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Biomedical subjects

A R Cools

Publications and source records attributed to A R Cools.

At least 109 records · Page 6Linked to original sources

Memory performance under varying cueing conditions in patients with Parkinson's disease.

The present study is a continuation of a previous study in memory performance which showed that Parkinson's disease (PD) patients increasingly relied on explicit cues which prompt the external strategy of serial clustering, in comparison to control subjects (CS), who profited increasingly from implicit cues which prompt the internal and more effective strategy of semantic clustering. In this study, we investigated whether the recall of PD patients can be affected by adding or removing explicit cues. We manipulated the California Verbal Learning Test in two ways. First, we told the subjects under study in advance from which categories the items to be recalled were derived, thus making the implicit cue to cluster semantically explicit (explicit condition). Next, we permuted the sequence of the items in each trial, thus preventing the subjects from adhering to the serial order, i.e. to explicit cues (permuted condition). We included the data of our previous study (mixed condition) in the analysis of memory and learning performance in the three conditions. Learning of PD patients, as reflected in the semantic ratio, proved to be more affected by the cueing conditions than that of CS. Total performance and the serial ratios did not show a significant interaction between group and cueing condition. The results are discussed in terms of external and internal generation of problem-solving strategies.

Adult↗

Prepulse inhibition and latent inhibition: the role of dopamine in the medial prefrontal cortex.

The prefrontal cortex has often been implicated in the pathophysiology of schizophrenia. Schizophrenic patients are known to suffer from certain information processing deficits, which can be detected, among others, in the prepulse inhibition and the latent inhibition paradigm. The present study was designed to investigate the role of dopamine receptors in the medial prefrontal cortex in prepulse inhibition and latent inhibition. The results show that the local application of the selective antagonist of the dopamine D1-like receptor family, SCH 39166, into the medial prefrontal cortex dose-dependently reduced prepulse inhibition. Likewise, the selective antagonist of the dopamine D2-like receptor family, sulpiride, injected into the medial prefrontal cortex dose-dependently reduced prepulse inhibition. Neither of these antagonists, however, influenced latent inhibition as measured with the conditioned taste aversion paradigm. These data further indicate that the neuronal substrates of latent inhibition and prepulse inhibition are clearly different. Since the prefrontal cortex is intimately related to subcortical dopamine, the possible differential involvement of subcortical dopaminergic terminal fields in prepulse inhibition and latent inhibition is discussed.

Animals↗

d-Sulpiride inhibits oral behaviour elicited from the nucleus accumbens of freely moving rats.

The present study analyzed the effect of intra-accumbens administration of the stereoisomers of sulpiride upon (3,4-dihydroxyphenylimino)-2-imidazoline (DPI)-induced changes in oral behaviours and electromyographic patterns of jaw muscles. In line with earlier findings, DPI (5 micrograms) administered into the nucleus accumbens increased chewing and tremor. l-Sulpiride (2-50 ng) had no effect on DPI-induced oro-facial behaviours. d-Sulpiride (10-50 ng) significantly antagonized the DPI-induced increase in chewing and had a biphasic effect on tremor with potentiation (10 ng) followed by attenuation (50 ng). When administered alone, l- or d-sulpiride did not affect oro-facial behaviours. The electromyographic signals, which were analyzed according to a previously described method, were described with the help of three classes: A (the seconds marked by frequency 3 Hz), B (the seconds marked by the frequencies 4-6 Hz); C (the seconds marked by the frequencies 7-15 Hz). DPI enhanced Class B and C of the masseter muscle but did not significantly affect any frequency class of the digastric muscle. l-Sulpiride (2-50 ng) had no effect on DPI-induced (5 micrograms) changes in electromyographic signals. d-Sulpiride (50 ng) antagonized the effects of DPI on Class B of the masseter muscle. Furthermore, d-sulpiride had a biphasic effect on Class C with potentiation (10 ng) followed by attenuation (50 ng). When administered alone, l- or d-sulpiride did not affect the frequency classes of the jaw muscles. It is concluded that d-sulpiride inhibits DPI-induced changes in oral behaviour and electromyographic patterns. It is suggested that d-sulpiride may be effective in the pharmacotherapy of oro-facial dyskinesias in man.

