Biomedical subjects

Alexander R Cools

Publications and source records attributed to Alexander R Cools.

45 records · Page 3Linked to original sources

PubMed2002

Reduced tumor growth, experimental metastasis formation, and angiogenesis in rats with a hyperreactive dopaminergic system.

Outgrowth of solid tumors requires blood supply to the tumor. Tumor angiogenesis is dependent on the interplay between tumor-derived angiogenic factors and stromal cells. Recently, it has been shown that the neurotransmitter dopamine is a potent inhibitor of VEGF-induced angiogenesis. Moreover, there is evidence that patients with schizophrenia have a hyperreactive dopaminergic system and are relatively protected from cancer. We hypothesized that hyperreactivity of the dopaminergic system is related to reduced angiogenesis and tumor development. Therefore, we investigated tumor growth and angiogenesis in two lines of Wistar rats with high (APO-SUS) or low (APO-UNSUS) dopaminergic reactivity. Subcutaneous implants of mammary adenocarcinoma cells (MADB106) in matrigel remained 35% smaller in APO-SUS rats than in APO-UNSUS rats (P<0.01). Moreover, APO-SUS rats developed less lung metastases after i.v. administration of MADB106 tumor cells. Furthermore, hemoglobin content (APO-SUS: 40.6+/-7.6; APO-UNSUS: 76.9+/-13 mg/dl, P<0.05) and expression of the endothelial determinant PECAM-1 in tumors from APO-SUS rats were reduced (APO-SUS: 37+/-18; APO-UNSUS 69+/-25 units, P<0.01), indicating that reduced angiogenesis is responsible for reduced tumor development in APO-SUS rats. These results suggest a novel link between dopaminergic reactivity, angiogenesis, and tumor development and may explain part of the individual differences in cancer progression.

Animals↗

PubMed2002

Dopaminergic and cholinergic stimulation of the ventrolateral striatum elicit rat jaw movements that are funnelled via distinct efferents.

It has been reported that two distinct types of jaw movements can be elicited by bilateral injections of drugs into the ventrolateral striatum: (1) dopamine receptor-mediated jaw movements that are elicited by a mixture of (+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol (SKF 82958; 5 microg) and quinpirole (10 microg), and (2) acetylcholine receptor-mediated jaw movements that are elicited by carbachol (2.5 microg). In the present study, electromyographic analysis was used to characterise these movements: the dopamine receptor-mediated jaw movements were marked by a dominant digastric activity during jaw opening and a dominant masseter activity during jaw closing (digastric/masseter type), whereas the acetylcholine receptor-mediated jaw movements were marked by a dominant digastric activity during jaw opening without any significant change in masseter activity during jaw closing (digastric type). The main goal was to (in)validate the hypothesis that these two types of jaw movements are funnelled via distinct gamma-aminobutyric acid (GABA)ergic output channels. Bilateral injections of both muscimol (25 and 50 ng/0.2 microl per side) and bicuculline (50 and 150 ng/0.2 microl per side) into the ventral pallidum, entopeduncular nucleus or dorsolateral part of the substantia nigra pars reticulata essentially inhibited dopamine receptor-mediated jaw movements to various degrees. In contrast, acetylcholine receptor-mediated jaw movements were inhibited by muscimol given into the entopeduncular nucleus and dorsolateral part of the substantia nigra pars reticulata, whereas these movements were enhanced by bicuculline. The acetylcholine receptor-mediated jaw movements were not affected by muscimol injections into the ventral pallidum, but were inhibited by bicuculline injections. Studies on such injections into the ventral pallidum, entopeduncular nucleus or dorsolateral part of the substantia nigra pars reticulata of naive rats revealed that jaw movements of the digastric/masseter type were elicited either by muscimol injections into the dorsolateral part of the substantia nigra pars reticulata or by combined injections of muscimol and bicuculline into the entopeduncular nucleus, and that jaw movements of the digastric type were elicited only by combined injections of muscimol and bicuculline into the entopeduncular nucleus. Together, the data allow the conclusion that dopamine receptor-mediated and acetylcholine receptor-mediated jaw movements are two distinct types of jaw movements that are funnelled via separate GABAergic output channels. It is suggested that the three different profiles of responses to GABAergic drugs in animals showing either dopamine receptor-mediated or acetylcholine receptor-mediated jaw movements reflect the involvement of three distinct types of output neurons of the striatum, namely: type I neurons with collateralised axons to the ventral pallidum, entopeduncular nucleus and dorsolateral part of the substantia nigra pars reticulata, mediating the dopamine receptor-mediated jaw movements; type II neurons with collateralised axons to the globus pallidus that, in turn, project to the entopeduncular nucleus and the dorsolateral part of the substantia nigra pars reticulata, mediating directly the acetylcholine receptor-mediated jaw movements; and type III neurons with a single axon to the ventral pallidum, mediating indirectly the acetylcholine receptor-mediated movements. It is evident that future studies are required to provide direct evidence in favour of the latter hypothesis.

