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Biomedical subjects

A R Cools

Publications and source records attributed to A R Cools.

At least 73 records · Page 4Linked to original sources
PubMed1999

6-hydroxydopamine lesion in the A8 cell group of cats produces a short-lasting decreased accuracy in goal-directed forepaw-movements.

Recently, feline studies have shown that a lesion in the retrorubral area, which includes the dopaminergic A8 cell group, produces motor programming deficits inherent to a hypofunction of the A9 system. A hypofunction in the striatal terminal area of A9 fibers, in turn, is known to produce a hypofunction of its first-order output station, namely the substantia nigra pars reticulata (SNR). The integrity of the SNR allows animals to execute (1) 'postural adjustments that rely on proprioceptive stimuli that originate in body parts at rest' and (2) 'non-externally guided' targeting movements. In view of these considerations, the (dys)function of the SNR of cats with a bilaterally 6-hydroxydopamine lesion of A8 cells in the retrorubral area was tested in an experimental set-up that allows the assessment of changes in these functions. The A8 lesion produced: (a) a short-lasting increase in the number of accurate targeting movements as well as an increase in the time required for the collection of six pellets: these deficits disappeared 4-7 days after the lesion; (b) a long-lasting disappearance of (1) 'postural adjustments that rely on proprioceptive stimuli that originate in body parts at rest' and (2) 'non-externally guided targeting movements'; and (c) a long-lasting display of a new strategy that allowed the lesioned cat to collect its pellets despite of its other deficits. These data led to the conclusion that a lesion of A8 cells even disrupts the function of the SNR, being one of the outputstations of the A8 cell group.

Animals↗
PubMed1999

High and low responders to novelty: effects of a catecholamine synthesis inhibitor on novelty-induced changes in behaviour and release of accumbal dopamine.

The purpose of the present study was two-fold: (i) to investigate to what extent novelty, i.e. a novel cage with slightly larger dimensions than the home cage and lacking the floor covering that was originally present, produced behavioural effects in high responders to novelty and low responders to novelty that could be correlated with the extracellular amount of accumbal dopamine, using the microdialysis technique, and (ii) to establish the ability of the catecholamine synthesis inhibitor alpha-methyl-p-tyrosine to inhibit the novelty-induced responses in high and low responders. The difference in the behavioural response to novelty between the high and low responders was limited to walking, which lasted significantly longer in high responders than in low responders. The novelty-induced increase in extracellular concentration of accumbal dopamine was significantly greater in high responders than in low responders; moreover, the shape of the growth curves differed between high and low responders. The behavioural changes did not correlate with the neurochemical effects, which outlasted the duration of the novelty-induced behavioural arousal. It is hypothesized that this long-lasting increase in accumbal dopamine produces "adaptive changes" that help and/or allow the animal to incorporate knowledge about the condition that it experienced. When the nucleus accumbens was perfused with alpha-methyl-p-tyrosine for a period of 40 min, given at the same time as the transfer of the rat to the novel cage, it reduced the novelty-induced increase in walking in the high responders, but did not alter the novelty-induced behaviour of low responders. Finally, alpha-methyl-p-tyrosine reduced the novelty-induced increase in the release of accumbal dopamine in high responders, but enhanced it in low responders. The present neurochemical data are discussed in view of the outcome of earlier reported pharmacobehavioural studies on the neurochemical state of the nucleus accumbens of non-challenged versus challenged high and low responders. It is hypothesized that, in the high responder, exposure to novelty enhances the release of accumbal dopamine from reserpine-resistant, alpha-methyl-p-tyrosine-sensitive pools that are under the stimulatory control of beta-adrenergic receptors in the nucleus accumbens, and that, in the low responder, exposure to novelty enhances the release of accumbal dopamine from reserpine-sensitive, alpha-methyl-p-tyrosine-resistant pools that are under the inhibitory control of alpha-adrenergic receptors in the nucleus accumbens.

Animals↗
PubMed1999

Fentanyl increases dopamine release in rat nucleus accumbens: involvement of mesolimbic mu- and delta-2-opioid receptors.

