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Biomedical subjects

A R Cools

Publications and source records attributed to A R Cools.

At least 37 records · Page 2Linked to original sources
PubMed2002

Differential effects of a small, unilateral, 6-hydroxydopamine-induced nigral lesion on behavior in high and low responders to novelty.

The goal of this study was to develop an animal model that evaluates striatal-specific behavior after partial, unilateral destruction of nigrostriatal neurons. 6-OHDA (1 microg) was injected intranigrally (day 0) to reduce dopaminergic innervation of the dorsal striatum (DS); 6-OHDA (5 microg) was injected to reduce innervation of DS and nucleus accumbens (ACC). We analyzed changes in (a) behavior regulated by dopamine (DA) release in the DS (hindpaw preference from day 5 to day 19, every other day) and the ACC (novelty-induced locomotion on day 16) and (b) apomorphine-induced rotation (on day 21). We used two types of rat that show differences in structure and function of the dopaminergic neurons, namely high (HR) and low (LR) responders to novelty. 6-OHDA (1 microg) significantly decreased TH immunoreactivity (TH-ir) in the DS and increased preference for the hindpaw controlled by the nonlesioned side in HRs and LRs in time. Only in LRs was the significant increase of novelty-induced locomotion accompanied by a significant increase in TH-ir density in the ACC: this suggests a lesion-induced shift in nigrostriatal/mesolimbic balance toward a dominance of the mesolimbic system. The higher 6-OHDA dose significantly decreased TH-ir in the DS and the ACC and increased preference for the hindpaw controlled by the nonlesioned side in HRs and LRs in time. However, this increase occurred significantly earlier in LRs than in HRs. Apomorphine elicited contralateral rotations solely in LRs, and not in HRs, indicating development of supersensitive dopamine receptors in the DS of LRs, but not HRs. The data show that LRs are more susceptible to 6-OHDA than HRs. The relevance of the present data for Parkinson's disease is discussed.

Animals↗
PubMed2002

SKF 83959 is an antagonist of dopamine D1-like receptors in the prefrontal cortex and nucleus accumbens: a key to its antiparkinsonian effect in animals?

SKF 83959 that has a unique antiparkinson profile in animal models of Parkinson's disease is an in vitro dopamine D1 antagonist of receptors coupled to adenylyl cyclase. We hypothesized that SKF 83959, among others, interacts with dopamine D1 receptors coupled to adenylyl cyclase in the nucleus accumbens and the prefrontal cortex. Effects of intra-accumbal injections of SKF 83959 on locomotor activity were compared to effects of the dopamine D1 agonist SKF 81297 and the dopamine D1 antagonist SCH 39166. Similarly to SCH 39166, SKF 83959 did not affect locomotor activity, but counteracted SKF 81297-induced locomotor activity. Effects of unilateral intra-prefrontal injections of SKF 83959 on rotational behaviour were compared to the effects of the dopamine D1 agonist SKF 81297 and the dopamine D1 antagonists SCH 23390 and SCH 39166 in rats selected on basis of their high locomotor response to novelty and pretreated with a subcutaneous injection of 0.75 mg/kg dexamphetamine. Like SCH 39166 and SCH 23390, SKF 83959 induced a bias for contralateral rotating and blocked the SKF 81297-induced bias for ipsilateral rotating. In conclusion, SKF 83959 is an in vivo antagonist of dopamine D1 receptors that are coupled to adenylyl cyclase in the nucleus accumbens and the prefrontal cortex. The role of these receptors in the antiparkinson profile of SKF 83959 is discussed.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2002

High and low responders to novelty and mesolimbic noradrenaline: effects of noradrenergic agents on radial-maze performance.

The authors used high and low responders to novelty (HRs and LRs, respectively) to examine the effects of noradrenergic injections into the nucleus accumbens using a special radial-maze task. During the 5 successive test days, solvent-treated HRs acquired this task faster than LRs. Isoproterenol (beta-agonist) combined with phenylephrine (alpha-agonist) improved acquisition in LRs but not in HRs; this effect was counteracted by propranolol (beta-antagonist) and phentolamine (alpha-antagonist). Propranolol combined with phentolamine, as well as phentolamine alone, disrupted acquisition in HRs but not in LRs. Data show that the effects of noradrenergic agents in HRs and LRs are due to differences in acquisition directed by type-specific differences in functional mesolimbic noradrenaline.