Animals↗

Efferent projections of the retrorubral nucleus to the substantia nigra and ventral tegmental area in cats as shown by anterograde tracing.

The aim of the present study was to determine whether the retrorubral nucleus projects to the dopaminergic nuclei in the ventral midbrain of the cat. For this purpose, injections of biotinylated dextran-amine or Phaseolus vulgaris-leucoagglutinin were placed into the retrorubral nucleus under stereotaxic guidance. The tracers were visualized by means of (immuno) histochemical procedures. In addition, tyrosine hydroxylase immunohistochemistry was used to evaluate the location of the injection sites and the distribution of the anterogradely labeled fibers. Both tracers reveal the same topography of labeled fibers in the ventral mesencephalon. Labeled fibers with varicosities were found ipsilaterally in the substantia nigra pars compacta, the substantia nigra pars lateralis, the ventral tegmental area and, contralaterally, in the substantia nigra pars compacta, the ventral tegmental area, and the retrorubral nucleus. A considerable number of labeled axons with varicosities were observed to be wrapped around the dendrites and perikarya of tyrosine hydroxylase-positive neurons in these areas. The present results are discussed in view of the possible role of the A8 dopaminergic cell group in the coordination of A9 nigrostriatal and A10 mesolimbic systems, as well as in the progressive pathology seen in patients suffering from Parkinson's disease.

Animals↗

Activity of "seroquel" (ICI 204,636) in animal models for atypical properties of antipsychotics: a comparison with clozapine.

The pharmacologic treatment of schizophrenia still suffers from two major problems: (1) most antipsychotic drugs still induce severe neurologic (extrapyramidal) side effects; (2) few antipsychotic drugs are effective in treating the negative symptoms of schizophrenia. In the present study, we have evaluated the effects of ICI 204,636 in the rat paw test and the amphetamine-induced social isolation in monkeys and compared them with the effects of clozapine. The paw test has been shown to be a valid model for differentiating classic and atypical neuroleptic drugs. The monkey social isolation model seems to represent one of the few animal models with validity for the negative symptoms of schizophrenia. The results show that both ICI 204,636 and clozapine had the profile of an atypical antipsychotic in the paw test, suggesting a reduced propensity to induce extrapyramidal side effects in humans. Likewise, ICI 204,636 and clozapine were found to prevent the amphetamine-induced social isolation in monkeys, suggesting a good therapeutic effect mitigating the negative symptoms in schizophrenia. Overall, the data suggest that ICI 204,636 may represent a new and interesting antipsychotic drug, closely resembling clozapine.

Animals↗

Neonatal maternally deprived rats have as adults elevated basal pituitary-adrenal activity and enhanced susceptibility to apomorphine.

Maternal deprivation of neonatal rats for 24 h enhances the adrenocortical response to stress and/or adrenocorticotropin hormone (ACTH) stimulation during the stress hyporesponsive period (SHRP). The present study tests the hypothesis that such maternally deprived neonatal male rats show altered hypothalamic-pituitary-adrenal (HPA) regulation not only immediately after deprivation but also in later life. In addition, we found previously that neonatal changes in HPA activity preceded modulation of nigrostriatal dopamine function. Therefore, we also measured dopamine responsiveness in adult rats which were deprived of their mother during infancy. Neonatal male rats were maternally deprived for 24 h at the age of 3 days, whereas rats of the control group were left undisturbed. At 60 days of age deprived and non-deprived rats were decapitated and brain, adrenal glands and thymus were removed. Trunk blood was collected for determination of plasma ACTH, corticosterone and prolactin concentrations using radioimmunoassay procedures. mRNA levels of mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs), corticotropin-releasing hormone (CRH) mRNA and tyrosine hydroxylase (TH) mRNA were measured in brain sections with in situ hybridization. In a second group of male deprived and non-deprived rats apomorphine-induced stereotypic gnawing behaviour was examined at 60 days of age as a measure for functional activity of the dopamine system. Deprived neonatal rats showed the following characteristics as compared with non-deprived rats: (i) lower basal CRH mRNA concentration in parvocellular neurons of the paraventricular nucleus of the hypothalamus (PVN), while basal plasma ACTH and corticosterone concentrations were significantly elevated. Basal prolactin levels were not different. (ii) Similar hippocampal MR and GR mRNA levels. (iii) Significantly reduced GR mRNA levels in PVN and anterior pituitary. (iv) Significantly enhanced apomorphine-induced stereotypic gnawing behaviour and (v) higher TH mRNA levels in substantia nigra, while no changes were found in the ventral tegmental area (VTA). It is concluded that maternally deprived neonatal male rats display as young adults elevated basal pituitary-adrenal activity and enhanced apomorphine susceptibility.

