Biomedical subjects

A Blokland

Publications and source records attributed to A Blokland.

At least 19 recordsLinked to original sources

PubMed2006

Serotonergic vulnerability and depression: assumptions, experimental evidence and implications.

In recent years, the term serotonergic vulnerability (SV) has been used in scientific literature, but so far it has not been explicitly defined. This review article attempts to elucidate the SV concept. SV can be defined as increased sensitivity to natural or experimental alterations of the serotonergic (5-HTergic) system. Several factors that may disrupt the 5-HTergic system and hence contribute to SV are discussed, including genetic factors, female gender, personality characteristics, several types of stress and drug use. It is explained that SV can be demonstrated by means of manipulations of the 5-HTergic system, such as 5-HT challenges or acute tryptophan depletion (ATD). Results of 5-HT challenge studies and ATD studies are discussed in terms of their implications for the concept of SV. A model is proposed in which a combination of various factors that may compromise 5-HT functioning in one person can result in depression or other 5-HT-related pathology. By manipulating 5-HT levels, in particular with ATD, vulnerable subjects may be identified before pathology initiates, providing the opportunity to take preventive action. Although it is not likely that this model applies to all cases of depression, or is able to identify all vulnerable subjects, the strength of the model is that it may enable identification of vulnerable subjects before the 5-HT related pathology occurs.

Animals↗

PubMed2006

Improving memory: a role for phosphodiesterases.

During the last decennia, our understanding of the neurobiological processes underlying learning and memory has continuously improved, leading to the identification of targets for the development of memory-enhancing drugs. Here we review a class of drugs which has more recently been identified: the phosphodiesterase (PDE) inhibitors. An overview is given of the different PDEs that are known and we focus on three PDEs which have been identified as possible relevant targets for memory improvement: PDE2, PDE4 and PDE5. PDEs differ in the substrate, i.e. cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP), being hydrolyzed. Since these cyclic nucleotides have been suggested to play distinct roles in processes of memory, selective PDE inhibitors preventing the breakdown of cAMP and/or cGMP could improve memory. The present data suggest that PDE4 (cAMP) is involved in acquisition processes, although a possible role in late consolidation processes cannot be excluded. PDE5 (cGMP) is involved in early consolidation processes. Since PDE2 inhibition affects both cAMP and cGMP, PDE2 inhibitors may improve both memory processes. The field of PDEs is highly dynamic and new isoforms of PDEs are still being described. This may lead to the discovery and development of new memory enhancing drugs that selectively inhibit such isoforms. Such drugs may exert their effects only in specific brain areas and hence possess an improved side effect profile.

Brain↗

PubMed2005

Rolipram reverses scopolamine-induced and time-dependent memory deficits in object recognition by different mechanisms of action.

In this study, the effect of the selective phosphodiesterase type 4 (PDE4) inhibitor rolipram on memory performance was investigated using the object recognition task. First, three doses of rolipram (0.01, 0.03 or 0.1 mg/kg) were tested with a 24h delay between the learning (T1) and the test (T2) trial. Doses of rolipram were injected at different time points (30 min before T1, immediately after T1 or 3 h after T1). In a second experiment, the effects of rolipram (0.03, 0.1 or 0.3 mg/kg) were tested in combination with scopolamine (0.1 mg/kg) applying a 1 h delay between trials. Both substances were administered 30 min before T1. Using a 24h interval, rolipram showed an improvement in long-term memory performance when injected 3 h after T1 at a dose of 0.03 mg/kg. Further, rolipram reversed the scopolamine-induced short-term memory deficit at a dose of 0.1 mg/kg. Although the improved memory performance in both conditions is likely to be explained by elevated cAMP levels, two separate working mechanisms might explain these effects.

Animals↗

PubMed2005

The selective PDE5 inhibitor, sildenafil, improves object memory in Swiss mice and increases cGMP levels in hippocampal slices.