Adrenergic alpha-Agonists↗
PubMed2001

Differential cortico-motoneuron vulnerability after chronic mitochondrial inhibition in vitro and the role of glutamate receptors.

Chronic treatment of rat cortical slices with a relative low concentration of mitochondrial inhibitor malonate leads to cortical motoneuron (CMN) death. In the neurodegenerative disease amyotrophic lateral sclerosis (ALS) corticospinal neurons, CMNs projecting to the spinal cord, degenerate. In the present study we compared the effect of chronic mitochondrial inhibition on the survival of CMNs located in the dorsal cortical areas (including corticospinal neurons) with that on ventrally located CMNs (non-corticospinal neurons) in vitro. In the explant culture model used, the dorsally located CMNs were less vulnerable to a 2-week period of mitochondrial inhibition with malonate as compared to ventrally located CMNs. Treatment with 5 mM malonate resulted in 50% surviving CMNs in the dorsal part and only 16% in the ventral part. Neuroprotection of the CMNs could be achieved with co-administration of the non-NMDA antagonist CNQX, the NMDA antagonist MK-801, or the glutamate release inhibitor riluzole, suggesting that chronic energy shortage leads to excitotoxicity. In the dorsal cortical areas CNQX, MK-801, and riluzole had a neuroprotective effect on the CMNs, whereas in the ventral cortical areas only MK-801 was neuroprotective. The sensitivity to energy depletion and consequently excitotoxicity may be related to glutamate receptor density and subunit composition in various cortical areas, but also to the projection length and input of CMNs in vivo. The present investigation gives insight in mechanisms leading to excitotoxic cell death of CMNs and may therefore be important for the development of treatment strategies in protection and survival of cortical motoneurons in ALS.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2001

Malonate-induced cortico-motoneuron death is attenuated by NT-4, but not by BDNF or NT-3.

Neurotrophins are promising candidates to slow the progression of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease in which spinal and cortical motoneurons selectively degenerate. In a long-term in vitro model, malonate-induced toxicity and cell death of motoneurons have been demonstrated. Here we studied the neuroprotective effect of BDNF, NT-3, and NT-4 on the cell death of cortical motoneurons in an organotypic culture model after chronic mitochondrial inhibition with malonate. Our data show that NT-4 completely prevents malonate-induced toxicity, whereas BDNF or NT-3 had no neuroprotective effect. In clinical trials for ALS, predominantly focussed on the survival of spinal motoneurons, BDNF has already been tested with disappointing results; our results suggest that NT-4 may be a better neurotrophin to prevent motoneuron loss.

Amyotrophic Lateral Sclerosis↗
PubMed2001

Chronic mitochondrial inhibition induces glutamate-mediated corticomotoneuron death in an organotypic culture model.

There is growing evidence that mitochondrial dysfunction is an important factor in a cascade of neurotoxic events as observed during pathogenesis of various neurodegenerative diseases. In the neurodegenerative disease amyotrophic lateral sclerosis (ALS) both spinal and cortical motoneurons degenerate, but in experimental studies most attention so far has been focussed on the spinal motoneurons. In order to study the role of mitochondrial dysfunction in the pathways leading to cortical (upper) motoneuron (CMN) death, a long-term culture system of rat cortical explants was used. CMNs were visualized by immunocytochemical labeling with antibodies directed against nonphosphorylated neurofilament, SMI-32, and for their identification we also used their location in layer V of the explant, their size, and their morphological appearance. In this model the effect of mitochondrial inhibition was studied through chronic malonate treatment. For 2 weeks, low doses of complex II inhibitor malonate were added to the cultures twice a week. The malonate-induced chronic mitochondrial inhibition resulted in a dose-dependent increase of CMN death in the slices. Neuroprotection was achieved with the NMDA antagonist MK-801 and the non-NMDA antagonist CNQX indicating the involvement of glutamate in the malonate-induced CMN death. Furthermore, our data indicate that chronic mitochondrial inhibition results in CMN death, which is mediated by glutamate excitotoxicity via both non-NMDA and NMDA receptors. In this respect the present in vitro approach may act as a model for understanding mechanisms underlying CMN death in ALS.

Animals↗
PubMed2001

Auditory information processing in rat genotypes with different dopaminergic properties.