The effects of the mu-receptor agonist fentanyl on extracellular levels of dopamine in rat nucleus accumbens were studied in awake animals by in vivo brain microdialysis. Fentanyl dose-dependently increased the levels of dopamine when given intravenously (microg/kg) or via a microdialysis probe placed into the ventral tegmental area or the nucleus accumbens (nmol). The effect of fentanyl given into the nucleus accumbens was blocked by systemic administration of the non-selective opioid receptor antagonist naloxone and by accumbens administration of D-Phe-Cys-Tyr-D-Trp-Om-Thr-Phe-Thr-NH2 (nmol), a mu-opioid receptor antagonist, and naltrindole (nmol), a non-selective delta-opioid receptor antagonist, in a dose-dependent manner. The delta2-opioid receptor antagonist, naltriben (nmol), also blocked the effects of fentanyl, whereas the delta1-opioid receptor antagonist, (E)-7-benzylidenenaltrexone (nmol), was ineffective. When marginally effective doses of D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH2 and naltriben were given simultaneously, the effect of fentanyl was nearly fully blocked; the pretreatment itself had no effect. Administration of the mu-opioid receptor agonist [D-Ala2, N-Me-Phe4,Gly5-ol]-enkephalin (nmol), the delta1-opioid receptor agonist [D-Pen2,5]-enkephalin (nmol) or the delta2-opioid receptor agonist [D-Ala2,Glu4]-deltorphin (nmol) into the nucleus accumbens enhanced the amount of accumbal dopamine. This study provides evidence that not only activation of delta1- and delta2-opioid receptors, but also activation of mu-opioid receptors in the nucleus accumbens increases the release of accumbal dopamine in freely moving rats. We suggest that the effect of intra-accumbens administration of fentanyl upon accumbal release of dopamine is either due to the simultaneous activation of mu-opioid receptors and delta2-opioid receptors or due to activation of mu-opioid receptors that interact with delta2-opioid receptors in a complex manner.

Analgesics, Opioid↗
PubMed1999

Variation in hippocampal dynorphin b-immunoreactive mossy fiber terminal fields of apomorphine-(un)susceptible rats.

The size of distinct hippocampal sub-fields were measured in the apomorphine-susceptible and apomorphine-unsusceptible rat lines. Mossy fiber terminal fields were delineated using dynorphin B immunoreactivity and area measurements were taken from (1) the supra-pyramidal mossy fiber terminal field; (2) the intra- and infra-pyramidal mossy fiber terminal field; (3) the hilus of the fascia dentata (4) the non dynorphin B immunoreactive area of the regio inferior and fascia dentata and (5) the total area of regio inferior and fascia dentata. The data indicate that statistically significant differences in the morphometry of the hippocampal subfields of the apomorphine susceptible and unsusceptible rats are confined to the intra- and infra terminal field: the relative size of the left and right intra- and infra terminal field of apomorphine unsusceptible rats are significantly larger than those of the apomorphine susceptible rats. These data explain at least in part the differential response of these rats to novelty.

Animals↗
PubMed1999

Relationship between memory strategies and motor symptoms in Parkinson's disease.

Patients with Parkinson's disease(PD) show a serious decrease in performance on tasks which lack explicit guidelines and which necessitate the subject to develop his or her own strategy. Using the California Verbal Learning Task(CVLT) we have found evidence that this phenomenon becomes also manifest in learning and memory. The goal of the present study on PD was to investigate whether or not there is an intrinsic relationship between PD-specific deviant learning characteristics and the severity of motor symptomatology. The results show, as expected, a significant correlation between the severity of bradykinetic/hypokinetic symptoms and the serial clustering gradient of the CVLT: the more bradykinetic PD patients (n = 48) were, the more they were dependent on the externally guided serial learning strategy. The findings are discussed in the context of our hypothesis that the actual deficit in patients with PD is a deficient processing of ambiguous internal cues.