Animals↗

PubMed2002

Early maternal deprivation and prepulse inhibition: the role of the postdeprivation environment.

Early postnatal maternal deprivation leads to a variety of biochemical and behavioural alterations in the offspring, some of which do not develop until adulthood, like deficits in prepulse inhibition. Since a number of these deficits are similar to abnormalities observed in schizophrenic patients, maternal deprivation has been proposed as an interesting model for schizophrenia. However, little is still known about the processes that determine these long-term consequences. Previous experiments showed that the strain of rats and the deprivation procedure are important factors. In the present set of experiments, we focussed on the postdeprivation period. We showed that rearing normal Wistar rats in social isolation from weaning disrupts prepulse inhibition. However, if maternally deprived Wistar rats were reared in social isolation, the prepulse inhibition was normal. We further showed that if only half of the litters were maternally deprived at postnatal day 9, the animals had only a small disruption in prepulse inhibition compared to animals that came from litters where all the animals were deprived. In a final experiment, we crossfostered maternally deprived mothers to nondeprived pups and vice versa. This experiment showed that both the nondeprived pups raised by a deprived mother and the deprived pups raised by a nondeprived mother had small deficits in prepulse inhibition. Taken together, these data clearly show that the postdeprivation period is of crucial importance for the development of prepulse inhibition deficits in maternally deprived rats. We present a working model in order to explain the long-term behavioural consequences of maternal deprivation.

Animals↗

PubMed2002

Maternal deprivation of rat pups increases clinical symptoms of experimental autoimmune encephalomyelitis at adult age.

Maternal deprivation of neonatal animals has been shown to induce long-lasting changes in the reactivity of the neuroendocrine system. The aim of the present study was to investigate whether maternal deprivation also affects susceptibility to immune-mediated diseases such as experimental autoimmune encephalomyelitis (EAE) in adult life. To this end, 9-day-old rat pups were subjected to a short-lasting maternal deprivation for a period of 24 h. At the age of 8 weeks, we induced EAE in these rats by immunization with myelin basic protein (MBP) in complete Freund's adjuvant. Our data demonstrate that short-lasting maternal deprivation induces a marked increase in the severity of EAE in the animals in later life. The histopathological evaluation of spinal cord and cerebellum corresponded with the observed differences in clinical symptoms of EAE. Moreover, neonatal maternal deprivation affects macrophage functioning at adult age. In contrast, no differences were observed in in vitro mitogen- and MBP-induced cytokine production by splenocytes. LPS-induced corticosterone release did not differ either between maternally deprived and control animals. We conclude that short-lasting neonatal maternal deprivation of rat pups has long-lasting consequences for macrophage activity and for susceptibility to the inflammatory autoimmune disease EAE.

Aging↗

PubMed2002

Apomorphine susceptibility and animal models for psychopathology: genes and environment.