Previous studies have shown memory enhancing effects of phosphodiesterase type 5 (PDE5) inhibitors in rats. However, differences in nitric oxide (NO)-mediated cyclic GMP (cGMP) signaling in the hippocampus have been described between rats and mice. In the present study we investigated the memory enhancing effects of the PDE5 inhibitor, sildenafil on memory performance in Swiss mice using the object recognition task. Sildenafil (0.3, 1 and 3 mg/kg) was administered orally directly after the first trial. The memory for the objects was retested 24 h later when mice show no memory for the familiar object. Sildenafil improved the object discrimination performance of Swiss mice at a dose of 1 mg/kg. Hippocampal slices of Swiss mice incubated with sildenafil (10 microM) increased cGMP levels in varicosities in the CA3 region of the hippocampus and a number of short, thin fibers. Addition of DEA/NO, an NO donor (10 microM), in the presence of sildenafil (10 microM) strongly increased cGMP immunoreactivity of varicosities in the CA3 region. Double immunostaining of cGMP with the presynaptic marker synaptophysin did not reveal any co-localization of these markers under any circumstance. Taken together, inhibition of PDE5 improves object recognition memory in mice. Furthermore, a postsynaptic role of cGMP could be involved in this respect.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2005

Evaluation of DOI, 8-OH-DPAT, eticlopride and amphetamine on impulsive responding in a reaction time task in rats.

We examined the effects of DOI (2,5-dimethoxy-4-iodoamphetamine), 8-OH-DPAT (8-hydroxy-2-(N,N-dipropylamino)tetralin, eticlopride and amphetamine in a reaction time (RT) task. In this task a trial is initiated after a rat pushes a panel. Rats have to wait (0.5-1.5 s) until a tone is presented before making a response. The number of premature responses, releasing the panel before tone was switched on, was taken as a measure of motor impulsivity. A group of 10 Lewis rats was tested in the RT task after treatment with different doses of drugs which have been shown previously to affect impulsive responding: DOI (0.1, 0.2 mg/kg), 8-OH-DPAT (0.1, 0.3 mg/kg), eticlopride (0.01, 0.03 mg/kg) and D-amphetamine (0.3, 1 mg/kg). A progressive ratio test was used to control for drug effects on food motivation. DOI (0.1 mg/kg) and D-amphetamine (0.3 mg/kg) increased impulsive responding in the RT task. Conversely, 8-OH-DPAT decreased impulsive responding in the RT task. These effects of DOI, D-amphetamine and 8-OH-DPAT on impulsive responding were not associated with changes in food motivation, as assessed by performance in the progressive ratio task. Eticlopride did not affect impulsive responding. The present data suggest that 5-HT2A receptors and dopamine (but not D2 receptors) are associated with motor impulsivity.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2004

Acute tryptophan and serotonin depletion using an optimized tryptophan-free protein-carbohydrate mixture in the adult rat.

In contrast to humans, a tryptophan (TRP)-free amino acid (AA) mixture only leads to moderate depletion in plasma TRP levels in adult rats. In this study we evaluated the effects of an acute administration of a TRP-free protein-carbohydrate nutritional mixture in adult male Wistar rats. Plasma amino acid levels were examined at 2 and 4h starting after the first administration. Furthermore, the concentrations of amino acid, serotonin (5-HT), dopamine (DA) and their metabolite (5-hydroxyindolacetic acid (5-HIAA) and 3,4-dihydroxyphenylacetic acid (DOPAC), respectively) were measured within the striatum, hippocampus and cortex. In the TRP depleted animals, the TRP/sigmaLNAA ratio (LNAA: large neutral amino acids) was substantial decreased at 2 and 4h after the first administration of the oral administration (by 71 and 78%, respectively). Four hours after treatment central TRP and 5-HT concentrations were decreased by 50%. Both peripheral and central TRP levels returned to basal values in the group treated with the nutritional mixture supplemented with TRP. Surprisingly, tyrosine levels were also reduced after oral administration of the protein-carbohydrate mixture without affecting central DA concentrations. In conclusion, the TRP-free protein-carbohydrate nutritional mixture appears to be an efficient tool to substantially reduce plasma and central TRP levels in adult rat.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2003

Impact of perinatal asphyxia on the GABAergic and locomotor system.

