Search PubMed⌕ Search

Biomedical subjects

M G Feenstra

Publications and source records attributed to M G Feenstra.

At least 37 records · Page 2Linked to original sources
PubMed1995

C-Fos expression in the rat brain after pharmacological stimulation of the rat "mediodorsal" thalamus by means of microdialysis.

In order to visualize target cells of thalamic projections in the rat brain we examined the induction of c-fos messenger RNA and Fos-like immunoreactivity following stimulation of the "mediodorsal" thalamus (midline, mediodorsal and intralaminar nuclei) in freely moving rats. The thalamic neurons were activated through disinhibition by perfusion of the GABAA antagonist bicuculline-methyl chloride via a microdialysis cannula placed in the mediodorsal nucleus of the thalamus. The rats were allowed a recovery period of at least 20 h after surgery before being coupled to the perfusion pump. Cannula implantation with or without 4 h of Ringer perfusion caused hardly any detectable c-fos expression in the brain, but 20 min of bicuculline (0.1 mM) perfusion induced high levels of c-fos messenger RNA and Fos protein expression in the area adjacent to the dialysis membrane, indicating activated thalamic neurons. In situ hybridization as well as immunohistochemical analysis of the frontal cortical areas and limbic structures showed a rapid, specific and transient c-fos expression in the medial and lateral prefrontal cortex, nucleus accumbens, mediodorsal striatum, claustrum, nucleus reticularis of the thalamus and amygdala. The overall spatial distribution of the c-fos response was comparable to the innervation patterns of thalamic efferents known from anatomical tracing experiments. The rats were perfused with Ringer while asleep, but they woke up during treatment with bicuculline and displayed an increase in general behavioural activity, which could be correlated to the amount of bicuculline measurable in the dialysate. Pathological behaviours, such as epilepsy, were not noticeable during bicuculline treatment. These results show that it is possible to selectively activate defined anatomical pathways by pharmacological application of drugs using microdialysis in unanesthetized unrestrained animals and to visualize the transsynaptically activated target neurons of these projections. We conclude that this novel experimental approach is indeed suitable for studying functional anatomical pathways.

Animals↗
PubMed1995

Early postnatal appearance of enhanced noradrenaline content in the brain of vasopressin-deficient Brattleboro rat; normal adrenoceptor densities and aberrant influences of vasopressin treatment.

The course of postnatal development of noradrenaline (NA) and its unconjugated free metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), as well as the influence on early chronic vasopressin treatment, were investigated in various brain regions of the hereditary vasopressin-deficient (homozygous di/di) Brattleboro rat. In addition, the densities of the adrenergic receptor subtypes were measured in adult brain. Brain NA levels of di/di pups appeared enhanced already at 7 days of age when compared with data of heterozygous (+/di) controls. This was also seen in areas not known to receive a vasopressinergic input, e.g. the frontal cortex. Levels of MHPG also differed between genotypes, but changes were slight and either a decrease or increase, depending on age and region tested. Saturation analyses of alpha 1-, alpha 2-, and beta-adrenoceptor binding on crude membrane preparations of some brain regions revealed no differences in adulthood. Chronic treatment with vasopressin between 6 and 13 days of age reduced the enhanced NA brain levels throughout the brain of the di/di Brattleboro pups. The known vasopressin-mediated enhancement of NA turnover in adult brain was also measurable in +/di pups of this neonatal period (MHPG/NA ratios), indicating the early maturation of the interaction of vasopressinergic and NAergic systems. However, the dose-response in the di/di Brattleboro rat was biphasic with a decrease at a low dose of vasopressin. Since changes were found throughout the brain, it was concluded that vasopressin deficiency had altered the maturation of NA neurons of the locus coeruleus which may be due to the absence of a presumed inhibitory control of vasopressin on synthesis and storage mechanisms at the perikaryal level.

Animals↗
PubMed1994

Effects of neonatal exposure to clonidine on basal and activated central noradrenaline metabolism and in vivo overflow.