Cluster Analysis↗
PubMed1999

Sensory gating in rats: lack of correlation between auditory evoked potential gating and prepulse inhibition.

This study was designed to evaluate the possible similarities between two paradigms designed to measure sensory gating: (1) an auditory evoked potential (AEP), called the P50 gating paradigm; and (2) an acoustic startle (ASR), called the prepulse inhibition paradigm. These paradigms show a number of methodological, pharmacological, and neurobiological similarities, and they are both disturbed in patients with schizophrenia. In the first of three experiments, the AEP gating and the ASR gating were measured in rats. Although both AEP and ASR gating could readily be obtained, there appeared to be no correlation between the performance in these two paradigms. This lack of correlation was confirmed using a factor analytical approach, where the AEP gating and the ASR gating parameters were found to load on different factors. In the second experiment, the interstimulus interval in the ASR paradigm was increased to 500 ms (identical to the interstimulus interval of the AEP gating paradigm). This increase reduced the degree of ASR gating, although some gating could still be obtained. Again no correlation was found between AEP and ASR gating, and this was again confirmed by the factorial analysis. In the final experiment, the effects of the dopamine D2/3 agonist 7-OHDPAT were evaluated in both paradigms. This selective agonist dose dependently reduced ASR gating but had no effect on AEP gating. Together, these data strongly suggest that AEP and ASR gating measure two different aspects of information processing and indicate that both paradigms may be important for investigating the neurobiological disturbances observed in patients with psychoses.

Animals↗
PubMed1999

The validity of the pretreated, unilaterally MPTP-treated monkeys as a model of Parkinson's disease: a detailed behavioural analysis of the therapeutic and undesired effects of the D2 agonist quinpirole and the D1 agonist SKF 81297.

The goal of this study was to evaluate the validity of the pretreated, unilaterally MPTP-treated monkey as an animal model of Parkinson's disease (PD). For that purpose, a detailed ethogram was developed and assessed in four male rhesus monkeys that had received MPTP (2.5 mg) in the carotid artery contralateral to the dominant limb. Subsequently, the behavioural effects of the dopamine D2 agonist quinpirole and the dopamine D1 agonist SKF 81297 were studied. The ethogram was found to allow a clear-cut and objective separation of drug-induced behaviours into therapeutic and undesired effects in the MPTP-treated monkeys. Saline-treated monkeys predominantly displayed ipsilateral goal-directed fore-limb movements, and distinct types of ipsilaterally directed rotations. Although quinpirole and SKF 81297 increased motor behaviours, such as body displacement, contralateral fore-limb movements and contralateral rotational behaviours, assessment of the new detailed ethogram revealed that this increase was completely due to the activation of abnormal, non-goal-directed behaviours, such as dyskinetic fore-limb movements, pivoting and shuffling. Moreover, the new ethogram made clear that the drug treatments induced not only dyskinesia and dystonia, but also epileptoid behaviour, which was confirmed by EEG analysis. In summary, the detailed behavioural analysis showed that this model does not adequately predict the clinical effects of the D2 agonist. It is concluded that the pretreated, unilaterally MPTP-treated monkey is not a valid model to predict the therapeutic and undesired effects of dopaminergic drugs in humans.

Animals↗
PubMed1999

The predictive validity of the drug-naive bilaterally MPTP-treated monkey as a model of Parkinson's disease: effects of L-DOPA and the D1 agonist SKF 82958.