Perinatal asphyxia can cause neuronal loss and depletion of neurotransmitters within the striatum. The striatum plays an important role in motor control, sensorimotor integration and learning. In the present study we investigated whether perinatal asphyxia leads to motor deficits related to striatal damage, and in particular to the loss of GABAergic neurons. Perinatal asphyxia was induced in time-pregnant Wistar rats on the day of delivery by placing the uterus horns, containing the pups, in a 37 degrees C water bath for 20 min. Three motor performance tasks (open field, grip test and walking pattern) were performed at 3 and 6 weeks of age. Antibodies against calbindin and parvalbumin were used to stain GABAergic striatal projection neurons and interneurons, respectively. The motor tests revealed subtle effects of perinatal asphyxia, i.e. small decrease in motor activity. Analysis of the walking pattern revealed an increase in stride width at 6 weeks of age after perinatal asphyxia. Furthermore, a substantial loss of calbindin-immunoreactive (-22%) and parvalbumin-immunoreactive (-43%) cells was found in the striatum following perinatal asphyxia at two months of age. GABA(A) receptor autoradiography revealed no changes in GABA binding activity within the striatum, globus pallidus or substantia nigra. We conclude that perinatal asphyxia resulted in a loss of GABAergic projection neurons and interneurons in the striatum without alteration of GABA(A) receptor affinity. Despite a considerable loss of striatal neurons, only minor deficits in motor performance were found after perinatal asphyxia.

Animals↗

PubMed2003

Effects of repeated anaesthesia on central cholinergic function in the rat cerebral cortex.

BACKGROUND AND OBJECTIVE: General anaesthesia may contribute to postoperative cognitive decline in the elderly. The aim was to determine the effects of repeated pentobarbital anaesthesia throughout life on central cholinergic function in the rat. METHODS: Young Lewis rats were randomly allocated to two groups. The anaesthesia group (n = 15) was anaesthetized with pentobarbital 20 mg kg(-1) intraperitoneally at 6, 8.5, 11, 13.5, 16, 18.5, 21 and 23.5 months of age. The control group (n = 12) was treated identically, apart from the anaesthesia. At 26 months of age, the animals were killed and the brain dissected and stored for analysis. Central cholinergic function in the cortex and hippocampus was assessed by measuring [3H]-epibatidine and [125I]alpha-bungarotoxin binding to nicotinic receptors and choline acetyltransferase (ChAT) activity. RESULTS: Tissue from nine rats in the anaesthesia group and eight in the control group was available for analysis. There was a significant reduction in alpha-bungarotoxin binding in the anaesthetized compared with the control group in the superior cortex (P < 0.0002) and molecular cortex (P < 0.04). There were no significant differences between the groups for epibatidine binding or ChAT. CONCLUSIONS: Repeated anaesthesia in rat reduces central nicotinic cholinergic binding in the cortex. The findings may have implications for postoperative cognitive function studies.

Anesthesia, General↗

PubMed2002

Effects of two selective phosphodiesterase type 5 inhibitors, sildenafil and vardenafil, on object recognition memory and hippocampal cyclic GMP levels in the rat.

The present study investigated the effects of two cyclic GMP-specific phosphodiesterase enzyme type 5 inhibitors, sildenafil and vardenafil, on the memory performance in the object recognition task. Both compounds were given per orally (1, 3 and 10 mg/kg sildenafil; 0.1, 0.3, 1 and 3 mg/kg vardenafil) immediately after the exposure to two identical objects. The memory for the objects was tested 24 h later. Vehicle-treated rats spent equal times exploring a new and the familiar object demonstrating that they did not remember the familiar one. However, sildenafil improved the object discrimination performance of the rats with a high discrimination performance at a dose of 3 mg/kg. Rats treated with vardenafil also showed an improved object discrimination performance. Compared with sildenafil, vardenafil appeared to be even more potent in this respect since it already produced a high discrimination performance at a dose of 0.3 mg/kg. The effects of both compounds on cyclic GMP and cyclic AMP accumulation were studied in rat hippocampal slices incubated in vitro. Cyclic GMP levels were increased after incubation with the highest concentration of 100 microM vardenafil (together with 0.1 mM sodium nitroprusside), although no changes in cyclic GMP levels were detected after incubation with different concentrations of sildenafil. Both compounds had no effect on cyclic AMP levels. Additional cyclic GMP immunocytochemistry showed that incubation with vardenafil (in the presence of sodium nitroprusside) resulted in a concentration-dependent staining of cyclic GMP. Staining was predominantly found in neuronal fibres in the hippocampal CA2/CA3 region. It was already detected at a concentration of 0.1 microM vardenafil. Also positive fibres were detected after incubation with sildenafil but at a higher concentration of 10 microM. Taken together, these results suggest that inhibition of phosphodiesterase enzyme type 5 improves object recognition memory. This effect might be explained by increased levels of central cyclic GMP.