The occurrence of persistent effects of chronic neonatal exposure to the alpha 2-adrenoceptor agonist clonidine was investigated by determination of tissue concentrations of monoamines and metabolites and in vivo overflow of noradrenaline and its metabolites, in various rat brain regions during adulthood. Rat pups were treated with clonidine from postnatal day 10-20 and all measurements were carried out between postnatal day 40 and 58. Tissue concentrations of monoamines and metabolites of the early clonidine-treated rats did not differ significantly from the control group. A challenge with yohimbine did not reveal altered responses of monoaminergic systems, except for the failure of an increased serotonergic activity in the medulla pons. In vivo microdialysis measurements revealed an elevated basal extracellular noradrenaline level in amygdala, but not in frontal cortex and hippocampus. Pharmacological challenge in vivo with idazoxan did not reveal differences between clonidine- and saline-exposed rats. These results confirm previous findings that continuous activation of alpha 2-adrenoceptors during a particular period of rat brain development may result in long-lasting but small changes in monoaminergic activity. However, these alterations are not very consistent and may depend on the parameter chosen to reflect monoaminergic activity and are not revealed more clearly by activating (challenging) the noradrenaline system with alpha2-adrenoceptor antagonists.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed1994

Increased alpha 2-adrenoceptor mediated regulation of adult rat brain noradrenaline overflow after chronic neonatal exposure to propranolol; a microdialysis study.

Direct and persistent effects of chronic neonatal administration of the beta-adrenoceptor antagonist propranolol on brain noradrenergic activity were investigated by measuring tissue concentrations of noradrenaline and its metabolites and in vivo overflow of noradrenaline during adulthood. Rat pups were chronically treated with propranolol from postnatal day 1 to day 10. Determination of monoamine metabolism after the last injection showed an increase in noradrenaline metabolism in frontal cortex, limbic system and hippocampus of propranolol-exposed rats, but 47 days after this last injection it was apparent that these effects were not long-lasting. Moreover, basal noradrenaline overflow in vivo in the hippocampus of 40-55 day-old propranolol-exposed rats did not differ from that in controls. However, the regulation of noradrenaline release seemed to have been altered, since a pharmacological challenge with the alpha 2-adrenoceptor antagonist idazoxan induced an enhanced increase in the in vivo noradrenaline overflow in propranolol-exposed rats compared to controls. It is suggested that the neonatal beta-blockade induced a supersensitivity of the presynaptic alpha 2-adrenoceptor. The precise mechanism underlying this effect has to be elucidated.

Aging↗
PubMed1994

Regional differences in the in vivo regulation of the extracellular levels of noradrenaline and its metabolites in rat brain.

Microdialysis was used to determine extracellular levels of both noradrenaline and its metabolites in several brain regions of rats under basal conditions and in response to drugs selective for the alpha 2-adrenoceptor to study regional differences in the regulation of noradrenaline overflow. Basal overflow of noradrenaline was about 1.3 fmol/min in frontoparietal cortex, amygdala and hippocampus and in the medial prefrontal cortex 2.4 fmol/min was measured, whereas the overflow of the noradrenaline metabolites 3,4-dihydroxyphenylglycol and 3-methoxy-4-hydroxyphenylglycol was 10-fold higher. After correction for recovery and membrane length no regional differences in the basal overflow of noradrenaline (NA) were found. There were, however, regional differences in the drug-induced effects: locally applied moxonidine decreased extracellular noradrenaline stronger in the frontoparietal cortex than in the medial prefrontal cortex. The increase in noradrenaline overflow caused by idazoxan (10(-4) M) was stronger in frontoparietal cortex than in amygdala and hippocampus. The metabolites were also generally decreased by moxonidine and increased by idazoxan, although less markedly. The present study shows that the regulation of noradrenaline overflow by the presynaptic alpha 2-autoreceptor was stronger in cortical regions than in amygdala and hippocampus. In those latter regions the uptake mechanism probably plays a relatively more important role in the regulation of noradrenaline overflow.

Adrenergic alpha-Agonists↗
PubMed1994

Activity-dependent plasticity of inhibitory and excitatory amino acid transmitter systems in cultured rat cerebral cortex.