The aim of this study was twofold: (1) to study the predictive validity of the drug-naive, bilaterally MPTP-treated monkey as an animal model of Parkinson's disease (PD), and (2) to investigate the therapeutic and undesired effects of the D1 agonist SKF 82958 as compared to L-DOPA treatment, in drug-naive and L-DOPA pretreated monkeys. A detailed ethogram was used, allowing the separation of therapeutic and undesired effects. Eight weeks after bilateral intracarotid MPTP administration, SKF 82958 (1 mg/kg, n = 4, SKF 82958, naive group) or methyl-L-DOPA + carbi-dopa (10 + 2.5 mg/kg, n = 4, L-DOPA group) was administered intramuscularly for 22 days. After a drug-free period of eight weeks, the L-DOPA group was treated with SKF 82958 for 22 days (SKF 82959, 1 mg/kg, n=4, pretreated). All drug treatments increased the parameters used classically to evaluate dopaminergic drugs, namely body displacement, dyskinesia and dystonia. However, the new detailed analysis revealed that L-DOPA, but not SKF 82958, had therapeutic effects, reflected by an increase in goal-directed fore-limb use. SKF 82958, but not L-DOPA, induced additional undesired effects; including epileptoid behaviours in both drug-naive and drug-pretreated monkeys. In one L-DOPA-unresponsive monkey, SKF 82958 did induce minor therapeutic effects, as well as undesired effects. Although the effects of SKF 82958 on fore-limb movements, rotational behaviours and body displacement were comparable in the naive and pretreated group, SKF 82958 re-initiated undesired effects in the L-DOPA pretreated group from day one. It is concluded that the bilaterally MPTP-treated monkey is an animal model with predictive validity for PD: it adequately predicts the therapeutic effects and undesired effects of L-DOPA. Furthermore, it is concluded that SKF 82958 is less effective than L-DOPA in the treatment of PD, because it did not induce therapeutic effects, but instead elicited several undesired effects.

Animals↗
PubMed1998

Infusion of a D-1 receptor agonist into the nucleus accumbens enhances cocaine-induced behavioural sensitization.

The present study was designed to evaluate the effect of dopamine (DA) D-1 receptor activation in the nucleus accumbens (NAC) on the locomotor sensitizing effects of repeated intra-accumbens (intra-NAC) infusions of cocaine. Repeated infusion of cocaine (10 microg/0.5 microl daily for 2 days) resulted in an enhanced locomotor response to a subsequent intra-NAC and systemic (i.p.) challenging dose of the psychostimulant. Pretreatment with the selective D-1 agonist SK&F82958 (1.0 microg) markedly enhanced the sensitizing effects of both intra-NAC and systemic cocaine. The effect of SK&F82958 was completely blocked by systemic administration of the D-1 antagonist SCH23390 (0.1 mg/kg, i.p.). These data give further support to the idea that activation of D-1 receptors plays an important role in the induction of locomotor sensitization and show that the NAC may, in fact, be an anatomical locus of initiation of behavioural sensitization.

Analysis of Variance↗
PubMed1998

The effects of an early stressful life event on sensorimotor gating in adult rats.

There is increasing evidence that patients suffering from schizophrenia have disturbances in the brain and other parts of the body indicative of a disturbed development. These findings have led to the so-called neurodevelopmental hypotheses of schizophrenia, which state that schizophrenia (or a predisposition for this disease) results from perinatal disturbances which affect the normal development of the central nervous system. In order to study such a possible relationship we have used early short-lasting (24 h) maternal deprivation, and studied the influence of this life event on prepulse inhibition of the acoustic startle at adult age in rats, since it has been shown that schizophrenic patients show a disruption of prepulse inhibition. The results show that early maternal deprivation significantly reduced prepulse inhibition when the animals were tested at postnatal day (pnd) 69 (birth being pnd 0). The effects were qualitatively similar when deprivation took place on pnd 3, 6 or 9, although at the later days the effects were stronger. There was little influence on baseline startle response (except for a small reduction seen after deprivation on pnd 6). In separate experiments it was shown that the effect of maternal deprivation on prepulse inhibition was not seen before puberty and was similar for male and female offspring. Moreover, the effects could be reversed by treatment with the classical antipsychotic, haloperidol, or the putative atypical antipsychotic, quetiapine (both given 15 min before the prepulse inhibition experiment). In summary, the results show that an early stressful life event can have a delayed influence on prepulse inhibition in rats, qualitatively similar to the disturbances seen in schizophrenic patients. These data suggest that maternal deprivation (i.e., a 24 h separation of rat pups from their mother early in life) may represent an interesting animal model for investigating the influence of early life events on the information processing and general functioning of an individual at adult age.

