Biomedical subjects

A R Cools

Publications and source records attributed to A R Cools.

At least 55 records · Page 3Linked to original sources

PubMed2000

Responses to apomorphine of pigs with different coping characteristics.

RATIONALE: Classification of pigs based on the degree of resistance they display in a so-called "backtest" seems, to a certain extent, predictive for their coping strategy. OBJECTIVE: The present study examined whether, as found in rodents, the behavioral response to apomorphine of pigs relates to individual coping characteristics. METHODS: During the suckling period pigs were subjected to the backtest. In this test, each pig is restrained on its back for 1 min and the resistance (i.e. number of escape attempts) is scored. Pigs classified as low-resisting (LR, n=10) or high-resisting (HR, n=10) were selected. At 17-18 weeks of age they received a saline and an apomorphine injection (0.2 mg/kg SC) on 2 consecutive days in a balanced design. Behavior was recorded until 120 min after injection. RESULTS: Apomorphine increased locomotion in all pigs and reduced standing, standing alert and defecating. In addition, apomorphine induced the occurrence of some peculiar activities, rarely seen in saline-treated pigs, which seemed to represent either a transition between different postures or a conflict between hind- and forelimb activities. Apomorphine-treated LR pigs performed significantly more of these activities than HR pigs. However, snout contact with the floor, an oral stereotypy, was significantly increased in apomorphine-treated HR pigs, but not in apomorphine-treated LR pigs. CONCLUSIONS: In conclusion, the response to apomorphine of pigs relates to their behavioral response, high-resisting (HR) versus low-resisting (LR), in the backtest. The contrasts in behavioral response to apomorphine suggest a difference in the dopaminergic system between HR and LR pigs.

Adaptation, Psychological↗

PubMed2000

The role of genetic and early environmental factors in determining apomorphine susceptibility.

RATIONALE: There is ample evidence that rats show large individual differences in their response to dopaminergic drugs, such as apomorphine. OBJECTIVE: The aim of the present study was to investigate the role of genetic and (early) environmental factors in determining the adult susceptibility to apomorphine. Four experiments were performed: In experiment 1, the original selective breeding of rats for apomorphine susceptibility (leading to APO-SUS and APO-UNSUS rats) was extended and replicated in an independent group of Wistar rats. In experiment 2, APO-SUS males were cross-bred with APO-UNSUS females and vice versa. In experiment 3 APO-SUS litters were cross-fostered to APO-UNSUS mothers or infostered to unknown APO-SUS mothers and vice versa. In experiment 4 APO-SUS and APO-UNSUS rats were maternally deprived on postnatal day 9, for a single 24-h period. METHODS: Adult rats were subcutaneously injected with 1.5 mg/kg apomorphine and their gnawing response was automatically recorded in a gnawing box for 45 min. RESULTS: In experiment 1, the original breeding was extended up to generation 24, leading to a strong and consistent difference in gnawing scores. The replication experiment also succeeded in differentiating APO-SUS and APO-UNSUS. The cross breeding experiments showed that the APO-SUS/UNSUS offspring showed gnawing scores in between the original selection lines. Cross-fostering APO-SUS with APO-UNSUS significantly reduced the gnawing response in the offspring, whereas it did not affect the gnawing score in the APO-UNSUS animals. Maternal deprivation had the opposite effect: increase in gnawing response in APO-UNSUS, with no effect in APO-SUS. CONCLUSION: The results show a clear-cut contribution of both genetic and early environmental factors to the susceptibility of apomorphine.

Animals↗

PubMed2000

Genetic, sex, and early environmental effects on the voluntary alcohol intake in Wistar rats.

The aim of this study was to investigate the effects of genetic, sex, and early environmental factors on the voluntary alcohol intake in Wistar rats. Genetic correlates were examined by comparing animals pharmacogenetically selected for high susceptibility to apomorphine (APO-SUS) with animals selected for low susceptibility (APO-UNSUS). Early environmental factors were investigated through postnatal manipulations (cross-fostering in APO-SUS and maternal deprivation in APO-UNSUS). Voluntary alcohol intake was measured using a two-bottle, free-choice protocol, in which animals could choose either water or an ascending series of alcohol concentrations every second day. Genetic correlates were only observed in male rats, with APO-UNSUS animals consuming more alcohol than APO-SUS animals. No effect of the early postnatal manipulations was detected: neither cross-fostering nor maternal deprivation influenced the voluntary alcohol intake. As for the influence of gender on ethanol self-administration, APO-SUS females consume more alcohol than APO-SUS males, while no sex differences were observed in APO-UNSUS animals.