Animals↗

PubMed2001

Apolipoprotein E protects against neuropathology induced by a high-fat diet and maintains the integrity of the blood-brain barrier during aging.

SUMMARY: The present study provides evidence that chronic intake of a high-fat diet induces a dramatic extravasation of immunoglobulins, indicating alterations in blood-brain barrier (BBB) functioning, in the brains of apolipoprotein E (apoE)-knockout mice, but not of C57Bl/6 control mice. Using sodium fluorescein as a marker for the permeability of the BBB, we found additional support for age-related disturbances of BBB function in apoE-knockout mice. Behavioral analysis of apoE-knockout mice compared with C57Bl/6 mice indicated that they were also less efficient in acquiring the spatial Morris water maze task. Furthermore, apoE-knockout mice are known to develop severe atherosclerosis, which is exacerbated with a high-fat diet. We therefore compared the apoE-knockout mice with the apoE3-Leiden transgenic mice, which are known to develop atherosclerosis. However, apoE3-Leiden mice that were kept on a high-fat, high-cholesterol diet and that developed atherosclerosis to an extent similar to the apoE-knockout mice, showed no signs of BBB disturbances. These results indicate for the first time that apoE plays an essential role in the maintenance of the integrity of the BBB during aging and that it protects the brain from neuropathology induced by a high-fat diet. We therefore hypothesize that the role of apoE in the maintenance of the integrity of the BBB may be the mechanism by which apoE affects the progression of neurodegeneration, as seen in Alzheimer's disease.

Aging↗

PubMed2001

Long-term consequences of repeated pentobarbital anaesthesia on choice reaction time performance in ageing rats.

Recent studies have suggested that anaesthesia may be a factor in cognitive decline with age. We examined the effect of repeated (eight times) anaesthesia with pentobarbital on reaction time performance in rats in a longitudinal study. Treated rats had faster response times and made more premature responses than the control rats when they were older than 21 months. The results suggest that repeated anaesthesia during the lifespan can lead to an increase in impulsivity, as assessed by a choice reaction time test, during the later stages of life in the rat. These findings support the theory that repeated anaesthesia is a biological factor that affects cognitive ageing.

Adjuvants, Anesthesia↗

PubMed2000

Nitric oxide synthase does not mediate neurotoxicity after an i.c.v. injection of streptozotocin in the rat.

In the present study we evaluated the possible role of nitric oxide (NO) in mediating neuronal damage in middle-aged rats after an i.c.v. injection of streptozotocin (STREP). An i.c.v. injection of STREP has been reported to decrease the central metabolism of glucose. This inhibition of the energy metabolism after STREP treatment might induce an excitotoxic mechanism, which may lead to the stimulation of NO synthase and, consequently to the synthesis of NO. On the other hand, STREP might induce oxidative stress directly by liberation of NO from its nitroso moiety. To investigate whether NO synthase is involved in a possible excitotoxic mechanism after STREP treatment, some of the rats treated with STREP (1.25 mg/ kg in 4 microl, bilaterally 2 microl/injection site) were also treated with the NO synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME, 20 mg/kg i.p. 10 min, 6, 24 and 96 h after STREP injection). To investigate whether NO liberated from STREP may be responsible for neurotoxic effects, one additional group of control rats received an i.c.v. injection of the NO donor sodium nitroprusside (SNP, 10 microg in 4 microl). We found that STREP affected the behavioral performances in the open field and two-way active avoidance task. In addition, immunostaining for glial fibrillary acidic protein, an indicator of reactive astroglial changes to neuronal damage, showed that this was mainly located in peri- and paraventricular regions of the third and lateral ventricles, like for instance in the septum, caudate putamen and hippocampus. L-NAME treatment had no protective effect on the behavioral impairments and neuronal damage of STREP-treated rats. This suggests that the neuronal damage of STREP may still be a result of the decrease in the central energy metabolism, but without the involvement of NO synthase. This was supported by measuring, using immunostaining, the NO-mediated cyclic GMP production by the enzyme soluble guanylyl cyclase in cortical slices, i.e. L-NAME did not prevent NO production after STREP administration in vitro. In addition, it was found that SNP liberated NO in vitro, whereas in vivo SNP administration did not lead to any behavioral and neuronal deficits at all. However, the present study cannot exclude the involvement of NO liberated from STREP in neuronal damage.

