by alpha 1 adrenergic receptors, although a minor role of dopamine D2 receptors cannot be fully excluded.

Animals↗
PubMed1988

The Paw test: an animal model for neuroleptic drugs which fulfils the criteria for pharmacological isomorphism.

Recently we have developed an animal model which could discriminate between classical and atypical neuroleptic drugs: the PAW TEST. This test measures the ability of rats to spontaneously withdraw its force- and hindlimbs. It was found that the ability of drugs to affect the rat's forelimb retraction time was associated with the liability of the drug to induce so-called extra-pyramidal side-effects in man. Likewise the ability of drugs to affect the rat's hindlimb retraction time was associated with the antipsychotic efficacy of the drug. These data open the perspective that the forelimb retraction time (FRT) is an animal analogue of parkinsonian side-effects, and that the hindlimb retraction time (HRT) is an animal analogue of antipsychotic effects In the present series of experiments we further evaluated the validity of these notions by applying the criteria of "pharmacological isomorphism" as proposed by Matthysse (1). Thus HRT had to fulfil the criteria of pharmacological isomorphism for the therapeutic effects of neuroleptics, whereas FRT had to fulfil these criteria for the parkinsonian side-effects. The results of the present study show that both FRT and HRT met these criteria. Thus both classical and atypical neuroleptics were effective in prolonging HRT, whereas only the classical neuroleptics prolonged FRT (criterion 1); the nonneuroleptic phenothiazine promethazine (as well as the narcotic morphine, the muscle relaxant diazepam and the antidepressant desipramine) were ineffective in this respect (criterion 2); the acetylcholinergic antagonist scopolamine blocked the FRT, but not the HRT (criterion 3); chronic neuroleptic treatment reduced the FRT, but not the HRT (criterion 4). In conclusion the paw test, an animal model for testing antipsychotic drugs, was found to fulfil the criteria for "pharmacological isomorphism". Although the exact mechanism underlying the paw test is as yet unknown, the present data improve its validity as an animal model.

Animals↗
PubMed1988

Behavioural correlates of a progressive dysfunctioning of the caudate nucleus: effects of apomorphine.

During the ontogeny of many mammalian species there exists a remarkable resemblance with respect to the strict order in the appearance of distinct motor patterns during development. Moreover, along a cephalocaudal gradient more and more body parts become involved in these motor patterns. The same sequence in motor behaviour can be observed when adult animals start to explore a novel environment. On the other hand, s.c. injections of apomorphine result in a reversed 'ontogenetic' sequence of motor patterns: a 'breakdown' of motor behaviour. The present study investigated whether striatal injections of apomorphine produced a reversed 'breakdown' of a motor pattern sequence. Therefore, cats were tested in a paradigm in which they executed sequences of distinct motor patterns in order to collect food pellets when walking on the belt of a treadmill. As only one of the motor patterns in the sequence is caudate-specific, disturbances at the level of the caudate nucleus as well as disturbances at the level of other brain structures can be distinguished. In contrast to 0.6 and 2.5 micrograms, doses of 5.0 and 10.0 micrograms of apomorphine resulted in the successive breakdown of motor pattern sequences, whereby not only caudate-specific motor patterns were reduced, but also non-caudate-specific motor patterns. Moreover, this regression appeared in the reversed order compared to the order in which distinct patterns are executed during eating behaviour. The regression in motor behaviour following 5.0 micrograms apomorphine was induced via caudate dopamine receptors since it could be prevented by pretreatment with haloperidol. Because of the fact that 5.0 and 10.0 micrograms of apomorphine also affected motor patterns which are not caudate- and dopamine-specific, it is concluded that also brain structures receiving (in)directly caudate output signals are involved in the regression of the motor pattern sequence as observed in the present study. The clinical relevance of the presented data is discussed.

Animals↗
PubMed1987

The paw test: a behavioural paradigm for differentiating between classical and atypical neuroleptic drugs.