Chronic suppression of spontaneous bioelectric activity in cultures of dissociated fetal rat cerebral cortex increases neuronal cell death and results in electrophysiological changes which indicate an altered balance between excitatory and inhibitory neurotransmission in culture. To delineate whether alterations in neurotransmitter release could underlie this imbalance, we investigated the effects of chronic tetrodotoxin (TTX) treatment on the content and release of glutamate, aspartate and gamma-aminobutyric acid (GABA) in culture. Chronic TTX treatment decreased the content of all amino acids investigated. However, only GABA was decreased relative to the neuronal marker NSE (neuron-specific enolase), indicating a disproportionate loss of GABA production following chronic silencing. Depolarization-induced release of GABA, glutamate and aspartate increased about 10-fold between 7 and 21 days in control cultures. Chronic TTX treatment significantly increased the depolarization-induced release of glutamate and aspartate at 7 days in vitro relative to control levels. At all ages it caused a two-fold increase in the ratio of evoked excitatory amino acid release to that of GABA. These observations suggest that chronic silencing of developing neocortex cell cultures increases the ratio of excitatory to inhibitory synaptic activity either by differential cell death or by reduced synaptic efficiency, on which a decrease in GABA neurotransmission appears to play a major role. Since similar mechanisms may be involved in activity-dependent plasticity in vivo, these cultures provide a useful model to analyse this phenomenon at the cell biological and molecular level.

Animals↗
PubMed1993

Determination of propranolol, labetalol and clenbuterol in rat brain by high-performance liquid chromatography.

A rapid and simple HPLC method for the measurement of adrenergic drugs (propranolol, labetalol and clenbuterol) in rat brain is described. This method was applied to establish if these drugs can pass the blood-brain barrier in prenatal or early post-natal life. The chromatography was performed using a C18 column and a phosphate buffer (pH 3)-acetonitrile (65:35, v/v) mixture. After homogenization of the brain tissue in perchloric acid, the supernatant was buffered at pH 9 and extracted with diethyl ether, followed by back-extraction in sulphuric acid. Recoveries of between 80 and 100% were achieved. The method was found to be accurate (100%) and precise (coefficient of variation around 10%). All three drugs were readily detected in the brain of neonatal rats after peripheral administration. In addition, we demonstrated the presence of propranolol in the fetal brain after maternal administration.

Animals↗
PubMed1993

Monoamine concentrations in rat prefrontal cortex and other mesolimbocortical structures in response to partial neonatal lesions of the medial prefrontal cortex.

In an earlier study it was found that partial neonatal lesions of the medial prefrontal cortex (mPFC) resulted in an increased dopaminergic innervation in the remaining part of mPFC along with functional sparing. The present study assessed whether this response is restricted to this part of the cortex or whether also other structures of the mesolimbocortical system are involved. Furthermore, it was investigated whether the other monoaminergic systems were affected by neonatal mPFC lesions. In 6-day-old rats, the mPFC was partially ablated or a sham operation was made. The concentrations of dopamine (DA) and its metabolites increased to 250-350% in the remaining part of the mPFC compared to the sham-operated controls. The response was most prominent in this part of the cortex; no other mesolimbocortical structure showed such major changes of DA and its metabolites. In addition, a small increase in the concentrations of noradrenaline, serotonin and their metabolites was also spotted in the remaining mPFC and some other mesolimbocortical structures of the lesioned animals. The present data support the suggested involvement of DA in the neural mechanism of sparing of function, and this DA response seems to be most prominent in the remaining mPFC. However, the responses of the noradrenergic and serotonergic systems may also be important for sparing of function to occur.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Postnatal exposure to the beta-adrenoceptor agonist clenbuterol has regionally selective direct and long-term effects on rat brain beta-adrenoceptors and monoamine metabolism.