Animals↗

PubMed2000

Effects of hypothermia and gender on survival and behavior after perinatal asphyxia in rats.

Previous studies in rats have demonstrated that perinatal asphyxia (PA) produces long-term morphological alterations, particularly affecting hippocampus. neostriatum, and cerebral cortex. These changes were prevented by applying hypothermia during the asphyctic insult. Because these cerebral areas are involved in cognitive and motor functions, the aim of the present study was to determine whether periods of PA during normothermia or hypothermia produces long-term behavioral impairments in rats of both sexes. The cognitive and motor functions were studied using the spatial Morris water maze (MWM) task at 1.5 months, and the open field at 5 months, respectively. The present study revealed that female rats had a higher survival rate than males after PA in normothermic conditions (p < 0.014). and that hypothermia drastically prolonged the time of survival in both sexes (p < 0.001). There were no differences in learning and memory functions between groups or male and female rats when tested with MWM. Rats subjected to hypothermia treatment did not show differences in the MWM compared to controls. A lower locomotor activity in the open field test was only observed in male rats that suffered 15 and 20 min of PA in normothermia (p < 0.05). Hypothermia treatment prevented this hypoactivity. PA in females, even if severe, did not affect the motor activity. The data of both behavioral tests showed differences between sexes, i.e., the female rats learned the MWM task slower, and were more active in the open field. This work lends further support for the hypothesis that hypothermia can prevent mortality as well as long-term sequelae induced by PA.

Animals↗

PubMed2000

Modelling cognitive dysfunctions with bilateral injections of ibotenic acid into the rat entorhinal cortex.

Neurodegenerative diseases, traumatic brain injury and stroke are likely to result in cognitive dysfunctioning. Animal models are needed in which these deficits and recovery of the affected functions can be investigated. In the present study, the entorhinal area was chosen as the target for lesioning and for assessing the lesion-induced deficits in the Morris water maze. The entorhinal cortex is regarded as an interface between the hippocampus and neocortex. Deafferentiating the hippocampus through entorhinal lesions impairs spatial learning. The effects of lesions, induced by either electrocoagulation (experiment 1) or ibotenate excitotoxicity (experiment 2), on spatial orientation behaviour were investigated. Water maze performance after unilateral or bilateral ibotenate injections into the entorhinal cortex was studied in the third experiment. In an additional study, the replicability of the spatial learning deficit after lesions induced by bilateral injections of ibotenic acid into the entorhinal cortex was assessed by comparing the results of nine experiments. We found that spatial learning was impaired after bilateral lesions aimed at the entorhinal cortex. The electrolytic lesion technique produced a relatively large sham effect, whereas the excitotoxic lesioning method did not. Unilateral injections of ibotenic acid into the entorhinal cortex did not affect spatial navigation. The ibotenate-induced lesions replicably produced deficits in the Morris tasks. The degree of the induced spatial learning impairments and the effects on the rate of acquisition during training, however, differed between experiments. This result suggests that the fundamental biological diversity between shipments of rats can account for variation in the effects of parahippocampal damage on spatial learning even in highly standardized experimental set-ups. Rats lesioned by bilateral injections of ibotenic acid into the entorhinal cortex provide an interesting and reliable model for investigating cognitive dysfunctions in neurodegenerative diseases, stroke or traumatic brain injury.

Brain Injuries↗

PubMed2000

Perinatal asphyxia results in changes in presynaptic bouton number in striatum and cerebral cortex-a stereological and behavioral analysis.