Many years ago we found a bimodal distribution of a number of different behaviors in our regular outbred Wistar stock. This was observed in the response to novelty, the response in a resident-intruder test as well as in the stereotypy response to the dopamine agonist apomorphine. On the basis of that, we decided to selectively breed these animals, which resulted in the the APO-SUS and APO-UNSUS lines. The APO-SUS rats show a strong, stereotyped gnawing response, whereas APO-UNSUS show only a weak gnawing response. Follow-up studies have shown that the phenotypical expression of these rats depend on genetic and early and late environmental factors. Because these rats were not selected on the basis of a specific behavioral trait, but rather on the basis of a difference in susceptibility for a specific neurotransmitter, it is not surprising that these animals show major differences in the neurochemical state of the central nervous system. In fact, in many respects they represent mirror images of each other. Moreover, these animals show clear differences in their endocrine and immunological systems. APO-SUS rats can be characterized as having a hyper-reactive hypothalamus-pituitary-adrenal axis, and a dominance of the T(H2) system. Apart from discussing the main differences between APO-SUS and APO-UNSUS rats, the review specifically focuses on the former as a potential model for schizophrenia. We have been able to show that APO-SUS rats indeed share a large number of behavioral, neurochemical, endocrinological, and immunological similarities with patients suffering from schizophrenia. Because schizophrenia is also likely to result from an interaction between genetic and early stressful life events, the APO-SUS rat might represent a promising animal model for studying this severe mental disorder.

Animals↗

PubMed2002

The role of hippocampal dopamine receptors in prepulse inhibition.

Although it has long been realized that the hippocampal formation receives a projection from the midbrain dopaminergic cell groups and contains mRNA for all five dopamine receptors, the functional role of this dopaminergic projection has not been studied so far. The present study aimed to investigate the role of dopamine receptors in the dorsal CA1 area of the hippocampus in prepulse inhibition. The results show that local application of amphetamine reduced prepulse inhibition without affecting the baseline startle amplitude. This effect of amphetamine could be reversed by coadministration of the D1 antagonist SCH23390. Moreover, local application of the D1 agonist SKF81297 also disrupted prepulse inhibition without altering basal startle amplitude. These data clearly suggest that the hippocampal D1 receptor plays an important role in prepulse inhibition. The effects of amphetamine could not be reversed by coadministration of the D2 antagonist sulpiride. Interestingly, the D2/3 agonist quinpirole did reduce prepulse inhibition, again without affecting basal startle amplitude. Because quinpirole has a much higher affinity for the D3 receptor than does sulpiride, it is suggested that the D3 receptor might be involved in this effect.

Amphetamine↗

PubMed2002

Creatine kinase B-driven energy transfer in the brain is important for habituation and spatial learning behaviour, mossy fibre field size and determination of seizure susceptibility.

Creatine kinases are important in maintaining cellular-energy homeostasis, and neuroprotective effects have been attributed to the administration of creatine and creatine-like compounds. Herein we examine whether ablation of the cytosolic brain-type creatine kinase (B-CK) in mice has detrimental effects on brain development, physiological integrity or task performance. Mice deficient in B-CK (B-CK-/-) showed no gross abnormalities in brain anatomy or mitochondrial ultrastructure, but had a larger intra- and infrapyramidal mossy fibre area. Nuclear magnetic resonance spectroscopy revealed that adenosine triphosphate (ATP) and phosphocreatine (PCr) levels were unaffected, but demonstrated an apparent reduction of the PCr left arrow over right arrow ATP phosphorus exchange capacity in these mice. When assessing behavioural characteristics B-CK-/- animals showed diminished open-field habituation. In the water maze, adult B-CK-/- mice were slower to learn, but acquired the spatial task. This task performance deficit persisted in 24-month-old, aged B-CK-/- mice, on top of the age-related memory decline normally seen in old animals. Finally, a delayed development of pentylenetetrazole-induced seizures (creating a high-energy demand) was observed in B-CK-/- mice. It is suggested that the persistent expression of the mitochondrial isoform ubiquitous mitochondrial CK (UbCKmit) in the creatine/phospho-creatine shuttle provides compensation for the loss of B-CK in the brain. Our studies indicate a role for the creatine-phosphocreatine/CK circuit in the formation or maintenance of hippocampal mossy fibre connections, and processes that involve habituation, spatial learning and seizure susceptibility. However, for fuelling of basic physiological activities the role of B-CK can be compensated for by other systems in the versatile and robust metabolic-energy network of the brain.