Alcohol Drinking↗

PubMed2000

D1 and D2 dopamine receptor agonists improve deficits in motor programming of cats with a 6-hydroxydopamine lesion in the A8 cell group.

Recently, it has been shown that a small 6-hydroxydopamine lesion in the A8 cell group of cats trained to walk on a treadmill produces long-lasting deficits (Arts and Cools, 1998, Behav. Neurosci. 112; pp. 102-105). Some deficits could be attributed to a hypofunction of A9 cells, that is a reduced ability to switch arbitrarily motor patterns, and other deficits to a hyperfunction of A10 cells, that is an improved ability to switch motor patterns with the help of cues. This experiment was repeated in this study and the elicited behavioural symptoms were systemically treated with the dopamine D1 receptor agonist SKF 81297 and dopamine D2 receptor agonist LY 171555. The results show that a cocktail of these agonists restored both the lesion-induced reduced ability to switch arbitrarily motor patterns and the lesion-induced increased ability to switch motor patterns with the help of cues, suggesting that this treatment restored the functional misbalance between the A9 and A10 cells.

Adrenergic Agents↗

PubMed2000

Dopamine characteristics in different rat genotypes: the relation to absence epilepsy.

Dopaminergic neurotransmission has been shown to participate in the control of absence epilepsy. This type of epilepsy, a generalized non-convulsive form, is associated with bursts of bilateral synchronous spike wave discharges (SWDs) recorded in the EEG. In a previous study, it was suggested that two features of the apomorphine-susceptible (APO-SUS) rat genotype, a relatively low dopaminergic reactivity of the nigrostriatal system and relatively high dopaminergic reactivity of the mesolimbic system, contribute to the high incidence of SWDs. Indeed, apomorphine-unsusceptible (APO-UNSUS) rats, characterized by opposite dopaminergic features, show considerably less SWDs than APO-SUS rats. The first goal of the present study was to assess the baseline SWD incidence in four rat genotypes (WAG/Rij, ACI, APO-SUS and APO-UNSUS) in order to replicate previous findings. It was expected that both the APO-SUS and WAG/Rij rats would show a considerably higher SWD incidence in comparison to the APO-UNSUS and ACI rats. For this purpose, rats were registered for a 19 hour period. Assuming that haloperidol decreases dopaminergic transmission in the nigrostriatal system via inhibition of the dopamine receptors and enhances dopaminergic transmission in the mesolimbic system via inhibition of the noradrenergic receptors, it was postulated that haloperidol would enhance the difference in dopaminergic reactivity between both systems in favor of the accumbens. Therefore, the second purpose in the present study was to investigate whether haloperidol (2 mg/kg, IP) could further potentiate SWD incidence when injected in the APO-SUS rats, already characterized by a relatively low dopaminergic reactivity of the nigrostriatal system and relatively high dopaminergic reactivity of the mesolimbic system, in comparison to the APO-UNSUS rat genotype. Finally, the third aim was to study if another epileptic rat genotype, the WAG/Rij, would show similar increases in SWD incidence following an injection with haloperidol as expected for the APO-SUS. First, previous findings were replicated: the value of the hourly number of SWDs decreased in the following order: APO-SUS > WAG/Rij > APO-UNSUS and ACI. Secondly, earlier data were extended by the fact that the APO-SUS responded to a systemic injection of haloperidol with an increase in SWD number and duration, in contrast to the APO-UNSUS rats. The hypothesis that the SWD incidence would be mostly affected by haloperidol in the APO-SUS rats, was confirmed by these findings. It is suggested that haloperidol increases the SWD incidence in APO-SUS rats by enhancing the difference between the dopaminergic reactivity in the nigrostriatal and mesolimbic system. Finally, further research is required to provide evidence in favor of the hypothesis that the relative dominance of the dopaminergic mesolimbic system is smaller in WAG/Rij than in APO-SUS.

Action Potentials↗

PubMed2000

High and low responders to novelty: effects of adrenergic agents on the regulation of accumbal dopamine under challenged and non-challenged conditions.