RATIONALE: Auditory filtering disturbances, as measured in the sensory gating and prepulse inhibition (PPI) paradigms, have been linked to aberrant auditory information processing and sensory overload in schizophrenic patients. In both paradigms, the response to the second stimulus (S2) is attenuated by an inhibitory effect of the first stimulus (S1). Dopamine (DA) agonists have been found to reduce gating of auditory evoked potentials (AEPs) and PPI in healthy human subjects and in rats. These effects have been linked to DA hyperactivity in the mesolimbic system. A non-invasive approach in studying the role of the DA system in PPI and AEP gating is to compare rat genotypes that are marked by distinct DA systems. OBJECTIVES: Several questions were asked in the present study. Are PPI and AEP gating disturbed in (a) rats that are marked by a relatively high DA reactivity of the mesolimbic system, namely apomorphine-susceptible (APO-SUS) and WAG/Rij rats or in (b) rats that are marked by a relatively high DA activity of the nigrostriatal system, namely apomorphine-unsusceptible (APO-UNSUS) and ACI rats? Moreover, is the particular DA balance (c) between the nigrostriatal and mesolimbic system related to deficits in PPI and AEP gating? METHODS: For this purpose, the above-mentioned four rat genotypes (APO-SUS, APO-UNSUS, ACI and WAG/Rij) that vary in DA balance between both systems, were compared in the AEP gating paradigm. PPI was only measured in the ACI and WAG/Rij rats, since it has already been shown in a previous study that APO-SUS rats show diminished PPI as compared to rats of the APO-UNSUS genotype. RESULTS: AEP gating of the vertex N50 was significantly reduced in WAG/Rij rats as compared to the remaining three rat genotypes (APO-SUS, APO-UNSUS and ACI). No PPI deficits were found in the ACI and WAG/Rij rats, although ACI rats had a significantly higher basal startle amplitude. CONCLUSIONS: The PPI deficit in APO-SUS and not in the other genotypes, suggests that especially a relatively high DA reactivity of the mesolimbic system, together with a relatively low activity of the nigrostriatal system, contributes to this deficit. In contrast, the N50 gating deficit in WAG/Rij rats and not in the other genotypes suggests that a relatively high DA activity of the nigrostriatal system together with a relatively high DA reactivity of the mesolimbic system is necessary for the presence of a N50 gating deficit. On the basis of these results we have concluded that both auditory filtering processes are differently regulated by DA in the nigrostriatal and mesolimbic systems.

Acoustic Stimulation↗
PubMed2001

Sensory gating of auditory evoked potentials in rats: effects of repetitive stimulation and the interstimulus interval.

In the P50 gating or conditioning-testing (C-T) paradigm, the P50 response, a small positive midlatency ( approximately 50 ms after stimulus onset) component of the human auditory evoked potential (AEP), is reduced towards the second click (S2) as compared to the response to the first click (S1). This phenomenon is called sensory gating. The putative function of sensory gating is thought to protect subjects from being flooded by irrelevant stimuli. Comparative studies have been done in rats in order to elucidate the underlying neural substrate of sensory gating. However, for a direct comparison of rat and human AEP components, it is imperative for both components to show similar characteristics. The amount of sensory gating in humans is dependent on repetitive stimulation and the interstimulus interval (ISI). In the present study effects of repetitive stimulation (Experiment 1) and various ISIs (Experiment 2) were determined on rat AEP components. The results demonstrate that gating is not limited to a restricted cortical area or a single midlatency component and that repetitive stimulation and ISI affect gating of several rat AEP components. Components such as the vertex P17 and N22 show a decrease in gating within several S1-S2 presentations, mainly due to a decrease in amplitude to S1 (Experiment 1). Gating for vertex components (such as the P17, N22 and N50) is ISI dependent (Experiment 2), but there is no interval in the 200-600 ms range at which optimal gating occurs. The ISI effects on gating are due to an increase of the amplitude to S2. The results have implications for the discussion about the rat homologue of the human P50.

Animals↗
PubMed2001

GABA(A) agents injected into the ventral pallidum differentially affect dopaminergic pivoting and cholinergic circling elicited from the shell of the nucleus accumbens.