Animals↗

Movement preparation in Parkinson's disease. Time course and distribution of movement-related potentials in a movement precueing task.

Investigations of the effects of advance information on movement preparation in Parkinson's disease using reaction time (RT) measures have yielded contradictory results. In order to obtain direct information regarding the time course of movement preparation, we combined RT measurements in a movement precueing task with multi-channel recordings of movement-related potentials in the present study. Movements of the index and middle fingers of the left and right hand were either precued or not by advance information regarding the side (left or right hand) of the required response. Reaction times were slower for patients than for control subjects. Both groups benefited equally from informative precues, indicating that patients utilized the advance information as effectively as control subjects. Lateralization of the movement-preceding cerebral activity [i.e. the lateralized readiness potential (LRP)] confirmed that patients used the available partial information to prepare their responses and started this process no later than controls. In conjunction with EMG onset times, the LRP onset measures allowed for a fractionation of the RTs, which provided clues to the stages where the slowness of Parkinson's disease patients might arise. No definite abnormalities of temporal parameters were found, but differences in the distribution of the lateralized movement-preceding activity between patients and controls suggested differences in the cortical organization of movement preparation. Differences in amplitude of the contingent negative variation (CNV) and differences in the way in which the CNV was modulated by the information given by the precue pointed in the same direction. A difference in amplitude of the P300 between patients and controls suggested that preprogramming a response required more effort from patients than from control subjects.

Adult↗

Divergent prolactin and pituitary-adrenal activity in rats selectively bred for different dopamine responsiveness.

The present study explores the significance of brain dopamine phenotype for individual variation in the neuroendocrine stress response of the rat. For this purpose, we used two Wistar rat lines previously selected for high or low responsiveness of the dopamine system to apomorphine using the gnawing response as the selection criterion. Systemic administration of the drug evoked in apomorphine-susceptible (apo-sus) rats a vigorous gnawing response, whereas apomorphine-unsusceptible (apo-unsus) rats did not gnaw under these conditions. These two rat lines represent individuals displaying extreme differences in gnawing behavior that otherwise coexist in a normal Wistar population. In this study basal and stress-induced hypothalamic-pituitary-adrenal activity and PRL release were measured in chronically cannulated, freely moving rats that endured a conditioned emotional response. Tyrosine hydroxylase messenger RNA (mRNA), corticosteroid receptor mRNA, and in vivo retention of [3H]corticosterone were measured in rat brain sections using in situ hybridization and in vivo autoradiography. The result show that 1) apo-sus rats had a markedly reduced PRL response to stress compared to apo-unsus animals, whereas basal levels were not significantly different. A12 dopaminergic neurons in the arcuate nucleus expressed significantly higher levels of tyrosine hydroxylase mRNA in apo-sus rats, suggesting that the reduced stress-induced PRL release could be due to an increased inhibitory control by dopaminergic neurons; 2) in apo-sus rats, stress resulted in a sustained elevation of ACTH and free corticosterone levels, whereas the total corticosterone levels were not different between the two rat lines; 3) under basal morning conditions, apo-sus rats had significantly higher plasma ACTH, but, in contrast, lower free corticosterone than apo-unsus rats; total plasma corticosterone levels were not different; 4) the basal evening ACTH level was elevated in apo-sus rats; after removal of the adrenals in the morning, this increased ACTH level in apo-sus rats persisted into the afternoon 6 h postadrenalectomy; and 5) hippocampal mineralocorticoid (MR), but not glucocorticoid (GR), receptor capacity for the ligand comparable between the groups; the MR of apo-sus rats displayed an increased retention of [3H]corticosterone in all hippocampal cell fields measured 24 h adrenalectomy; MR and GR mRNA in hippocampus as well as GR mRNA in the paraventricular nucleus were not significantly different in the two rat lines. In conclusion, the data suggest a common genetic background for individual variation in stress responsiveness and dopamine phenotype. High dopamine reactivity is linked to a reduced PRL and an increased ACTH response after stress. These high dopamine responders display a hyporesponsive adrenal cortex and corticosteroid feedback resistance associated with altered brain corticosteroid receptor properties.