The effects of chronic postnatal beta 2-adrenoceptor activation on the maturation of the rat brain noradrenergic system have been studied. For that purpose, rat pups have been treated twice daily during the first 10 days of life with the beta 2-agonist clenbuterol-HCl (2.5 mg/kg s.c.), and the effects on the beta-adrenoceptor number and monoamine metabolism have been determined directly after the treatment and in adulthood. On postnatal day 10, 90 min after the last clenbuterol injection 4.5 micrograms/g of the drug was present in the brain. At the end of the treatment the beta-receptor binding had decreased in the cerebellum (35%), but not in the frontal cortex or mesolimbic system. Clenbuterol significantly increased the steady-state brain levels of noradrenaline (NA) in the striatum 90 min after the last injection, whereas the levels in the frontal cortex, meso-limbic system, medulla pons and cerebellum were unaffected. The NA metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), had significantly increased in the frontal cortex and striatum. The serotonergic (5-HT) and dopaminergic (DA) system were not altered. In general, no long-lasting effects on beta-adrenoceptor number and affinity or monoamine metabolism were measurable, except for the frontal cortex which showed a sustained increase of MHPG, a decrease of 5-HT and an increase of 5-HIAA/5-HT on PN 60. In conclusion, chronic postnatal activation of beta 2-adrenoceptors by clenbuterol treatment selectively causes changes in the setting of the neurochemical parameters investigated in the frontal cortex.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Developmental changes in rat brain monoamine metabolism and beta-adrenoceptor subtypes after chronic prenatal exposure to propranolol.

The aim of this study was to investigate whether a chronic prenatal beta-blockade can alter the maturation of the noradrenergic system in the rat brain. Pregnant female and adult male rats were treated for 10 days with the beta-antagonist propranolol dissolved in the drinking water (40-50 mg/kg/day). Direct and long-term effects on beta-adrenoceptors and monoamine metabolism in various rat brain regions were determined. After the prenatal treatment the propranolol level in the foetal brain was 0.9 micrograms/g, while in the adult brain 2.0 micrograms/g was present. The foetal beta 1-receptors were significantly up-regulated by propranolol (200%), whereas the beta 2-receptor number remained unaltered. On postnatal days 4 and 21 the number of both beta-subtypes was the same as that of controls. Noradrenaline, its metabolite 3-methoxy-4-hydroxyphenylglycol and their ratio were unaltered directly after the prenatal treatment. In the PN 21 offspring, however, the metabolite level had increased in the frontal cortex (+ 17%) and hippocampus (+ 32%), and the ratio in the hippocampus (37%) and medulla pons (+ 34%). Prenatal treatment also induced a significant increase of the 5-hydroxyindoleacetic acid.5-hydroxytryptamine ratio (+ 15%) in the medulla pons at GD 21. No direct or lasting effects were found on dopamine metabolism. Propranolol treatment of adult rats gave no direct changes in monoamine metabolism. We concluded that chronic prenatal propranolol exposure (a) reversibly up-regulates foetal beta 1-adrenoceptors, and (b) increases the NA activity in the brain in later life.

Animals↗
PubMed1993

In vivo microdialysis of noradrenaline overflow: effects of alpha-adrenoceptor agonists and antagonists measured by cumulative concentration-response curves.

1. The purpose of the present study was to compare the effects of several alpha-adrenoceptor agonists and antagonists on cerebral cortical overflow of endogenous noradrenaline (NA) in freely moving rats. One or two days after the implantation of transcerebral dialysis tubes in the frontoparietal cortex, extracellular NA levels were monitored on-line with high performance liquid chromatography and electrochemical detection. The drugs were applied locally via the dialysis membrane, and effects on NA overflow were determined in cumulative concentration-response curves. 2. The average basal cortical NA overflow of all experiments was 0.25 pg min-1. The alpha 2-adrenoceptor agonists caused a concentration-dependent decrease in NA levels. UK-14,304 was the most potent and B-HT 933 the least potent agonist. The maximal decrease in NA overflow was to 10-15% of control levels after UK-14,304 or moxonidine, to 30% after clonidine and to 50% after B-HT 933 administration. Continuous activation of the presynaptic alpha 2-adrenoceptor with 10(-6) M UK-14,304 caused a decrease in NA levels to 40-50% of basal levels. This decrease was reached within 1 h and remained stable for the entire 3 h measurement period. The alpha 1-adrenoceptor agonists, phenylephrine and methoxamine, induced an increase in NA levels to 225% and 300%, respectively, at a concentration of 10(-3) M. 3. Local application of alpha 2-adrenoceptor antagonists caused an increase in NA levels, with idazoxan being more potent than piperoxan. Yohimbine did not cause any significant change. 4. All drugs used in these in vivo experiments had in vitro recoveries across the dialysis membrane between 10 and 20%. 5. We conclude that microdialysis with local drug application is suitable for the comparison of the pharmacological effects of drugs with affinity for alpha-adrenoceptors on cortical NA overflow in vivo,provided that the passage across the membrane is equal for the different drugs.