The ability of GABA(A) receptors in the ventral pallidum to modulate shell-specific behavior was studied. Injections of the non-selective acetylcholine receptor agonist, carbachol (5 microg), into the shell of the nucleus accumbens elicited contraversive circling, namely turning marked by normal stepping; in contrast, injections of a mixture of dopamine D(1) (SKF 38393, 5 microg) and D(2) (quinpirole, 10 microg) receptor agonists into this brain structure elicited contraversive pivoting, namely turning marked by abnormal hindlimb stepping. Unilateral injections of the GABA(A) receptor agonist muscimol (10, 25 and 50 ng) into the ventral pallidum dose-dependently mimicked shell-specific circling, especially when given at a level +8.6mm anterior to the interaural line; this effect was GABA(A) receptor specific, because it was prevented by the GABA(A) receptor antagonist bicuculline (150 ng). Unilateral pallidal injections of a dose of muscimol that was ineffective per se (10 ng) abolished contraversive pivoting elicited by shell injections of dopamine receptor agonists; instead, it elicited moderate ipsiversive pivoting. Pallidal injections of bicuculline (150 ng) replaced the contraversive pivoting elicited by dopamine receptor agonist with ipsiversive circling. In contrast, unilateral pallidal injections of 10 ng muscimol (anterior +8.6mm level) suppressed the contraversive circling elicited by shell injections of carbachol; instead, it elicited moderate ipsiversive pivoting. Pallidal injections of bicuculline (150 ng) produced short-lasting ipsiversive circling that was followed by contraversive pivoting. We conclude that the ventromedial portion of the ventral pallidum contains GABA(A) receptors that are crucial for the transmission of information from the shell of the nucleus accumbens via the ventral pallidum towards other brain structures; this holds especially for information about shell-specific circling elicited by carbachol. The same portion of the ventral pallidum also contains GABA(A) receptors that control the transfer of information from the nucleus accumbens towards structures outside the ventral pallidum; this holds especially for information about shell-specific pivoting elicited by dopaminergic agonists.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2001

Hippocampal and cortical sensory gating in rats: effects of quinpirole microinjections in nucleus accumbens core and shell.

Sensory processing disturbances, as measured in the P50/sensory gating paradigm, have been linked to aberrant auditory information processing and sensory overload in schizophrenic patients. In this paradigm, the response to the second of paired-click stimuli is attenuated by an inhibitory effect of the first stimulus. Sensory gating has been observed in most healthy human subjects and normal laboratory rats. Because mesolimbic dopamine has been implicated in other filtering disturbances such as prepulse inhibition of the acoustic startle response and given the fact that amphetamine and apomorphine have been shown to disrupt gating, this study was performed to investigate the role of mesolimbic dopamine in sensory gating. The dopamine D2 receptor agonist quinpirole (10 microg/0.5 microl) was injected bilaterally in nucleus accumbens core and shell and effects on cortical and hippocampal sensory gating were investigated. Also, effects of the dopamine D2 receptor antagonist haloperidol (0.1 mg/kg, subcutaneously) as pretreatment were studied. First, quinpirole significantly reduced both the amplitude to the first click and gating as measured in the cortex and in the hippocampus. There was a tendency for the quinpirole effects on hippocampal gating to be more pronounced in rats injected in the shell. Secondly, haloperidol did not antagonize effects of quinpirole on hippocampal parameters, whereas haloperidol pretreatment fully antagonized quinpirole effects on cortical parameters. In conclusion, gating can be significantly reduced when a dopamine agonist is specifically targeted at mesolimbic dopamine D2 receptors. However, an important consideration is that the dopaminergic effects in the present study on gating are predominantly mediated by the effects on the amplitude to the first click. This has also been suggested for systemic amphetamine injections in rats and schizophrenic patients. This casts doubt on whether dopamine receptor activation affects the putative inhibitory process between the first and the second stimulus.

Acoustic Stimulation↗
PubMed2001

Cognitive styles in high-functioning adolescents with autistic disorder.

This study addressed the operationalization, the identification, and the prevalence of weak central coherence and poor cognitive shifting in 35 high-functioning adolescents with autism. Central coherence and cognitive shifting were represented by two factors in a factor analysis, each reflecting a constituent aspect of the domain in question. With regard to central coherence, these aspects were the ability of piecemeal processing and the ability to process meaning. The aspects related to cognitive shifting concerned internally and externally controlled shifting. Weak central coherence and poor cognitive shifting did not appear to be related to measures of symptom severity, social understanding, and social competence. Both these cognitive styles did not appear to be universal to autism. In our sample, weak central coherence and poor cognitive shifting were found to be significantly more common than in normative control subjects.