Adrenal Glands↗

Role of dopamine D1 and D2 receptors in the nucleus accumbens in jaw movements of rats: a critical role of the shell.

Given the differences in the dopamine neurotransmission between the shell and the core of the nucleus accumbens, as well as the differential involvement of these two domains in oral behaviour of rats, it was decided to determine whether or not dopamine D1 and/or dopamine D2 receptors differentially direct oral behaviour in these two domains in rats. Intra-accumbens injections of the dopamine D1 receptor agonist (+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine (SKF 82958: 5 micrograms/0.2 microliters), the dopamine D2 receptor agonist quinpirole (10 micrograms/0.2 microliters) and their combination were used to assess the role of these accumbens domains in jaw movements of rats. The present study shows that the combined administration of SKF 82958 and quinpirole into the shell, but not the core, of the nucleus accumbens produced a highly significant increase in jaw movements, when doses which per se were nearly ineffective, were injected. This effect was fully inhibited by prior administration of either the dopamine D1 receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH 23390: 0.5 microgram/0.2 micrograms) or the dopamine D2 receptor antagonist (-)-sulpiride (25 ng/0.5 microliter) into the same region. It is concluded that dopamine D1 and D2 receptors in the shell, but not the core, of the nucleus accumbens are involved in jaw movements of the rat, providing the first piece of evidence that dopamine D1 and D2 receptors in the shell of the nucleus accumbens mediate a particular behaviour.

Animals↗

The hypothalamic paraventricular nucleus in two types of Wistar rats with different stress responses. I. Morphometric comparison.

The present study evaluates the role of the hypothalamic paraventricular nucleus (PVH) in stress regulation by a morphometric comparison of the vascular, neuronal and synaptic properties of this nucleus in two lines of Wistar rats. It has been previously reported that these two lines of rats, indicated as APO-SUS (apomorphine-susceptible) and APO-UNSUS (apomorphine-unsusceptible) rats on the basis of their reactivity to a subcutaneous injection of apomorphine, display a variety of pharmacological and behavioral differences, including differences in their stress-coping mechanisms (Cools et al., Neuropsychobiology, 28 (1993) 100-105). The results show a similar vascular and neuronal organization of the PVH in both lines, but distinct synaptic differences. The PVH (0.12 mm3 volume with about 15,000 neurons on one side) has an overall vascular density of 5.6%, with significant differences between subdivisions (parvocellular central part: 8.3%, parvocellular dorsal/ventral/posterior part: 4.6-5.3%), which means that vascularity is a useful tool to delineate subdivisions in the parvocellular PVH. The neuronal density of 132 x 10(3)/mm3 as found in the present study is two times higher than reported in a previous study Possible reasons for this discrepancy are extensively discussed. The most significant finding of the present study is the observation that APO-SUS rats have a significantly higher synaptic density (158 x 10(6)/mm3) in the PVH than APO-UNSUS rats (108 x 10(6)/mm3). It is discussed in which way this synaptic difference may be correlated with the different activity of the hypothalamo-pituitary-adrenal axis in both lines of Wistar rats.