Deficits in cognitive function have been related to quantitative changes in synaptic population, particularly in the cerebral cortex. Here, we used an established model of perinatal asphyxia that induces morphological changes, i.e. neuron loss in the cerebral cortex and striatum, as well as behavioural deficits. We hypothesized that perinatal asphyxia may lead to a neurodegenerative process resulting in cognitive impairment and altered presynaptic bouton numbers in adult rats. We studied cognitive performance at 18 months and presynaptic bouton numbers at 22 months following perinatal asphyxia. Data of the spatial Morris water escape task did not reveal clear memory or learning deficits in aged asphyctic rats compared to aged control rats. However, a memory impairment in aged rats versus young rats was observed, which was more pronounced in asphyctic rats. We found an increase in presynaptic bouton density in the parietal cortex, whereas no changes were found in striatum and frontal cortex in asphyctic rats. An increase of striatal volume was observed in asphyctic rats, leading to an increase in presynaptic bouton numbers in this area. These findings stress the issue that volume measurements have to be taken into account when determining presynaptic bouton density. Furthermore, perinatal asphyxia led to region-specific changes in presynaptic bouton numbers and it worsened the age-related cognitive impairment. These results suggest that perinatal asphyxia induced neuronal loss, which is compensated for by an increase in presynaptic bouton numbers.

Adult↗

PubMed1999

Metrifonate improves working but not reference memory performance in a spatial cone field task.

The effects of metrifonate (3, 10 and 30 mg/kg, p.o.) on the working and reference memory performance of the rat were assessed in a spatial cone field task. The highest dose of metrifonate (30 mg/kg) improved the working memory performance, whereas none of the doses affected the reference memory performance. Other parameters of spatial discrimination performance were not affected by metrifonate treatment. The present results suggest that metrifonate has cognition-enhancing properties which are likely to be related to aspects of (spatial) working memory.

Animals↗

PubMed1999

Behavioral effects of apamin, a selective inhibitor of the SK(Ca)-channel, in mice and rats.

Apamin, a highly selective and potent peptide that blocks the SK(Ca)-channels has been suggested to be a cognition enhancer. We tested apamin in the Morris water escape task, in shock motivated avoidance tasks, and in operant tasks in the Skinnerbox. We also used non-cognitive tests, such as the rat forced swimming test and cocaine-induced locomotor activity in the open field, and a test to assess the side effect profile. Mice and rats from different strains, and rats of different ages were used. The rat studies provided only weak support for the notion that apamin acts as a cognition enhancer. More convincing evidence was obtained from the mouse studies. Overt side effects of apamin were found at the dose of 0.3 mg kg(-1). This dose was close to, or even overlapped, the doses which improved cognition in mice. We conclude that apamin is a poor tool to assess the role of SK(Ca)-channels in learning and memory processes.

Aging↗

PubMed1999

Cognitive performance and biochemical markers in septum, hippocampus and striatum of rats after an i.c.v. injection of streptozotocin: a correlation analysis.

In the present study we evaluated the effects of an intracerebroventricular injection of streptozotocin on cognitive behavior and biochemical markers in the brain of middle-aged Wistar rats. Intracerebroventricular injected streptozotocin has previously been reported to decrease the central metabolism of glucose. We found that streptozotocin-treated rats showed an impaired cognitive performance in the delayed non-matching to position task and the Morris water escape task. Glial fibrillary acidic protein, an indicator of reactive astroglial changes, was measured in three different (soluble, Triton X-100 soluble and crude cytoskeletal) protein fractions and its content in the fractions of the septum, hippocampus and striatum of streptozotocin-treated rats was increased. Furthermore, the glial fibrillary acidic protein response of each protein fraction to streptozotocin treatment appeared to be differently regulated. In streptozotocin-treated rats the choline acetyltransferase activity was decreased in the hippocampus only, which was correlated with the hippocampal glial fibrillary acidic protein contents of all three hippocampal protein fractions, thus suggesting that the cholinergic deficit is a consequence of direct damage to the hippocampus. The cognitive deficits in both tasks were related to the increased glial fibrillary acidic protein contents, especially of the soluble and cytoskeletal fraction, and the decreased choline acetyltransferase activity in the hippocampus. Taken together, these findings indicate that it is important to take into account which protein fraction has been used for measuring the glial fibrillary acidic protein response to a stressor. Furthermore, intracerebroventricular injected streptozotocin may provide a relevant model for studying neurodegenerative changes due to a metabolic insufficiency and testing neuroprotective effects of substances.

Animals↗