Biomedical subjects

A R Cools

Publications and source records attributed to A R Cools.

At least 127 records · Page 7Linked to original sources

PubMed1995

Card sorting performance in Parkinson's Disease: a comparison between acquisition and shifting performance.

In the present study we tested the hypothesis that learned irrelevance underlies the frequently observed poor performance of Parkinson's disease (PD) patients on card sorting tests. If learned irrelevance accounts for the poor performance of PD patients on card sorting tests, PD patients and control subjects (CS) will not differ in the acquisition phase, during which basic concept formation is assessed, but they will differ in the subsequent shifting phases. We presented three distinct card sorting tests with an identical format to 51 PD patients and 24 normal controls. The groups did not differ with respect to intelligence, memory, or attention. PD patients showed a slightly better performance in the acquisition phase. In the first shifting phase, the performance of PD patients was significantly poorer than that of control subjects after correction for basic concept formation. In the second shifting phase this difference disappeared. We conclude that learned irrelevance does not account for the poor performance of PD patients in card sorting tests. The results are discussed in terms of self-generation of problem solving strategies.

Age of Onset↗

PubMed1995

Corticosteroid feedback resistance in rats genetically selected for increased dopamine responsiveness.

Pharmacogenetically selected Wistar rat lines were used to investigate the implication of either high or low responsiveness of the dopamine system for the activity of the hypothalamus-pituitary-adrenal (HPA) axis. As selection criterion the gnawing response induced by the dopamine agonist apomorphine was used. This criterion allows to distinguish apomorphine susceptible (apo-sus) rats which show a vigorous gnawing response from apomorphine unsusceptible (apo-unsus) rats. The present study, using male animals of the 9-12th generation of the two rat lines, revealed the following characteristics of the stress response system: (i) in apo-sus rats under basal conditions corticotrophin-releasing hormone (CRH) mRNA level in the paraventricular nucleus (PVN) and plasma adrenocorticotropin (ACTH) concentration were significantly higher; total corticosterone (B) plasma level was similar but free B level was lower; (ii) exposure to a novel environment resulted in a higher and prolonged plasma ACTH and total B response in the apo-sus rats. Moreover, the elevated free B level was also prolonged; (iii) apo-sus rats had increased CRH-induced pituitary ACTH release and B secretion was also increased, but not as prolonged as during novelty. (iv) In dexamethasone-pretreated rats an intravenous ACTH1-24 injection resulted in a similar plasma B response in rats of both lines; (v) In vitro, ACTH1-24 produced a significantly higher B secretion by adrenocortical cells of apo-sus rats reflecting the higher in vivo ACTH priming of the adrenal glands in these animals. (vi) apo-sus rats had higher body and thymic weight.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex Hormones↗

PubMed1995

The behavior of APO-SUS rats in animal models with construct validity for schizophrenia.

Schizophrenic patients are known to suffer from a number of information processing disturbances, including deficits in both prepulse inhibition of startle and latent inhibition. Since these behavioral phenomena can also be observed in animals, they represent an ideal starting point for developing animal models having construct validity for specific deficits observed in schizophrenia. The principal question is how to induce a condition in animals most similar to the schizophrenic deficit. In the present study, we have selected rats on the basis of their response to an open filed or to the dopaminergic agonist apomorphine, and evaluated their prepulse inhibition and latent inhibition. We used three different selection procedures (open field selection for novelty response, gnawing cage selection for apomorphine response, and pharmacogenetic selection for apomorphine response). The results show that, irrespective of the selection procedure used, rats with a high response to novelty or apomorphine susceptible (collectively called APO-SUS rats) show diminished prepulse inhibition of the acoustic startle response as compared to rats with a low response to novelty or apomorphine unsusceptible (collectively called APO-UNSUS rats). This difference was apparent only at low prepulse intensities. Moreover, these APO-SUS rats show diminished latent inhibition in a conditioned taste aversion paradigm as compared to APO-UNSUS rats. Given the fact that the pharmacogenetically bred APO-SUS rats show several central nervous, endocrinological, and immunological similarities to schizophrenic patients, they are hypothesised to represent an interesting nonpharmacological animal model for schizophrenia-prone patients.

Animals↗

PubMed1994

Clozapine injected into the nucleus accumbens potentiates apomorphine-induced jaw movements.