Animals↗

The hypothalamic paraventricular nucleus in two types of Wistar rats with different stress responses. II. Differential Fos-expression.

The present study investigates the role of corticotropin-releasing hormone (CRH) neurons in stress regulation by a comparison of stress induced Fos-immunoreactivity and CRH-immunoreactivity in the hypothalamic paraventricular nucleus (PVH) of APO-SUS (apomorphine-susceptible), APO-UNSUS (apomorphine-unsusceptible), normal Wistar and adrenalectomized Wistar (ADX) rats. The first two types represent a good model to study the role of the PVH in stress regulation, since they show different stress responses and a differential synaptic organization of the PVH. After placement on an open field for 15 min all rats showed an increase in the number of Fos-immunoreactive nuclei compared to control handling. Interestingly, open field stress, but not control handling, induces significantly fewer Fos-immunoreactive nuclei in the PVH of APO-SUS rats (1255 +/- 49) compared to APO-UNSUS rats (1832 +/- 201). Experiments with ADX rats revealed that 93% of the CRH-immunoreactive neurons contained a Fos-immunoreactive nucleus, which suggests that the differential Fos-expression in APO-SUS and APO-UNSUS rats represents a differential activation of the CRH neurons. This hypothesis is discussed in relation to reported differences in stress responses, stress-induced ACTH levels and synaptic organization of the PVH.

Adrenal Glands↗

Descending efferent connections of the sub-pallidal areas in the cat: projections to the lateral habenula.

The descending efferent connections of the sub-pallidal areas to the lateral habenula were investigated in the cat using Phaseolus vulgaris leucoagglutinin (PHA-L) as an anterograde tracer. Several injections of PHA-L were made in various regions of the feline sub-pallidal regions. Subsequently, the distribution of anterogradely labelled fibres in the lateral habenula was charted. PHA-L injections into the rostral part of the sub-pallidal regions resulted in a limited number of labelled fibres in the lateral habenula, while PHA-L injections into the caudal regions of the sub-pallidum resulted in an extensive distribution of anterogradely labelled fibres in this area. Thus, the lateral habenula is an important output structure of the sub-pallidal areas in the cat.

Animals↗

YM-14673, a thyrotropin-releasing hormone analogue, injected into the nucleus accumbens and the striatum produces repetitive jaw movements in rats.

Bilateral injections of the thyrotropin-releasing hormone (TRH) analogue, N alpha-[((S)-4-oxo-2-azetidinyl)-carbonyl]-L-histidyl-L-prolinamide dihydrate (YM-14673, 0.1 microgram and 1 microgram/0.2 microliters), into the nucleus accumbens, the dorsal and ventrolateral striatum produced repetitive jaw movements in a dose-dependent manner. The effects were greatest in the nucleus accumbens and smallest in the ventrolateral striatum. Pattern of the movements differed from that produced by injections of a mixture of SKF 38393 (5 micrograms) and quinpirole (10 micrograms); frequent tongue protrusions were evident in rats treated with the mixture but those were not seen in YM-14673-treated rats. TRH (1 microgram, 10 micrograms and 30 micrograms/0.2 microliters) did not evoke jaw movements from any of the sites. The non-selective dopamine receptor antagonist, cis-(Z)-flupentixol (10 micrograms), significantly reduced the response to administration of YM-14673 (1 microgram) into the nucleus accumbens or dorsal striatum, while the 5-hydroxytryptamine (5-HT)2A receptor antagonist, 2-(2-dimethylaminoethylthio)-3-phenylquinoline hydrochloride (ICI 169,369, 0.2 micrograms), did not affect the response to YM-14673 (1 microgram). Given intrathecally (0.5 microgram/5 microliters), both YM-14673 and TRH produced wet-dog shakes. Although the mechanisms giving rise to the display of jaw movements after intrastriatal injections of YM-14673 remain unknown, stimulation of the dopamine D1/D2 receptors may at least partly contribute to these effects. Anyhow, these mechanisms differ from that underlying the ability of YM-14673 and TRH to elicit wet-dog shakes, a mechanism that is known to involve serotonergic processes.