Adolescent↗
PubMed2001

The role of medial prefrontal cortical dopamine in spontaneous flexibility in the rat.

In rat studies, both lesions in the medial prefrontal cortex (mPFC) and alterations of the level of mPFC dopamine (DA) have been found to induce disturbances in behavioural flexibility, as measured with switching tasks. It is not clear whether mPFC DA is also involved in spontaneous flexibility. Therefore, the aim of the present study was to investigate the role of mPFC DA in spontaneous flexibility. As a measure for spontaneous flexibility, the diversity in spatial distribution of exploration on a large open field was used. The rats received local injections into the mPFC with a D1 or D2 antagonist, or the dopamimetic, amphetamine. The results showed that both DA antagonists reduced spontaneous flexibility, due to increased stimulus-bound behaviour. Amphetamine had a similar effect to the DA antagonists. It is suggested that this is most likely due to an amphetamine-induced increase in extracellular DA, leading to a suboptimal level of mPFC DA.

Amphetamine↗
PubMed2001

Dopamine characteristics in rat genotypes with distinct susceptibility to epileptic activity: apomorphine-induced stereotyped gnawing and novelty/amphetamine-induced locomotor stimulation.

Rat genotypes differ in their susceptibility to spontaneously occurring spike-wave discharges and in their dopaminergic properties. In a previous study, it was found that spike-wave discharge incidence decreased in the following order in four rat genotypes during baseline and following injection with the dopamine antagonist haloperidol: apomorphine-susceptible (APO-SUS) > WAG/Rij > apomorphine-unsusceptible (APO-UNSUS) and ACI rats. The question in the present study was to what extent certain dopaminergic properties are pathognomonic for epileptic rats. Therefore, behavioral responses were assessed in order to investigate the dopaminergic properties in the four rat genotypes. Apomorphine-induced gnawing data imply that the dopamine activity of the nigrostriatal system in the WAG/Rij rats is higher than in APO-SUS but lower than in the ACI and APO-UNSUS rats. Furthermore, in previous studies APO-SUS have been shown to have a higher novelty/amphetamine-induced locomotion, indicative of a higher dopamine reactivity of the mesolimbic system as compared to APO-UNSUS rats. Results from the present study showed that WAG/Rij rats have a higher locomotor responsiveness to novelty/amphetamine, indicating a higher dopamine reactivity of the mesolimbic system in comparison to the ACI rats. It is suggested that the functional dopaminergic mesolimbic dominance is an important factor in the susceptibility to show spontaneously occurring spike-wave discharges.

Amphetamine↗
PubMed2001

Equal sensitivity to cocaine reward in addiction-prone and addiction-resistant rat genotypes.

Rat genotypes tentatively identified as addiction-prone or addiction-resistant on the basis of alcohol preference and locomotor responsiveness to novelty--Lewis versus Fischer strains and Nijmegen high versus low responder lines--differed in time to develop intravenous cocaine self-administration habits, but did not differ in sensitivity to the ability of cocaine reward to summate with lateral hypothalamic brain stimulation reward. Moreover, rats from the Nijmegen low-responder line that initiated self-administration came to do so compulsively and to the same degree as did the Nijmegen high-responder rats. Thus the differences between both sets of genotypes appeared to reflect differences in reactions to the testing situation more than differences in reaction to the reinforcing drug per se.

Alcohol Drinking↗
PubMed2001

Effects of JL13, a pyridobenzoxazepine with potential atypical antipsychotic activity, in animal models for schizophrenia.

JL13 [5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5] benzoxazepine fumarate] is a substance with a close structural resemblance to clozapine. However, it is less sensitive to oxidation and may therefore have less hematological side effects. In the present study, JL13 was compared with clozapine and haloperidol in several animal models for schizophrenia. The paw test represents a screening model for antipsychotic drugs that can discriminate between drugs with extrapyramidal side effects and drugs without. Haloperidol increased both forelimb retraction time and hindlimb retraction time (HRT), whereas both clozapine and JL13 increased only HRT. In the prepulse inhibition paradigm, all three drugs reversed the apomorphine- and the amphetamine-induced disruption of prepulse inhibition. However, whereas haloperidol was equally effective against both dopaminergic drugs, JL13 and clozapine were more effective against amphetamine. Finally, only JL13 was able to increase prepulse inhibition in normal rats, whereas only clozapine reduced basal startle amplitude. Taken together, these data suggest that JL13 may be an effective antipsychotic drug, with a profile similar to clozapine.