Animals↗
PubMed1998

Role of the retrorubral nucleus in striatally elicited orofacial dyskinesia in cats: effects of muscimol and bicuculline.

Orofacial dyskinesia (OFD) is a disorder characterized by involuntary movements of the oral and facial muscles. OFD attacks can be elicited acutely in cats by local injections of dopaminergic agents into the anterodorsal part (r-CRM) of the caudate nucleus. Because the dopaminergic A8 cell group, being embedded in the retrorubral nucleus (RRN), gives rise to fibres which terminate in the r-CRM, two questions arose: (1) whether the A8 cell group forms part of the circuitry that directs and/or modulates OFD, and (2) whether GABA-ergic compounds in the RRN play a role in OFD, and if so, whether a pharmacological GABA-ergic intervention of the activity in the RRN modulates or mediates OFD. For this purpose, the activity of the RRN was manipulated with local injections of the GABA(A) agonist muscimol and antagonist bicuculline. These local injections into the RRN were subsequently combined with manipulations of dopamine transmission in the r-CRM with local injections of the selective DAi receptor agonist (3,4-dihydroxyphenylimino)-2-imidazoline. The present study shows that local injections of GABA-ergic compounds into the RRN do not elicit OFD attacks in cats, but can modulate oral behaviour elicited from the r-CRM. The latter effect is dose dependent and GABA-ergic specific.

Animals↗
PubMed1998

Nijmegen high and low responders to novelty: a new tool in the search after the neurobiology of drug abuse liability.

Knowledge about the differences in structure, function, and reactivity of the brain and body between Nijmegen high responders to novelty and Nijmegen low responders to novelty may help us to understand which factors give rise to the vulnerability and/or susceptibility to drugs of abuse. For that purpose, this contribution provides a short overview of the outcome of the available studies on Nijmegen high responders to novelty and Nijmegen low responders to novelty. These animals can be selected using three major behavioral paradigms: (a) the open-field test (which allows the separation of high and low responders to novelty); (n) the intruder test (which allows the separation of fleeing and nonfleeing rats); (c) the apomorphine test (which allows the separation of apomorphine-susceptible and apomorphine-unsusceptible rats). Data to date suggest that the same traits have been selected by all three paradigms, and point to the hypothesis that the neurochemical state of the nucleus accumbens directs the sensitivity to drugs of abuse. In addition, recent evidence suggests that the sensitivity to the psychostimulant and/or reinforcing effects of dexamphetamine and ethanol is smaller in HR than in LR under certain experimental conditions, whereas the reverse is found when different experimental conditions are chosen. The data all together lay the foundation for the overall hypothesis that there are three factors ultimately determining the individual-specific sensitivity to drug of abuse: (a) the genetic background that predisposes an individual to become a HR or a LR, (b) early postnatal factors that direct the phenotypic expression of a particular genotype at adult age, and (c) the degree of stress during exposure to the drug of abuse. Further testing of this hypothesis may provide important information about the factors that contribute to individual differences in vulnerability to drugs of abuse.

Animals↗
PubMed1998

Clonidine reduces dopamine and increases GABA in the nucleus accumbens: an in vivo microdialysis study.