Animals↗

Role of striatal dopamine D2 receptors in the paw test, an animal model for the therapeutic efficacy and extrapyramidal side effects of neuroleptic drugs.

The effect of administration of the D2 antagonist sulpiride in three striatal areas (dorsal striatum, DS; nucleus accumbens, ACC; olfactory tubercle; OT) was studied in the so-called paw test. In the paw test two parameters are measured (the hindlimb retraction time (HRT) and the forelimb retraction time (FRT)) that model the therapeutic efficacy and the extrapyramidal side effects of neuroleptics, respectively. Sulpiride significantly enhanced the HRT in each of the three structures. Identical doses of sulpiride administered in the three structures produced similar effects. The FRT was enhanced after administration of sulpiride in the DS and in the ACC. The minimal effective dose was lower for the DS. Administration of sulpiride in the OT did not affect the FRT. The effects on the FRT were very slow in onset (strong effects 4 h or more following administration of sulpiride), especially in comparison to the rapid effect on FRT following systemic administration of classical neuroleptics. To analyze this slowness of effect, two additional experiments were performed: first, the inter-trial time was changed so that it was identical to that used in systemic studies; second, sulpiride was administered simultaneously in the DS and the ACC. Neither experiment produced an earlier effect on the FRT. The present data provide additional evidence for the theory that regional selectivity of drugs determines their propensity to induce extrapyramidal side effects. However, the data also suggest that the generally held view that the dorsal striatum is solely responsible for the extrapyramidal side effects of neuroleptic drugs is too simple.

Animals↗

Dissimilarities between cholinergic and dopaminergic turning elicited by nucleus accumbens stimulation in freely moving rats.

Contralateral turning was produced by unilateral injection of carbachol (0.5, 2.5, 5 micrograms) into the nucleus accumbens, but not into the dorsal or ventral striatum. This behaviour was inhibited by muscarinic M1 acetylcholine receptor blockade in the nucleus accumbens, and less effectively by blockade of muscarinic M2 and nicotinic acetylcholine receptors. Unilateral injection of a mixture of the dopamine D1 receptor agonist 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol (SKF 38393, 5 micrograms) and the dopamine D2 receptor agonist quinpirole (10 micrograms) also produced contralateral turning. The stepping pattern, however, completely differed from that induced by carbachol. The number of carbachol-induced turnings was reduced by dopamine D1 or D2 receptor blockade (8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol (SCH 23390) and l-sulpiride, respectively) in the nucleus accumbens. However, the reduction was due to a change in the turning pattern. Blockade of muscarinic acetylcholine receptors in the nucleus accumbens did not change the contralateral turning induced by unilateral injection of dopamine receptor agonists into the nucleus accumbens. The results demonstrate that there is no functional interaction between the cholinergic and dopaminergic substrates involved, although blockade of the dopamine receptors elicited behavioural deficits that competed with the turning elicited by carbachol. The contralateral turning elicited by carbachol injection into the nucleus accumbens requires an intact dopamine activity at the level of dopamine D1 and D2 receptors in the ipsilateral, but not contralateral, ventrolateral striatum.

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

Movement-related potentials preceding voluntary movement are modulated by the mode of movement selection.