The main goal of this study was to provide in vivo neurochemical evidence that mesolimbic alpha- and beta-adrenoceptors direct the release of mesolimbic dopamine. Both high responders to novelty and low responders to novelty were used to study the effects of intra-accumbal administered adrenergic agents on the dopamine release in the nucleus accumbens during two conditions, namely at rest (non-challenge) and when exposed to a "new cage" (challenge). Under non-challenged condition: phenylephrine (alpha-adrenergic agonist) induced a dose-dependent increase in dopamine release that was significantly larger in high responders; phentolamine (alpha-adrenoceptor antagonist) also induced a dose-dependent increase in dopamine that was significantly larger in low responders; isoproterenol (beta-adrenoceptor agonist) induced a dose-dependent increase in dopamine that did not differ between the two types of rat; propranolol (beta-adrenoceptor antagonist) did not change the dopamine release. Under challenged condition: phenylephrine and phentolamine both increased dopamine release without type-specific differences; only in low responders did isoproterenol increase the novelty-induced dopamine release; only in high responders did propranolol decrease the novelty-induced dopamine release. The in vivo neurochemical data are discussed in view of the outcome of earlier reported in vitro studies and pharmaco-behavioral studies. Overall the data reveal that mesolimbic noradrenaline has a dual role in the nucleus accumbens. It is argued that stimulation of alpha-adrenoceptors and beta-adrenoceptors, located postsynaptically on dopamine nerve-endings, inhibits and facilitates, respectively, dopamine release, whereas stimulation of presynaptic alpha-adrenoceptors inhibits the release of noradrenaline and, subsequently, disinhibits the release of dopamine. Moreover, it is argued that non-challenged high responders have a relatively low (alpha/beta) noradrenergic tonus that changes into a relatively high (alpha/beta) noradrenergic tonus during challenge, and that non-challenged low responders have a relatively high (alpha) adrenergic tonus that changes into a relatively low (alpha) noradrenergic tonus during challenge. In general, the present data clearly reveal that both alpha- and beta-adrenoceptors differentially regulate dopamine release in the nucleus accumbens. This regulation is individual-specific and depends on the test-condition (challenged versus non-challenged).

Adrenergic Agents↗

PubMed2000

Newly synthesized dopamine in the nucleus accumbens is regulated by beta-adrenergic, but not alpha-adrenergic, receptors.

Previous microdialysis studies have led to the hypothesis that activation of mesolimbic alpha-adrenoceptors inhibits the release of mesolimbic dopamine from alpha-methyl-p-tyrosine-resistant, reserpine-sensitive pools, and that activation of mesolimbic beta-adrenoceptors stimulates the release of mesolimbic dopamine from alpha-methyl-p-tyrosine-sensitive, reserpine-resistant pools. In the present study we analysed the ability of mesolimbic alpha- and beta-adrenoceptors to modulate the release of dopamine from alpha-methyl-p-tyrosine-sensitive pools in the nucleus accumbens of high and low responders to novelty. Under non-challenged conditions, alpha-methyl-p-tyrosine (10(-4)M, 40 min) produced a decrease in dopamine release that did not differ between high and low responders to novelty. The continuous infusion of 10(-6)M isoproterenol (beta-adrenoceptor agonist) diminished the alpha-methyl-p-tyrosine-induced decrease in dopamine, whereas the continuous infusion of 10(-5)M phenylephrine (alpha-adrenoceptor agonist) remained ineffective. It is concluded that the release of mesolimbic dopamine from alpha-methyl-p-tyrosine-sensitive, reserpine-resistant pools is under excitatory control of beta-adrenergic, but not alpha-adrenergic, receptors in both high and low responders to novelty. In general, this study implies that mesolimbic dopamine that is derived from different pools is regulated via different noradrenergic receptors.

Animals↗

PubMed2000

The long-term effects of maternal deprivation depend on the genetic background.