The effects of clozapine injected into the nucleus accumbens on apomorphine-induced jaw movements were studied. Jaw movements induced by apomorphine (0.5 mg/kg i.v.) were potentiated by clozapine (10 micrograms/0.2 microliters) injected into the nucleus accumbens 10 min before apomorphine. Enhancement of the apomorphine-induced jaw movements was also found with the muscarinic acetylcholine receptor antagonist, methylscopolamine (2.5 micrograms), whereas the acetylcholine receptor agonist, carbachol (2.5 micrograms), inhibited the effects of apomorphine. Injection of a smaller dose of carbachol (0.1 microgram) alone into the nucleus accumbens 10 min before failed to alter the effects of apomorphine but prevented the potentiation induced by clozapine. Both the 5-hydroxytryptamine(5-HT)2A receptor antagonist, 2-(2-dimethylaminoethylthio)-3-phenylquinoline hydrochloride (ICI 169,369, 0.1 and 0.2 microgram), and the alpha 1-adrenoceptor antagonist, prazosin (0.05 and 0.2 microgram), failed to affect the effects of apomorphine(0.5 mg/kg i.v.). In contrast, clozapine (1, 5 and 10 micrograms), ICI 169,369 (0.1 and 0.2 microgram) or prazosin (0.05 and 0.2 microgram) given into the ventral striatum inhibited the effects of apomorphine (0.5 mg/kg i.v.). It is suggested that the clozapine-induced potentiation in the nucleus accumbens might be due to its antimuscarinic properties.

Analysis of Variance↗

PubMed1994

Combined antagonism of adrenoceptors and dopamine and 5-HT receptors underlies the atypical profile of clozapine.

Previous studies have shown that alpha 1-adrenoceptors, dopamine D1-like and 5-HT2A receptors play an important role in the effects of the atypical neuroleptic, clozapine, on the parameter modelling antipsychotic efficacy in the paw test. Therefore, it became of interest to investigate whether antagonism of all these receptors together would give rise to effects characteristic of clozapine. The effects of the combined administration of the alpha 1-adrenoceptor antagonist phenoxybenzamine, the dopamine D1 receptor antagonist, SCH 39166 (4-(4-chloro-3-methoxyphenyl)-1,2- dihydronaphthalene), and the 5-HT2A receptor antagonist, ketanserin, were therefore measured in the paw test. The present data show that all three drugs together, but not simply combinations of two out of three, produced a profile similar to that of clozapine: a significant increase in the parameter modelling antipsychotic efficacy and no change in the parameter modelling extrapyramidal side-effects.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed1994

The role of serotonin receptor subtypes in the behavioural effects of neuroleptic drugs. A paw test study in rats.

The present study was designed to evaluate the roles of serotonin 5-HT1A and 5-HT2 receptors in the effects of neuroleptic drugs in the paw test. This behavioural test has been shown to model both the antipsychotic efficacy as well as the extrapyramidal side-effect liability of neuroleptic drugs. Whereas the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT) reduced the effects of the classical neuroleptic haloperidol, it increased the effects of the atypical neuroleptic clozapine. The 5-HT2 receptor antagonist ketanserin as well as the 5-HT1C/5-HT2 receptor antagonist ritanserin, on the other hand reduced the effects of haloperidol, whereas the 5-HT1C/5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) reduced the effects of clozapine. The most important finding, however, was that the behavioural effects of different (putative) neuroleptics (fluphenazine, SCH-39166, remoxipride, prothipendyl, thioridazine and risperidone) were differentially influenced by both 8-OHDPAT and DOI, suggesting that there are important differences between the neuronal mechanisms underlying the behavioural effects of these neuroleptic drugs, even within the subclasses of classical and atypical neuroleptics.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1994

Memory and learning strategies in patients with Parkinson's disease.

Parkinson's disease patients (PD) do not differ from control subjects (CS) when they have to execute a problem solving task in which external cues for solving the problem are given. However, when PD have to solve a problem by means of an internally generated strategy, they show a serious decrease in performance. We hypothesised that this distinction may also apply to the way PD and CS organize recall. In order to test our hypothesis the California Verbal Learning Test (CVLT) was administered to 59 PD and 30 CS. The test consists of five learning trials using a 16-word target list, composed of four items from each of four semantic categories. The fact that the word list was built on this implicit organization was not divulged in advance. The sequence in which the words were read is fixed; each subsequent word belongs to a category being different from the category to which the preceding word belongs. The organization in recall according to the semantic categories is considered to be the result of an unprompted, internally generated strategy. Recall according to the sequence in which the words are read by the experimenter, is viewed as an externally offered strategy. The results prove to be in line with our hypothesis: unlike CS who appeared to rely mainly and increasingly on an internally generated semantic organization, PD showed evidence of gradually adhering more to the externally imposed serial sequence.