Adrenergic alpha-Agonists↗
PubMed1992

Neonatal lesions of the ventral tegmental area affect monoaminergic responses to stress in the medial prefrontal cortex and other dopamine projection areas in adulthood.

A mean decrease of dopamine (DA) to 20% and serotonin to 25-30% of control levels was found in the medial prefrontal cortex (mPFC) and amygdala/piriform cortex (A/PC) of adult rats with neonatal lesions of the ventral tegmental area (VTA). The metabolites were less decreased suggesting an increased activity of the remaining terminals. Moderate decreases to 30-75% were detected for DA and serotonin in the nucleus accumbens, olfactory tubercle and striatum. Footshock stress in control animals resulted in a strong increase (200% of control) in DA metabolites in mPFC and A/PC. The noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in A/PC was strongly increased to 240%. When stress was given to the neonatally VTA-lesioned animals these neurochemical responses were reduced compared to the nonlesioned rats. In the case of DA in the mPFC this was clearly due to a loss of stress response in the severe lesion group where DA is depleted to less than 20% of control. The stress-induced small increases in DA metabolism in tubercle, accumbens and striatum and serotonin metabolism in the striatum (20-40%) were entirely lost, while the MHPG increase in the A/PC was blunted. The present results suggest that moderate and severe lesions of DA and serotonin alter or prevent the normal activation of these transmitter systems and even of the noradrenergic system to stress.

Aging↗
PubMed1992

Activation of mesocortical dopaminergic system in the rat in response to neonatal medial prefrontal cortex lesions. Concurrence with functional sparing.

Neonatal lesions of the medial part of the rat prefrontal cortex (mPFC) (performed at the age of 6 days) resulted in a sparing in the performance of spatial delayed alternation (SDA) and an increase in dopaminergic (DA) innervation. The increased DA innervation was primarily observed in the remaining part of the mPFC. The DA fibre density was considerably higher in the non-ablated part of the mPFC, and the fibres were thicker with more large varicosities compared with sham-operated controls. Biochemical measurements showed a 3.5-fold increase in DA concentration in the remaining part of the mPFC of the animals with neonatal lesions when compared with the mPFC of sham-operated animals. In addition the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were increased. The metabolite/transmitter ratios, indicating DA utilisation, did not significantly differ from controls. The increased DA innervation and the increased concentration of DA and its metabolites in the animals with neonatal lesions further support our hypothesis that the mesocortical DA system is involved in the neural mechanism of sparing of function observed after neonatal mPFC lesions. However, sparing of function in animals with no discernable mPFC forces us to conclude that this DA response cannot be the only factor involved in the mechanism of sparing of function.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Chronic neonatal NMDA receptor blockade with MK-801 alters monoamine metabolism in the adult rat.

Administration of non-competitive N-methyl-D-aspartate (NMDA) antagonists in rodents leads to a characteristic motor syndrome which has been related to changes in monoamine metabolism in a variety of brain regions. We examined the question whether chronic MK-801 treatment in neonatal rats from postnatal day 8 through 19, which has been shown previously to alter NMDA receptor function, would also affect monoamine metabolism in striatum and frontal cortex of adult rats. Monoamines and their metabolites were determined 5 months after the treatment using high-performance liquid chromatography with electrochemical detection. Dihydroxyphenylacetic acid (DOPAC) concentration was elevated (greater than 40%) in both regions tested, while 5-hydroxyindoleacetic acid (5-HIAA) concentration was significantly elevated only in the cortex (19%), and 3-methoxy-4-hydroxyphenylglycol (MHPG) only in the striatum (47%). These results demonstrate that the long-lasting effects of chronic neonatal MK-801 treatment are not restricted to glutamate transmission, but include monoamine transmission as well.