The neurodevelopmental hypothesis of schizophrenia has led to a series of new animal models in which the long term consequences of early manipulations are investigated. We have recently shown that a single 24-hr period of maternal deprivation (at postnatal day (pnd) 9) increases apomorphine susceptibility and decreases prepulse inhibition in Wistar rats, viz. phenomena also seen in schizophrenic patients. In the present paper, we investigated whether the effects of maternal deprivation were dependent on a specific genetic background, by using different rat strains (Fischer 344 and Lewis) that differ in the Hypothalamus-Pituitary-Adrenal axis and in dopaminergic sensitivity. The data show that in Wistar rats, basal startle amplitude was not affected by maternal deprivation, but prepulse inhibition was reduced, and apomorphine susceptibility enhanced. In Fischer 344 rats on the other hand, neither basal startle amplitude, nor prepulse inhibition were affected, but apomorphine susceptibility was reduced. In Lewis rats, maternal deprivation significantly reduced basal startle amplitude, but did not affect prepulse inhibition or apomorphine susceptibility. The differential response to maternal deprivation can best be explained by differences in baseline dopamine sensitivity between the rat strains. Since a reduced prepulse inhibition and an enhanced susceptibility to apomorphine is also seen in schizophrenic patients, the data indicate that maternally deprived Wistar rats may represent an interesting developmental model for (aspects of) schizophrenia.

Animals↗

PubMed2000

Retrieval of spatial information in Nijmegen high and low responders: involvement of beta-adrenergic mechanisms in the nucleus accumbens.

Rats selected on the basis of their apomorphine susceptibility or on the basis of their response to novelty were used to investigate the role of mesolimbic adrenoceptors in the retrieval of spatial information in the water maze task. Apomorphine-susceptible rats and high responders to novelty (HR) showed a relatively bad retrieval during the 1st trial of the 2nd day compared with apomorphine-unsusceptible rats and low responders to novelty (LR). Intra-accumbens injections of different doses of the beta-agonist isoproterenol, given just before that trial, disrupted the retrieval in LR rats but not in HR rats. The beta-antagonist propranolol, which itself did not have any direct effect, inhibited the effect of isoproterenol in LR rats. The effect of isoproterenol in LR rats was not modified by alpha-agents. It is concluded that the beta-adrenergic, but not alpha-adrenergic, activity in the nucleus accumbens directs the individual-specific ability to retrieve spatial information under stressful conditions.

Animals↗

PubMed2000

Localization and physiological regulation of the exocytosis protein SNAP-25 in the brain and pituitary gland of Xenopus laevis.

In mammals, the synaptosomal-associated protein of 25 kDa, SNAP-25, is generally thought to play a role in synaptic exocytosis of neuronal messengers. Using a polyclonal antiserum against rat SNAP-25, we have shown the presence of a SNAP-25-like protein in the brain of the South-African clawed toad Xenopus laevis by Western blotting and immunocytochemistry. Xenopus SNAP-25 is ubiquitously present throughout the brain, where its distribution in various identified neuronal perikarya and axon tracts is described. Western blot analysis and immunocytochemistry also demonstrated the presence of SNAP-25 in the neural, intermediate and distal lobes of the pituitary gland. Intensity line plots of confocal laser scanning microscope images of isolated melanotropes indicated that SNAP-25 is produced and processed in the rough endoplasmatic reticulum and Golgi apparatus, and is associated with the plasma membrane. Immunoelectron microscopy substantiated the idea that SNAP-25 is present in the plasma membrane but also showed a close association of SNAP-25 with the bounding membrane of peptide-containing secretory granules in both the neurohemal axon terminals in the neural lobe and the endocrine melanotropes in the intermediate lobe. Quantitative Western blotting revealed that adapting Xenopus to a dark background has a clear stimulatory effect on the expression of SNAP-25 in the neural lobe and in the melanotrope cells. This background light intensity-dependent stimulation of SNAP-25 expression was confirmed by the demonstration of increased immunofluorescence recorded by confocal laser scanning microscopy of individual melanotropes of black background-adapted toads. On the basis of this study on Xenopus laevis, we conclude that SNAP-25 (i) plays a substantial role in the secretion of a wide variety of neuronal messengers; (ii) functions in the central nervous system but also in neurohormonal and endocrine systems; (iii) acts at the plasma membrane but possibly also at the membrane of synaptic vesicles and peptide-containing secretory granules; (iv) acts not only locally (as in synapses), but at various sites of the plasma membrane (as in the endocrine melanotrope cell); and (v) can be upregulated in its expression by physiological stimuli that increase the extent of the molecular machinery involved in exocytosis.