An often used animal model based on the effects of neuroleptics on spontaneous behaviour is the catalepsy test. However, this test seems to be particularly insensitive to the atypical neuroleptics thioridazine and, especially, clozapine. We have therefore developed an alternative test, the paw test, which measures the ability of drugs to prevent the spontaneous withdrawal of fore- and hindlimbs in rats, and have compared this with the classical catalepsy test. The results show that: 1) the classical neuroleptic drugs haloperidol and chlorpromazine, the atypical neuroleptic drugs clozapine and thioridazine, the potential atypical neuroleptic drugs molindone and SCH 23390, and the potential classical neuroleptic drug metoclopramide are potent in increasing the hindlimb retraction time; 2) the paw test discriminates between classical neuroleptics which are equipotent in prolonging both the forelimb (FRT) and hindlimb retraction time (HRT) an atypical neuroleptics which are much more potent in prolonging HRT than in prolonging FRT; 3) the non-neuroleptic drugs desipramine, diazepam and morphine do not influence the variables measured in the paw test, although morphine does produce catalepsy; 4) Molindone as well as SCH 23390 behave like atypical neuroleptic drugs in the paw test. In comparison with the classical wood block catalepsy test, the paw test is shown to be superior for predicting the profile of the neuroleptics tested. Although more neuroleptics and non-neuroleptics have to be tested to determine whether false positives and false negatives do occur, we feel that the paw test might be an interesting animal model, because the increase in hindlimb retraction time was associated with the antipsychotic potential, whereas the increase in forelimb retraction time was associated with the potential to induce so-called extrapyramidal side effects.

Animals↗
PubMed1987

The nucleus accumbens and antidepressants: modulation of ergometrine-induced hyperactivity by typical and atypical antidepressants and neuroleptics in rats.

This study assesses the behavioural significance of the (-)sulpiride binding sites in the rat nucleus accumbens that bind antidepressants with high affinity and neuroleptics with low affinity. The effects were measured by intra-accumbens injections of typical and atypical antidepressants or neuroleptics, either given alone or in combination with ergometrine (1 microgram/0.5 microliter per side) on rat locomotor activity in a familiar environment. In addition, the after-effects of the combined ergometrine-drug treatment upon locomotor activity were analyzed. The antidepressants shared a common profile of effects. Thus, none of the antidepressants significantly altered locomotor activity in naive rats. Moreover, each antidepressant produced after-effects which were similar to those elicited in the acute ergometrine experiments. However, some antidepressants (amitriptyline and zimelidine) potentiated the ergometrine response, while other antidepressants (desipramine, mianserin and clorgyline) attenuated this response. (-)Sulpiride (0.5 microgram) decreased the ergometrine response when given together with ergometrine or 48 h earlier. Haloperidol had to be given in a dose that was 20 times higher than that of (-)sulpiride in order to be effective. Clozapine (1-10 micrograms) failed to alter the ergometrine response when given together with ergometrine. Only (-)sulpiride produced a dose-dependent attenuation of locomotor activity in naive rats. The present data are discussed in terms of the hypothesis that drugs with antidepressive effects mediate their behavioural effects via mesolimbic (-)sulpiride binding sites.

Amitriptyline↗
PubMed1987

The relationship between hindlimb disturbances, forelimb disturbances and catalepsy after increasing doses of muscimol injected into the striatal-pallidal complex.

To establish the role of the GABA-ergic mechanism within the striatal-pallidal complex in hindlimb disturbances, forelimb disturbances and catalepsy and the relationship between these phenomena, the effects of the locally injected GABA agonist muscimol (0.5 microliter per side) were investigated in rats using several specific tests of catalepsy. The time required for retracting free-hanging hindlimbs was dose-dependently prolonged by 2-10 ng muscimol. The time required for releasing a rod that was clasped between the forelegs of otherwise free-hanging rats was dose-dependently prolonged by 5-10 ng muscimol. Likewise, the time required for retracting the free-hanging forelimbs was dose-dependently prolonged over the same dose range. Finally, the time during which standing rats kept their forelimbs on a block of 9 cm height (the dependent variable used in "classic" tests of catalepsy) was only prolonged at the highest dose (10 ng) of muscimol. The effects of the latter dose, which lasted at least 30 min, were inhibited by the GABA antagonist bicuculline (50 ng) for a minimum period of 5 min. The present data show that the GABA-ergic mechanisms within the striatal-pallidal complex are involved in hindlimb disturbances, forelimb disturbances and catalepsy, and that catalepsy requires a stronger dysfunctioning of these GABA-ergic mechanisms than do disturbances in hindlimbs and forelimbs.

Animals↗
PubMed1987

Spasmodic torticollis: the problem of pathophysiology and assessment.