Aged↗

PubMed1994

Spatial localization in the Morris water maze in rats: acquisition is affected by intra-accumbens injections of the dopaminergic antagonist haloperidol.

Previous studies (G. E. Ploeger, B. M. Spruijt, & A. R. Cools, 1992) showed that low doses of systemically injected haloperidol affected spatial learning in the Morris water maze. This study investigated effects of intra-accumbens injections of haloperidol on spatial learning. To control for motivation and sensorimotor coordination, the researchers trained the rats to escape onto a visible platform. Low doses (50-100 ng) of haloperidol impaired spatial learning, whereas escaping on a visible platform was undisturbed. The 500-ng dose of haloperidol completely blocked acquisition because of combined learning and motor impairments. Retrieval of an acquired escape response was unaffected by 500 ng haloperidol. The data show that mesolimbic dopaminergic activity is involved in the acquisition of spatial localization. The results are related to studies demonstrating the involvement of the nucleus accumbens in cue-directed behaviors.

Animals↗

PubMed1994

Susceptibility to adjuvant arthritis: relative importance of adrenal activity and bacterial flora.

Previous studies on the regulation of bacterial-induced arthritis in rats have focused on endocrine aspects as well as differences in T cell immunity against bacterial epitopes. We analysed the role of both adrenal activity and bacterial flora in determining susceptibility to bacterial-induced arthritis. Outbred Wistar rats show a low incidence of adjuvant arthritis. Moderate sensitivity to adjuvant arthritis was found in a selected, stress-resistant line of the Wistar rat, whereas no arthritis was found in a stress-susceptible Wistar line. Plasma corticosterone responses after IL-1 alpha exposure were, however, identical in these two lines, excluding a direct correlation between susceptibility and corticosterone levels. In line with previous findings in germ-free (GF) F344 rats, GF Wistars also appeared highly susceptible to arthritis. We further analysed the corticosterone responses in GF and conventional (CV) rats. Administration of IL-1 alpha induced identical corticosterone responses in both CV and GF F344 rats. In addition, plasma corticosterone levels were measured around the time of onset of arthritis. Whereas no rise was seen in the arthritis-resistant CV rats, a significant increase was observed from day 14 in GF rats, at the moment of onset of arthritis. Although this corticosterone response was insufficient to prevent arthritis, it may have ameliorated disease expression in the GF F344 rats. Our data indicate that the bacterial flora, and therefore T cell tolerance, is of prime importance in determining susceptibility, whereas the activity of the hypothalamus-pituitary-adrenal (HPA) axis may modulate disease severity.

Adrenal Glands↗

PubMed1994

Peripheral and central adrenoceptor modulation of the behavioural effects of clozapine in the paw test.

1. In rats, the atypical neuroleptic, clozapine, has been found to increase the hindlimb retraction time but not the forelimb retraction time, in the paw test. These parameters have predictive validity for the antipsychotic efficacy and extrapyramidal side-effects of drugs, respectively. The present study analysed to what extent drugs acting on adrenoceptors affect the behavioural effect of clozapine in the paw test. 2. The alpha 1-adrenoceptor agonist, ST 587 but not the peripherally working alpha 1-agonist, methoxamine, decreased the effect of clozapine on the hindlimb retraction time. The alpha 1-antagonist phenoxybenzamine increased this effect of clozapine, and blocked the effect of ST 587 on clozapine at low doses. Only the combination of phenoxybenzamine with clozapine produced an increase in forelimb retraction time. 3. The alpha 2-adrenoceptor agonist, clonidine, decreased the effect of clozapine on the hindlimb retraction time. This effect was neither antagonized by the alpha 2-antagonist rauwolscine nor by the alpha 1-antagonist phenoxybenzamine. Rauwolscine or the peripherally working alpha 2-antagonist L-659,066 did not influence the effect of clozapine on the hindlimb retraction time. The forelimb retraction time was not affected by any of the drug combinations. 4. In contrast to the beta 2-adrenoceptor agonist, clenbuterol, which was ineffective, the peripherally acting beta-agonist, (-)-isoprenaline, increased the effects of clozapine on the hindlimb retraction time. The beta-antagonist, (-)-propranolol as well as the peripherally acting beta-antagonist, nadolol decreased this effect of clozapine. Low doses of the peripherally acting beta 1-antagonist, atenolol, as well as low doses of the beta2-antagonist, ICI-118,551, decreased the effect of clozapine. A low dose of nadolol blocked the effect of (-)-isoprenaline on clozapine. Only the combination of clenbuterol with clozapine produced an increase in forelimb retraction time.5. It is concluded that blockade of central alpha l-adrenoceptors plays an important role in the effect of clozapine on the hindlimb retraction time. Furthermore, the effect of clozapine on the hindlimb retraction time is strongly modulated by peripheral beta 1- and/or beta 2-adrenoceptors. Given the predictive validity of the paw test, the presented data suggest that the alpha 1-adrenoceptor antagonist properties of clozapine are important for its therapeutic effects, but not for its lack of extrapyramidal side-effects.