Animals↗

PubMed2000

Systemic administration of the propargylamine CGP 3466B prevents behavioural and morphological deficits in rats with 6-hydroxydopamine-induced lesions in the substantia nigra.

The ability of CGP 3466B to attenuate the behavioural and morphological consequences of experimentally induced cell death was investigated in a recently updated animal model of Parkinson's disease. 6-Hydroxydopamine was infused bilaterally into the substantia nigra pars compacta of rats that were pretreated with desimipramine. Treatment with CGP 3466B (0.0014-1.4 mg/kg, injected subcutaneously) or its solvent was begun 2 h after the 6-OHDA injection, and maintained twice daily for 14 days. After a washout period of 14 days, changes in motor behaviour were evaluated, using the open field test (analysis of normal and abnormal stepping, e.g.) and the paw test (analysis of retraction time of limbs). Changes in learning and memory were evaluated with the help of the Morris water maze task. Following immunocytochemical staining of tyrosine hydroxylase, the extent of the lesion was quantified using a computerized system. CGP 3466B prevented all deficits produced by 6-hydroxydopamine (6-OHDA), though at different doses. It prevented: abnormal stepping (0.0014-0.014 mg/kg); increased forelimb and hindlimb retraction time (0.014-0.14 mg/kg and 0.0014-0.14 mg/kg, respectively); delayed learning (1.4 mg/kg); and reduced tyrosine hydroxylase immunoreactivity in the substantia nigra (0.0014-0.014 mg/kg). CGP 3466B (0.0014-0.14 mg/kg) induced no deficits in sham-treated rats. CGP 3466B (1.4 mg/kg), however, did not show any benefit on motor deficits in 6-OHDA-lesioned rats, and induced abnormal movements and decreased the tyrosine hydroxylase immunoreactivity in the substantia nigra pars compacta and the ventral tegmental area of sham-lesioned animals. It is concluded that CGP 3466B prevents all 6-OHDA-induced behavioural and immunocytochemical deficits, though at different doses. CGP 3466B is suggested to be a valuable agent for inhibiting the dopaminergic degeneration in patients with Parkinson's disease.

Animals↗

PubMed2000

Animal models for the negative symptoms of schizophrenia.

Negative or defect symptoms refer to a reduction in normal functioning. In schizophrenia, negative symptoms encompass, among others, anhedonia, flat affect, avolition and social withdrawal. These symptoms have been found to be particularly prominent in the more chronic phase of the illness and seem to be virtually insensitive to current antipsychotic treatment. This review focuses on the possibilities and limitations of animal models for the negative symptoms of schizophrenia. Following a review of the negative symptoms in schizophrenia, attention is focused on the two symptoms most often modelled in animals - anhedonia and social withdrawal. We then look at the important question of how to model schizophrenic pathology in animals. Since the exact pathology is still far from clear, most efforts have in the past concentrated on using psychotomimetic drugs such as amphetamine or phencyclidine. The recently accumulated knowledge that schizophrenia probably results from disturbances in the normal development of the brain has led to a surge of new animal models in which the long-term consequences of early manipulations are investigated. However, so far these models have predominantly concentrated on the positive rather than the negative symptoms of schizophrenia. The last part of this review is dedicated to the question of validation of animal models for anhedonia and social withdrawal. The general conclusion is that very few models have so far been adequately tested. The lack of currently effective treatment further hampers the study of such validation.

Affect↗

PubMed2000

Classifying postures of freely moving rodents with the help of Fourier descriptors and a neural network.

A computerized method for classifying the postures of freely moving rodents is presented. The behavior of the rats was recorded on videotape by means of a camera hanging perpendicular to an open field. An automatic tracking system (10 images/sec) was used to transform the video images of postures into a binary image, thereby providing silhouettes in a computer format. The contours of these silhouettes were used for determining their characteristic features with the help of a Fourier transformation. The resulting features were classified with the help of a Kohonen network composed of 32 neurons. The four best winning neurons, rather than the usual one, were used for the classification. The resolution (11,090 distinct classes of postures), reliability (96.9%), and validity of this method were determined. With the use of the same approach, the effectiveness of this method for classifying behaviors was illustrated by analyzing grooming (247 grooming images vs. 4,950 nongrooming images). We found 15.4% false positives and 2.5% false negatives.