Animals↗

PubMed2002

Stress susceptibility as a determinant of the response to adrenergic stimuli in mesenteric resistance arteries of the rat.

Characterized by the behavioral response to apomorphine, two outbred lines of Wistar rats can be recognized with constitutionally determined high (apomorphine susceptible, APO-SUS) or low (apomorphine unsusceptible, APO-UNSUS) adrenal responses to similar environmental stress. Within the accumbens nucleus, the APO-SUS and APO-UNSUS rats differ in alpha -adrenergic receptor responsiveness. This study explored whether these differences in adrenergic receptor sensitivity also exist in mesenteric resistance arteries. A Mulvany myograph was used to study the vasomotor responses of isolated mesenteric resistance arteries to adrenergic receptor stimulation. Phenylephrine (alpha1-agonist)-induced vasoconstriction did not differ between the two lines (pEC : 5.8 +/- 0.05 microM versus 5.8 +/- 0.04 microM and Emax: 36 +/- 2 kPa versus 33 +/- 1 kPa for APO-SUS, n = 9, and APO-UNSUS, n = 11, respectively, p > 0.1). After precontraction with phenylephrine, salbutamol (beta -agonist)-induced relaxation was less in APO-SUS rats (pEC50 4.9 +/- 0.06 versus 5.3 +/- 0.06M for APO-SUS, n = 9, and APO-UNSUS, n = 7, respectively, p < 0.001). Likewise, clonidine (alpha2-agonist)-induced relaxation was reduced in APO-SUS rats (pEC50: 6.7 +/- 0.07 versus 7.0 +/- 0.04, for APO-SUS, n = 9, and APO-UNSUS, n = 8, respectively; p < 0.01). In conclusion, constitutionally determined high susceptibility to stress is accompanied by an impaired vasorelaxation to adrenergic stimuli whereas vasoconstriction is unaffected. An unopposed vasoconstrictor action of norepinephrine may place the APO-SUS rats at increased risk for the development of hypertension, insulin resistance, and atherosclerosis.

Animals↗

PubMedDate not supplied

Mice lacking the UbCKmit isoform of creatine kinase reveal slower spatial learning acquisition, diminished exploration and habituation, and reduced acoustic startle reflex responses.

Brain-type creatine kinases B-CK (cytosolic) and UbCKmit (mitochondrial) are considered important for the maintenance and distribution of cellular energy in the central nervous system. Previously, we have demonstrated an abnormal behavioral phenotype in mice lacking the B-CK creatine kinase isoform, regarding exploration, habituation, seizure susceptibility and spatial learning. The phenotype in these mice was associated with histological adaptations in the hippocampal mossy fiber field size. Here, mice lacking the ubiquitous mitochondrial creatine kinase isoform (UbCKmit-/- mice) showed, when subjected to a similar battery of behavioral tasks, diminished open field habituation and slower spatial learning acquisition in the Morris water maze task, but normal sensory or motor functions. A reduced acoustic startle response, higher threshold, and lack of prepulse inhibition were observed in UbCKmit-/- mice, suggesting that the unconditioned reflexive responsiveness is not optimal. Our findings suggest a role for mitochondrial CK-mediated high-energy phosphoryl transfer in synaptic signalling in the acoustic signal response network and hippocampal-dependent learning circuitry of brain. Finally, we demonstrate that UbCKmit has a widespread occurrence in the cell soma of neuronal nuclei along the rostro-caudal axis of the brain, i.e. cortex, midbrain, hindbrain, cerebellum and brainstem, similar to the occurrence of B-CK. This may explain the similarity of phenotypes in mice lacking B-CK or UbCKmit. We predict that the remaining functional intactness of the cytosolic B-CK reaction and perhaps the compensatory role of other phosphoryl transfer systems are sufficient to sustain the energy requirements for basic sensory, motor and physiological activities in UbCKmit-/- mice.

Acoustic Stimulation↗