Adrenergic alpha-1 Receptor Agonists↗

PubMed1994

Influence of the noradrenergic state of the nucleus accumbens in basolateral amygdala mediated changes in neophobia of rats.

High responders (HR) and low responders (LR) to novelty coexisting in a normal Wistar rat population were used to examine the effects of combined noradrenergic injections into the basolateral amygdala (BLA) and nucleus accumbens (ACC) on gustatory neophobia in a novel environment. During novelty, HR were marked by a high and LR by a low functional noradrenergic activity in ACC. Water-treated HR and LR mostly consumed familiar rat chow, indicating a high level of neophobia. The effects of BLA injections with noradrenergic agents differed completely between rat types. Propranolol, a beta-adrenergic antagonist, reduced neophobia in HR, but was ineffective in LR, whereas the respective agonist isoproterenol decreased neophobia only in LR. Subsequent ACC injections of noradrenergic agents modulated the effects of the noradrenergic BLA injections on neophobia in line with the theory of amygdala-accumbens gating of information (A. R. Cools, R. Van den Bos, G. Ploeger, & B. A. Ellenbroek, 1991).

Amygdala↗

PubMed1994

Evidence for a role of the shell of the nucleus accumbens in oral behavior of freely moving rats.

Behavioral effects of intra-accumbens administration of the dopamine DAi receptor agonist (3,4-dihydroxyphenylimino)-2-imidazoline (DPI) were studied in freely moving rats. Three distinct areas were examined: core, shell and "shore," namely, the border region of the core and shell. DPI (5 micrograms) administered into the shell, but not areas ventral to the shell, increased chewing, tongue protrusion, sniffing, and grooming; it also induced abnormal oral behavior, namely, large-amplitude chewing. A similar dose of DPI administered into the core did not affect any (peri-)oral behavior, except sniffing. Because of methodological constraints the receptor specificity of the DPI effects was studied in rats with cannulas directed at the shore. DPI (5.0-10.0 micrograms) administered into the shore increased oral behavior dose dependently; however, the dose-effect curve varied per distinct type of oral behavior. The dopamine DAi receptor antagonist ergometrine attenuated the effect of DPI on tremor, chewing, and sniffing frequencies. Taken together, the data show that the effects of DPI were DAi receptor specific. It is concluded that stimulation of dopamine DAi receptors in the shell modulates and induces (peri-)oral behaviors in freely moving rats.

Analysis of Variance↗

PubMed1993

Apomorphine-susceptible and apomorphine-unsusceptible Wistar rats differ in novelty-induced changes in hippocampal dynorphin B expression and two-way active avoidance: a new key in the search for the role of the hippocampal-accumbens axis.

The present study examines two characteristic traits of the hippocampus in apomorphine-susceptible (APO-SUS) and apomorphine-unsusceptible (APO-UNSUS) Wistar rat lines. Since hippocampal mossy fibers contain among others dynorphin B as transmitter, a radioimmunoassay was used to analyze the hippocampal dynorphin B expression in response to novelty in these lines. Dynorphin B expression at the end of the baseline condition was greater in APO-SUS rats than in APO-UNSUS rats, while exposure to novelty decreased and increased the dynorphin B expression in APO-SUS and APO-UNSUS rats, respectively. These interline differences in dynorphin B expression could be due to (a) an interline difference in the size of the mossy fiber terminal fields, (b) an interline difference in the regulation of the firing rate of mossy fibers by corticosteroids, and/or (c) an interline difference in the release of corticosteroids in response to novelty. Since the size of the mossy fiber infra/intrapyramidal terminal field is inversely related to two-way active avoidance performance, APO-SUS and APO-UNSUS rats (n = 9 per line) were given this task: APO-UNSUS rats performed much better than APO-SUS rats. It is concluded that the neurochemical and behavioural function of the hippocampus significantly differs between lines. Given the already known interline differences in the function of the nucleus accumbens, the present results provide a new avenue in search for the functional relationship between the hippocampus and the nucleus accumbens.

Animals↗

PubMed1993

Involvement of the nucleus accumbens in oral behaviour in the freely moving rat.