Animals↗

PubMed1999

The alleged dopamine D1 receptor agonist SKF 83959 is a dopamine D1 receptor antagonist in primate cells and interacts with other receptors.

So far, no clear correlation has been found between the effects of dopamine D1 receptor agonists on motor behavior in primate models of Parkinson's disease and their ability to stimulate adenylate cyclase in rats, the benzazepine SKF 83959 (3-methyl-6-chloro-7,8-hydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-]H- 3-benzazepine) being the most striking example. Since this discrepancy might be attributed to: (A) the different species used to study these effects or (B) the interaction of SKF 83959 with other catecholamine receptors, the aims of this study were: (1) to study the ability of SKF 83959 to stimulate adenylate cyclase in cultured human and monkey glial cells equipped with dopamine D1 receptors and (2) to evaluate the affinity for and the functional interaction of SKF 83959 with other catecholamine receptors. Binding studies revealed that SKF 83959 displayed the highest affinity for the dopamine D1 receptor (pKi=6.72) and the alpha2-adrenoceptor (pKi=6.41) and moderate affinity for the dopamine D2 receptor and the noradrenaline transporter. In monkey and human cells, SKF 83959 did not stimulate cyclic adenosine monophosphate (cAMP) formation to a significant extent, but antagonized very potently the dopamine-induced stimulation of cAMP formation in both cell types. The compound stimulated basal dopamine outflow and inhibited depolarization-induced acetylcholine release only at concentrations > 10 microM. Finally, SKF 83959 concentration dependently increased electrically evoked noradrenaline release, indicating that it had alpha2-adrenoceptor blocking activity and interfered with the noradrenaline transporter. In conclusion, SKF 83959 is a potent dopamine D1 receptor and alpha2-adrenoceptor antagonist. Thus, the anti-parkinsonian effects of SKF 83959 in primates are not mediated by striatal dopamine D1 receptors coupled to adenylate cyclase in a stimulatory way.

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

PubMed1999

Differential effects of ketamine on gating of auditory evoked potentials and prepulse inhibition in rats.

Schizophrenic patients suffer from deficits in information processing. Patients show both a decrease in P50 gating [assessed in the conditioning-testing (C-T) paradigm] and prepulse inhibition (PPI), two paradigms that assess gating. These two paradigms might have a related underlying neural substrate. Gating, as measured in both the C-T paradigm (the gating of a component of the auditory evoked potential (AEP)], and PPI can easily be measured in animals as well as in humans. This offers the opportunity to model these information processing paradigms in animals in order to investigate the effects of neurotransmitter manipulations in the brain. In order to validate the animal model for disturbances in AEP gating, d-amphetamine (0.5 and 1 mg/kg, i.p.) was administered. Gating of an AEP component was changed due to injection of d-amphetamine (1 mg/kg) in the same way as seen in schizophrenic patients: both the amplitude to the conditioning click and the gating were significantly reduced. Next, the effect of the N-methyl-D-aspartate (NMDA) antagonist ketamine (2.5 and 10 mg/kg, i.p.) was investigated to assess its effects in the two gating paradigms. It was found that ketamine (10 mg/kg) did not affect gating as measured with components of the AEP. However, ketamine (10 mg/kg) disrupted PPI of the startle response to the extent that prepulse facilitation occurred. Firstly, it is concluded that AEP gating was disrupted by d-amphetamine and not by ketamine. Secondly, PPI and the C-T paradigm reflect distinct inhibitory sensory processes, since both paradigms are differentially influenced by ketamine.

Animals↗

PubMed1999

Sub-chronic administration of the dopamine D(1) antagonist SKF 83959 in bilaterally MPTP-treated rhesus monkeys: stable therapeutic effects and wearing-off dyskinesia.