The effects of clonidine, an alpha2 adrenoceptor agonist, on extracellular concentrations of dopamine and gamma-aminobutyric acid (GABA) in the nucleus accumbens of rats were studied by using in vivo brain microdialysis. Clonidine (5 microg/kg i.v.) significantly decreased the brain microdialysate concentration of dopamine in the nucleus accumbens up to a maximum of 16% at its peak effect. This effect was inhibited by a dose of idazoxan (10 microg/kg i.v.), an alpha2-adrenoceptor antagonist. which itself did not affect the efflux of dopamine. A smaller dose of clonidine (1 microg/kg i.v.), which had no significant effect on dopamine efflux per se, decreased the dopamine efflux (21% reduction) when given together with an ineffective dose of midazolam (0.075 mg/kg i.v.), a benzodiazepine receptor agonist. The effect of clonidine (5 microg/kg i.v.) on mesolimbic dopamine efflux was abolished by bicuculline (1 mg/kg i.v.), a GABA(A) receptor antagonist, counteracted by beta-carboline-3-carboxylate ethyl ester (beta-CCE, 3 mg/kg i.p.), a benzodiazepine receptor inverse agonist, but not affected by flumazenil (6 microg/kg i.v.), a benzodiazepine receptor antagonist. Clonidine (5 microg/kg i.v.) increased the dialysate concentration of GABA in the nucleus accumbens up to a maximum of 250% at its peak effect, but not in the ventral tegmental area. It is hypothesized that GABA(A) binding sites in the nucleus accumbens form part of the sequence of events that is triggered by clonidine in an alpha2-adrenergic-specific manner and that ultimately results in a decreased release of dopamine in the nucleus accumbens.

Adrenergic alpha-Agonists↗
PubMed1998

Bilateral 6-hydroxydopamine lesion in the dopaminergic A8 cell group produces long-lasting deficits in motor programming of cats.

The effects of a small 6-hydroxydopamine lesion in the A8 cell group were studied in cats (N = 8) trained to walk on a treadmill. This setup allows the assessment of subtle changes in motor programming. The lesion produced long-lasting effects: (a) a decreased ability to switch arbitrarily motor patterns; (b) an increased ability to switch motor patterns with the help of stimuli provided by the apparatus; (c) alterations in the sequential patterning of motor behavior and in the kinetic melody of movements. It is suggested that the lesion produced a hypofunction of A9 cells that is compensated by a hyperfunction of A10 cells. It is concluded that subtle lesions in the A8 cell group produce long-lasting deficits in motor programming, implying that degeneration of this dopaminergic cell group may contribute to symptoms seen in Parkinson's disease.

Animals↗
PubMed1998

Reliance on external cues for movement initiation in Parkinson's disease. Evidence from movement-related potentials.

The aim of this study was to investigate the neurophysiological mechanisms underlying Parkinson's disease patients' increased reliance on external cues for the initiation of movement. Lateralized movement-related cortical potentials were recorded in a noise-compatibility task with seven patients and seven age-matched control subjects. In this two-choice task, visual stimuli containing incompatible target and distractor elements, which simultaneously instructed for responses from both hands, initially caused activation of the motor cortex controlling the wrong response hand. The incorrect response activation was of higher amplitude in patients than in control subjects, causing a longer response delay relative to response times when target and distractors instructed the same hand. In addition, hand-specific motor cortex activation started earlier in patients than in control subjects. These results indicate that visual stimuli exerted an earlier and stronger influence on movement initiation in patients than in control subjects. We hypothesize that information from sensory stimuli relevant for the generation of a response can have rapid access to motor structures in Parkinson's disease patients, thereby facilitating the initiation of movement. The findings may reflect a compensatory mechanism, but could also be related to excitability changes in the motor cortex intrinsic to the pathophysiology of Parkinson's disease.

Aged↗
PubMed1998

Cognitive deficits following stroke in the basal ganglia.

OBJECTIVE: To examine the effect of a stroke in the basal ganglia on cognitive functioning. DESIGN: As part of a larger prospective study on the neuropsychological and psychosocial consequences of stroke, 12 patients with a stroke confined to the basal ganglia were examined. SETTING: The patients were assessed in one of the three participating hospitals. SUBJECTS: The results of 12 patients with a stroke in the basal ganglia (mean age 55 years), were compared to 24 controls (mean age 54.3 years). MAIN OUTCOME MEASURES: Different aspects of memory, attention and concentration, visuospatial and visuoconstructive functions, language and arithmetic were assessed using neuropsychological tests. RESULTS: The data show a significant abnormality in cognitive functioning on all cognitive domains. CONCLUSIONS: The results stress the notion that subcortical damage may lead to substantial neuropsychological disorders and have clear implications for neurological rehabilitation.

Basal Ganglia↗