The role of the nucleus accumbens in oral behaviour was examined by intra-accumbens injections of a single dose of a selective dopamine D1 receptor agonist (SKF 38393: 5 micrograms/side), a selective dopamine D2 receptor agonist (quinpirole: 10 micrograms/side), and their combination in freely moving rats. Principal factor analysis revealed four factors to be involved in the scored behaviours, two of which concerned oral behaviour: a chew factor, comprising the behaviours chew, tongue protrusion, yawn and lick, and a groom factor, with high factor loadings of tremor and groom. The two remaining factors were the circle factor comprising circle, walk and rear, and the sniff factor comprising sniff, yawn and rear. Two-way ANOVA (independent variable D1 with H2O and SKF 38393 level; independent variable D2 with H2O and quinpirole level) of the factor scores revealed that SKF 38393 and quinpirole had similar or opposite effects which were additive or antagonistic, depending on which behaviour was studied. This study demonstrates that (a) the nucleus accumbens plays a major role in the oral behaviour of freely moving rats, and (b) an integrated study of all oral behavioural elements is necessary to describe the effects of drugs on oral behaviour.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1993

The effects of haloperidol and raclopride in the paw test are influenced similarly by SCH 39166.

We investigated the role of dopamine D1 and D2 receptors in the paw test, an animal model used to assess both the antipsychotic potential and extrapyramidal side effects of drugs. The dopamine D1 receptor antagonist, SCH 39166, as well as the dopamine D2 receptor antagonist raclopride, increased the hindlimb retraction time (HRT), viz. a parameter that models antipsychotic potential, at doses that were lower than those that increased the forelimb retraction time (FRT), viz. a parameter that models extrapyramidal side effects. In contrast, the same dose of haloperidol enhanced both parameters. SCH 39166 enhanced the haloperidol- and raclopride-induced effects on FRT, whereas neither haloperidol nor raclopride enhanced the SCH 39166-induced effects upon this parameter. Except at very high doses, SCH 39166 did not alter the haloperidol- and raclopride-induced effects on HRT, and vice versa. No difference between haloperidol and raclopride was found in the interaction experiments. The clinical impact of these findings is discussed.

Animals↗

PubMed1993

Descending efferent connections of the sub-pallidal areas in the cat: projections to the subthalamic nucleus, the hypothalamus, and the midbrain.

The efferent connections of the sub-pallidal regions to the mediodorsal thalamic nucleus, the subthalamic nucleus, the lateral hypothalamic area, and the midbrain were investigated in the cat, using Phaseolus vulgaris--leucoagglutinin (PHA-L) as an anterograde label. The results indicate that the sub-pallidal regions of the cat project to the (dorso)medial tip of the subthalamic nucleus and the adjoining lateral hypothalamic area as well as to the ventral tegmental area and the greater extent of the dorsolateral tier of the substantia nigra pars compacta. Extensive projections were also found to the peripeduncular nucleus. The central gray as well as the mesencephalic locomotor region receive some input from the basal forebrain too. In contrast only very limited projections were found to the mediodorsal thalamic nucleus. The results are discussed in view of the possible role of these output regions in oro-facial dyskinesia.

Animals↗

PubMed1993

Cognitive shifting as a predictor of progress in social understanding in high-functioning adolescents with autism: a prospective study.

Although striking and pervasive failure of social understanding is commonly viewed as a major defining characteristic of people with autism, few follow-up reports were published that have focused on improvement of social intelligence. In this prospective study in which 17 high-functioning adolescents with autism were involved, cognitive shifting as measured by card sorting tests, unlike overall intelligence, was shown to be the only significant factor in predicting progress in social understanding as assessed by social comprehension tests. A pretest-posttest design was used. During the 2-year follow-up all the subjects were in residential care and enrolled in educational curricula focusing on the development of social intelligence, living, and vocational skills.

Adolescent↗

PubMed1993

Impaired cognitive shifting in parkinsonian patients on anticholinergic therapy.

In this study we established that cognitive shifting, an ability that is known to be affected in PD, is more impaired in PD patients, treated with anticholinergics, than in de novo patients. Eleven PD patients on anticholinergic monotherapy were compared with 30 de novo patients. The groups did not differ with respect to age, duration and severity of PD, and depression, nor with respect to general intelligence or attention. We assessed cognitive shifting with three different card-sorting tests. The patients on anticholinergics showed a poorer performance on all card-sorting tests than the de novo patients did. The patients on anticholinergics needed significantly more trials in two card-sorting tests and discovered significantly less categories in total. There was also a significant difference in memory performance, but memory performance did not correlate with any score on the card-sorting tests. This indicates that the performance on card-sorting tests and the memory performance were independent.

Aged↗