In 17 patients with idiopathic spasmodic torticollis (ST) quantitative indices for both signs (extent and direction of the head deflexions) and complaints (of deflexion, shaking and pain) were collected. In the literature deflexion in the horizontal plane is most frequently considered, but analysis of the data shows that deflexion in the coronal and sagittal planes is also important. Furthermore, it is found that especially the deflexions in the coronal and sagittal plane covariate with the patients' complaints, but not with horizontal deflexion. On the basis of these and related data, it is suggested that we are dealing with at least two subtypes of ST. Finally, the patient's neuroticism and depression scale values are within the normal range and do not show significant correlations with ST duration. The present study provides no evidence that ST is a psychogenic disorder. ST should be regarded as a central nervous system disorder of unknown aetiology.

Adult↗
PubMed1987

A parametric analysis of human saccades in different experimental paradigms.

In this paper we report on human saccade dynamics in three different experimental paradigms: visual target, remembered target and anti-saccade task. We found that saccades to remembered targets and anti-saccades have strongly reduced peak velocities coupled with markedly increased durations. In addition we observed a considerable degree of asymmetry in the velocity profiles of these saccades. By using gamma functions to describe the shape of the velocity profiles a parameter characterizing the degree of asymmetry (skewness) was computed: it was found that skewness increases with saccade amplitude. Due to the large variability in saccade durations for any given amplitude in our data we could confirm the recent claim, based on pharmacologically induced slow saccades, that skewness is more tightly related to duration than to amplitude. The duration/skewness relationship appeared to be nearly invariant with saccade type. We conclude that the commonly used main-sequence description of saccades is incomplete and can be extended usefully by including skewness. The possible neural basis of the task-related differences in saccade properties and their implications for models of the saccadic system are discussed. It is suggested that the marked differences in dynamic properties among different saccade types may reflect processes in the visuomotor rather than in the motor system.

Adult↗
PubMed1987

Mesolimbic noradrenaline: specificity, stability and dose-dependency of individual-specific responses to mesolimbic injections of alpha-noradrenergic agonists.

The ability of intra-accumbens phenylephrine (PE) and oxymetazoline to potentiate the 'explosive motor behaviour' (EMB) elicited from the deeper layers of the superior colliculus by picrotoxin injections was examined in Wistar rats. Using a dose of intracollicular picrotoxin that was 10 ng lower than the threshold dose for generating EMB, evidence was obtained for the selective potentiation of EMB by alpha-noradrenergic agonists. The PE-induced potentiation was prevented by phentolamine given 48 h prior to PE. Damage caused by multiple injections of intra-accumbens PE prevented the PE-induced effect. It is concluded that the PE-induced effect is accumbens- and noradrenaline-specific. When rats were injected with intervals of 48 h or more, two types of rats could be discerned: responders, i.e. rats that consistently displayed EMB during all trials, and non-responders, i.e. rats that never displayed EMB. When the intertrial interval was 24 h, responders became temporary non-responders, and vice versa. This temporary change in sensitivity was found to be a drug-induced after-effect. The dose-dependency of the PE-induced after-effect in responders differed significantly from that in non-responders. It is concluded that rats belonging to the same strain are nevertheless marked by an individual-specific, neurochemical state within the nucleus accumbens. It is tentatively suggested that responders are marked by noradrenergic neurones with a low firing rate in contrast to non-responders which are marked by noradrenergic neurones with a high firing rate. Finally, evidence was obtained that ergometrine and (3,4-dihydroxyphenylamino)-2-imidazoline (DPI) act simultaneously at dopaminergic sites which are involved in the control of locomotor activity in a familiar environment and at alpha-noradrenergic sites which are involved in the control of EMB elicited from the superior colliculus.

Animals↗
PubMed1986

The colliculus superior modulates ACTH-induced excessive grooming.

In previous studies the involvement of nigrostriatal dopaminergic activity in ACTH(1-24)-induced grooming has been established. It was suggested that the dopaminergic modulation of ACTH(1-24)-induced excessive grooming is exerted through the striato-nigro-collicular pathway. To obtain further evidence it was investigated, whether local application of GABAergic agents into the colliculus superior modulates excessive grooming occurring after an intraventricular injection with ACTH(1-24). It appeared that intra-collicular picrotoxin (a GABAergic antagonist) suppressed ACTH-induced grooming, whereas muscimol (a GABAergic agonist) enhanced the grooming response. The picrotoxin-induced R(unning) F(it) B(ehavior), elicited from the colliculus superior was also seen after intraventricular administration of picrotoxin. A detailed comparison of this behavioral response seen after both routes of administration of picrotoxin suggests that intraventricularly injected picrotoxin may well induce the RFB via a direct effect on the colliculus superior. Lesions placed in the colliculus superior completely abolished picrotoxin-induced RFB, exploration and orientation behavior. Yet, these lesions did not reduce excessive grooming suggesting that although this region may be involved in the modulation of ACTH-induced grooming it is not the primary site of peptide action.