In two experiments movement-related cortical potentials preceding voluntary movement were recorded. In experiment 1, subjects performed four motor tasks involving joystick movements. The four tasks differed in complexity (single vs sequential movements) and in the mode of movement selection, i.e., whether a movement or movement sequence was made in fixed or in self-determined directions. The choice of these tasks was based, firstly, on previous electrophysiological studies suggesting an effect of task-complexity on the amplitude of the readiness potential (RP) and, secondly, on previous positron emission tomography (PET) studies showing that activity of the supplementary motor area (SMA) is influenced by the mode of movement selection. The results show that, for single movements, RP amplitude is higher preceding freely selected movements than preceding movements in a fixed direction. In experiment 2 this effect was replicated using button presses instead of joystick movements. The results converge with PET evidence obtained in similar tasks and establish that the RP is modulated by the mode of movement selection. This modulation is probably related to differential involvement of the SMA.

Adult↗

The olfactory tubercle as a site of action of neuroleptics with an atypical profile in the paw test: effect of risperidone, prothipendyl, ORG 5222, sertindole and olanzapine.

The paw test was used to detect the preclinical profile (classical versus atypical) of five putative, atypical neuroleptics, namely olanzapine, sertindole, risperidone, prothipendyl and ORG 5222. In the paw test classical neuroleptics increase the hindlimb reaction time (HRT), a parameter with predictive validity for antipsychotic efficacy, at doses comparable to those necessary for increasing forelimb reaction time (FRT), a parameter with predictive validity for extrapyramidal side-effects, whereas atypical neuroleptics increase HRT at doses that are much smaller than those increasing FRT. All tested compounds showed the profile of atypical neuroleptics in the paw test. Using the FRT/HRT ratio of minimum effective doses as overall predictor of a favourable ratio of extrapyramidal and therapeutic effects of these drugs, the following order was found: olanzapine (20) > sertindole = risperidone = prothipendyl (10) > ORG 5222 (3). The ability of compounds to attenuate locomotor activity elicited either from the olfactory tubercle (10 micrograms dopamine: OT test) or from the nucleus accumbens (1 microgram ergometrine: ACC test) was used to establish whether the compounds preferentially act in one of these structures. Previous research has shown that classical neuroleptics are far less potent in the OT test than in the ACC test, whereas atypical neuroleptics are far more potent in the OT test than in the ACC test. All five agents preferentially acted in the olfactory tubercle. The order of potency in the olfactory tubercle was as follows: sertindole > ORG 5222 > risperidone > olanzapine > prothipendyl. It is concluded that risperidone, prothipendyl, ORG 5222, sertindole and olanzapine not only show the profile of atypical neuroleptics in the paw test, but also preferentially act in the olfactory tubercle, but not in the nucleus accumbens, viz. two features that they share with the atypical neuroleptics clozapine and thioridazine and with the putative, atypical neuroleptics raclopride and remoxipride.

Animals↗

Interactions of the subthalamic nucleus and the subpallidal area in oro-facial dyskinesia: role of GABA and glutamate.

Previous studies have shown that lowering the GABAergic activity in the sub-pallidal area (SP) in the cat results in the display of oro-facial dyskinesia (OFD). There exists an intense, mutual anatomical connection between the SP and the subthalamic nucleus and the adjoining lateral hypothalamic area (STH). The present study investigated whether the STH is also involved in OFD. Once this turned out to be true (see below), it was investigated whether the SP-specific OFD is funneled via the STH, or vice versa. Bilateral injections of low doses (50-250 ng) of picrotoxin, a non-competitive GABA antagonist, into the STH were found to elicit OFD. This effect which was quantified in terms of numbers of tongue protrusions, was dose-dependent: a bell-shaped dose-response was found (50-500 ng). The OFD elicited by the most effective dose of picrotoxin (250 ng) was significantly antagonized by muscimol, a specific GABAA agonist, in a dose (50 ng) which itself was ineffective, indicating GABA specificity. In addition, it was found that OFD elicited by local injections of picrotoxin (250 ng) into the STH was significantly attenuated by SP injections of the broad spectrum glutamate antagonist kynurenic acid in a dose (1000 ng) which itself was ineffective, but not by muscimol (100 ng), indicating that the STH-elicited OFD needs an intact and functioning glutaminergic, but not GABAergic, transmission process in the SP for its expression.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