RATIONALE: SKF 83959 acts as a D(1) antagonist in vitro but has been claimed to induce anti-parkinsonian effects after acute administration in MPTP-treated marmosets. OBJECTIVE: The aim of the present study was to evaluate the therapeutic and undesired effects of sub-chronic administration of SKF 83959 in bilaterally MPTP-treated rhesus monkeys and to compare these effects with the effects of l-dopa and the dopamine agonist SKF 82958. METHODS: MPTP was given in the left carotid artery (2.5 mg) and 6 weeks later, the right carotid artery (1.25 mg). The monkeys (n = 4) had previously been treated chronically with l-dopa (22 days, 10 mg/kg) and SKF 82958 (22 days, 1 mg/kg). Three months after the last administration of SKF 82958, SKF 83959 was given in a dose of 0.5 mg/kg from day 1 to day 15 and in a dose of 1.0 mg/kg from day 16 to day 18. RESULTS: SKF 83959 increased goal-directed limb movements in all animals, including those unresponsive to l-dopa. This therapeutic effect did not diminish during treatment. With respect to body displacement and undesired effects, a large variation in the response to SKF 83959 was found: a large increase in body displacement co-occurred with oro-facial dyskinesia (n = 2), whereas a small increase in body displacement co-occurred with dystonia (n = 2). In contrast to the undesired effects of l-dopa, the dyskinetic effects of SKF 83959 were primarily limited to the first treatment day. Unlike l-dopa and SKF 82958, SKF 83959 did not induce epileptoid behaviour. CONCLUSION: Sub-chronic administration of SKF 83959 induced both clear-cut therapeutic effects that remained stable in time, and a limited number of dyskinetic effects that wore off during the treatment. The dopamine D(1) antagonist SKF 83959 may be considered as an alternative treatment in Parkinson's disease, especially in those patients who do not respond to L-dopa.

Animals↗

PubMed1999

Effects of chronic haloperidol and clozapine on vacuous chewing and dopamine-mediated jaw movements in rats: evaluation of a revised animal model of tardive dyskinesia.

Rats received haloperidol (1.0 mg/kg i.p.) or clozapine (10 mg/kg i.p.), twice daily for 4 weeks: vacuous chewing--recorded 26 h after the final injection--similarly increased in both groups. Three h later, the rats were challenged with dopaminomimetics, and automatically recorded jaw movements were analysed. Both apomorphine and a mixture of D1 and D2 receptor agonists (SKF 38393 resp. quinpirole) increased jaw movements in haloperidol-treated, but not clozapine-treated rats; SKF 38393 or quinpirole remained ineffective, when given alone. A fixed dose of quinpirole together with increasing doses of SKF 38393, but not a fixed dose of SKF 38393 together with increasing doses of quinpirole, produced a dose-dependent increase in jaw movements in otherwise non-treated rats, suggesting that the noted haloperidol-induced increase was due to a shift in the D1-D2 receptor balance towards a predominance of D1 receptors. This study presents a new animal model of tardive dyskinesia with predictive validity, good reliability and, especially, great efficiency.

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

PubMed1999

Behavioural and neurochemical effects of cholinergic and dopaminergic agonists administered into the accumbal core and shell in rats.

The first goal of this study was to investigate whether turning behaviour elicited by unilateral injections of the cholinergic agonist carbachol into the shell of the nucleus accumbens differs from that elicited by similar injections into the core of this nucleus, and to compare the behavioural effects with the known effects of such injections of the mixture of the dopamine D1 and D2 receptor agonists SKF 38393 (5 microg) and quinpirole (10 microg). The second goal was to investigate whether these injections of carbachol produce neurochemical alterations in the ventrolateral striatum that differ from similar injections of the mixture of the dopamine D1 and D2 receptor agonists into these brain regions. Injections of carbachol into the shell produced predominantly (a) contralateral circling marked by normal stepping and running in wide circles during the initial 50 min and (b) postural asymmetry during the following 75 min; similar injections into the core produced (a) contralateral pivoting, namely pathological head-to-tail turning marked by abnormal hindlimb stepping during the initial 50 min and (b) postural asymmetry during the next 75 min. The postural asymmetry seen after the carbachol injections was closely associated with the drug-induced increase in the dopamine release measured by microdialysis in the ipsilateral striatum. Injections of the mixture of dopamine agonists into the shell, but not core, also produced pivoting. These shell injections increased the dopamine release in the ipsilateral striatum, and decreased it in the contralateral striatum. The relative increase in the ipsilateral striatum was closely associated with the drug-induced pivoting. The data show that stimulation of cholinergic and dopaminergic receptors in the shell and core elicit effects that vary according to the subregion of the nucleus accumbens. It is concluded that the accumbens-specific, cholinergic effects are mediated via substrates that differ from those involved in the shell-specific, dopaminergic effects.

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