Adrenocorticotropic Hormone↗
PubMed1986

Differential effects of striatal injections of dopaminergic, cholinergic and GABAergic drugs upon swimming behavior of rats.

The present study provides a detailed report about similarities and dissimilarities between the effects of neostriatally applied dopaminergic (apomorphine, 250-300 ng; haloperidol, 250-500 ng), cholinergic (carbachol, 50-100 ng; scopolamine, 200-500 ng), and GABAergic (muscimol, 1-2 ng; bicuculline, 5-35 ng) drugs upon swimming of rats. The used swimming test consisted of 4 parts: (a) open-field test for analyzing drug-induced changes in normal behavior; (b) 'swimming without escape' test for analyzing drug-induced changes in the ability to switch from one type of behavior to another; (c) 'swimming with escape' test for analyzing drug-induced changes in the ability to switch from ongoing swimming behavior to climbing behavior by allowing the rats to escape via a rope; and (d) 'rope' test for analyzing drug-induced changes in the kind of contact behaviors needed to switch to the latter climbing behavior. In the open-field test the drugs produced neither abnormal behavior nor motor disturbances, which prevented the display of normal behavior in the remaining tests. Both apomorphine and carbachol produced identical effects in all tests. Muscimol produced overall effects which were not only opposite to those of apomorphine and carbachol, but also comparable to those of scopolamine. All effects elicited by apomorphine, carbachol and muscimol were antagonized by their corresponding antagonists: haloperidol, scopolamine and bicuculline respectively, whereas the effects of the latter were suppressed by their corresponding agonists. These data globally show that dopamine and acetylcholine act in the same direction but opposite to that of GABA as far as it concerns the regions investigated. The finding that haloperidol injected into the GABA target area produced effects which were not only similar to those of haloperidol injected into the dopamine target area, but also dissimilar to those of muscimol and bicuculline injected into the GABA target area, shows that the effects were drug-specific rather than region-specific. Though 3 distinct cholinergic regions were investigated, cholinergic-specific effects could only be elicited from one region, suggesting that the neostriatum is heterogeneous in this respect. Finally, well-delineated dissimilarities between haloperidol-, scopolamine-, and muscimol-treated rats were found in the rope test. These data show that behavior-relevant information transmitted by GABAergic drugs surmounted that transmitted by cholinergic drugs which, in turn, surmounted behavior-relevant information transmitted by dopaminergic drugs.

Acetylcholine↗
PubMed1986

Dopaminergic modulation of ACTH-induced grooming.

ACTH-(1-24)-induced grooming was studied after administration of the peptide into the substantia nigra or intracerebroventricularly (i.c.v.). The modulation of dopamine receptors in neostriatum (with haloperidol and apomorphine) and nucleus accumbens (with 3,4-dihydroxyphenylamino-2-imidazoline hydrochloride; DPI and ergometrine) was investigated. In the nucleus accumbens, the modulatory effects of ergometrine and DPI on ACTH-(1-24)-induced grooming were based on their affinity for dopamine receptors and not on their affinity for adrenoceptors. Intrastriatal application of dopaminergic agents inhibited i.c.v. ACTH-(1-24)-induced excessive grooming, whereas the grooming score was enhanced if ACTH-(1-24) was administered into the substantia nigra. The finding of differential effects of dopaminergic agents on ACTH-induced excessive grooming depending on the route of administration indicate that i.c.v. ACTH-induced excessive grooming is not mediated solely through the substantia nigra. The increase in grooming behavior seen after the intrastriatal administration of dopaminergic agents - when ACTH was injected into the substantia nigra - suggests the involvement of the striato-nigral GABAergic pathway. Local injections of ACTH-(1-24) into the periaqueductal gray also induced excessive grooming. Since a second injection of ACTH-(1-24) into the periaqueductal gray did not lead to a grooming response, irrespective of where the first injection of ACTH-(1-24) was given (i.c.v. into the nigra or via the periaqueductal gray) it is suggested that this structure seems to play a primary role in the induction of excessive grooming. Therefore the modulatory effects of the dopaminergic influence on ACTH-(1-24)-induced grooming may be exerted via the striato-nigro-collicular pathway.

Adrenocorticotropic Hormone↗