Amphetamine↗
PubMed2000

Neurorescuing effects of the GAPDH ligand CGP 3466B.

(-)-Deprenyl, used for the treatment of Parkinson's disease, was reported to possess neurorescuing/antiapoptotic effects independent of its MAO-B inhibiting properties. It is metabolized to (-)-desmethyldeprenyl, which seems to be the active principle, and further to (-)-amphetamine and (-)-methamphetamine, which antagonize its rescuing effects. These complications may explain the limited neurorescuing potential of (-)-deprenyl observed clinically. CGP 3466 (dibenzo[b,f]oxepin-10-ylmethyl-methyl-prop-2-ynyl-amine), structurally related to (-)-deprenyl, exhibits virtually no MAO-B nor MAO-A inhibiting properties and is not metabolized to amphetamines. It was shown to bind to glyceraldehyde-3-phosphate dehydrogenase, a glycolytic enzyme with multiple other functions including an involvement in apoptosis, and shows neurorescuing properties qualitatively similar to, but about 100-fold more potent than those of (-)-deprenyl in several in vitro and in vivo paradigms. In concentrations ranging from 10(-13)-10(-5) M, it rescues partially differentiated PC12 cells from apoptosis induced by trophic withdrawal, cerebellar granule cells from apoptosis induced by cytosine arabinoside, rat embryonic mesencephalic dopaminergic cells from death caused by MPP+, and PAJU human neuroblastoma cells from death caused by rotenone. However, it did not affect apoptosis elicited by a variety of agents in rapidly proliferating cells from thymus or skin or in liver or kidney cells. In vivo, it rescued facial motor neuron cell bodies in rat pups after axotomy, rat hippocampal CA1 neurons after transient ischemia/hypoxia, and mouse nigral dopaminergic cell bodies from death induced by MPTP, in doses ranging between 0.0003 and 0.1 mg/kg p.o. or s.c., depending on the model. It also partially prevented the loss of tyrosine hydroxylase immunoreactivity in the substantia nigra of 6-OHDA-lesioned rats and improved motor function in these animals. Moreover, it prolonged the life-span of progressive motor neuronopathy (pmn) mice (a model for ALS), preserved their body weight and improved their motor performance. This was accompanied by a decreased loss of motor neurons and motor neuron fibers, and protection of mitochondria. The active concentration- or dose-ranges in the different in vitro and in vivo paradigms were remarkably similar. In several paradigms, bell-shaped dose-response curves were observed, the rescuing effect being lost above about 1 mg/kg, a fact that must be considered in clinical investigations.

Animals↗
PubMed2000

The neuroprotective effects of CGP 3466B in the best in vivo model of Parkinson's disease, the bilaterally MPTP-treated rhesus monkey.

The propargylamine CGP 3466B prevents dopamine cell death both in vitro and in rodent models of Parkinson's disease. The present study investigates the efficacy of this compound to prevent the behavioral consequences of dopaminergic cell death in the best animal model of Parkinson's disease, the bilaterally MPTP-treated monkey. Rhesus monkeys were bilaterally treated with MPTP, using a two-step procedure: 2.50 mg MPTP was infused into the left carotid artery followed by a second bolus of 1.25 mg into the right carotid artery, 8 weeks later. Subcutaneous injection of either 0.014 mg/kg CGP 3466B (n = 4) or its solvent (distilled water; n = 4), twice daily for fourteen days, started two hours after the second MPTP infusion. A Parkinson rating scale was assessed for the evaluation of the effects. After the first MPTP treatment, the monkeys developed mild to moderate parkinsonian symptoms. The second MPTP treatment strongly increased the severity of Parkinson scores in all control monkeys, as assessed on day 3, 7, 14, 21, 28 and 35 after the second MPTP treatment. In contrast, CGP 3466B nearly completely prevented the increase of parkinsonian symptoms after the second MPTP treatment. The therapeutic effects of CGP 3466B were still present after a washout period of 3 weeks, implying that the effects were not symptomatic. These data are the first to show that the systemic administration of CGP 3466B is able to prevent the development of MPTP-induced motor symptoms in primates. This compound may have great value for inhibiting the progression of the neurodegenerative process in patients with Parkinson's disease.

Animals↗