Age Factors↗
PubMed1992

Early postnatal clonidine treatment results in altered regional catecholamine utilisation in adult rat brain.

Clonidine is a clinically used antihypertensive which has been suggested to produce physiological changes in children after exposure in utero. The aim of our study was to test the hypothesis that chronic exposure of the developing brain to an alpha 2-adrenergic agonist like clonidine would influence the adult neurochemical setting of central monoamine neurotransmitter systems. Male rat pups were treated from postnatal day 8 to 21 twice daily with saline or with 0.1 mg/kg clonidine. After the last injection on day 21, brain regional catecholamine utilisation was determined using synthesis inhibition with alpha-methyl-p-tyrosine in a subgroup of the pups. The expected decrease in noradrenaline utilisation after clonidine was observed, although statistical significance was not reached in a number of brain regions. Dopamine utilisation was not affected. The other pups were left to reach young adulthood and catecholamine utilisation was measured on day 90. Noradrenaline utilisation on day 90 was significantly decreased in two regions: the medulla-pons and the mesolimbic (dopamine projection) areas. Dopamine utilisation was decreased in the hypothalamus and increased in the amygdala and the cerebellum. These adult neurochemical alterations corroborate previous findings of adult behavioural, physiological and central biochemical alterations in rats exposed to clonidine in early postnatal life.

Aging↗
PubMed1992

Changes in adrenoceptors and monoamine metabolism in neonatal and adult rat brain after postnatal exposure to the antihypertensive labetalol.

1. The purpose of the present study was to investigate the acute (single injection), direct (chronic treatment) and the long-lasting effects after exposure to the alpha 1/beta-adrenoceptor antagonist labetalol during rat brain development on adrenoceptors and monoamine metabolism. 2. In 10-day-old rat pups, subcutaneously administered labetalol (10 mg kg-1) passed the blood-brain barrier, reaching a level of 2.1 micrograms g-1 tissue in the brain 90 min after injection. 3. Chronic labetalol treatment (10 mg kg-1, s.c., twice daily) during the first 10 days of life significantly increased alpha 1-adrenoceptor binding in the hypothalamus (+39%), but not in the occipital cortex. 4. This chronic postnatal labetalol treatment did not result in long-lasting changes in alpha 1- and beta-receptors measured on day 60. 5. A single labetalol injection (10 mg kg-1, s.c.) on postnatal day 10 significantly increased noradrenaline (NA) metabolism in all brain regions tested (+25 to 105%), but had no effects on 5-hydroxytryptamine (5-HT) or dopamine metabolism. 6. Chronic labetalol treatment between postnatal (PN) days 1 and 10 also increased NA metabolism on PN 10 (3-methoxy-4-hydroxyphenylglycol (MHPG)/NA, +20 to 100%), suggesting that tolerance to the acute effect of labetalol did not occur. A slight increase in 5-HT metabolism (20%) was induced by the chronic labetalol treatment in the hippocampus and meso-limbic system. 7. In general, long-lasting effects on NA metabolism could not be detected on day 60 more than one month after the treatment. However, 5-HT metabolism was significantly increased in all four brain regions measured (+20 to 70%). 8. We conclude that chronic labetalol exposure during early postnatal rat brain development does not cause long-lasting changes in beta-receptor number or NA metabolism, but appears to be critical for the rate of 5-HT metabolism in later life.

Animals↗
PubMed1992

Functional neuroteratology of drugs acting on adrenergic receptors.

Noradrenaline neurotransmission becomes functional early in the development of the brain. Therefore, interference with this transmission by receptor agonists or antagonists, which are used clinically in various conditions in pregnancy, may alter brain development. Long-term biochemical, morphological, behavioural and electrophysiological effects have been reported after pre- or postnatal exposure of rats to adrenergic drugs, the alpha 2-agonist clonidine and the beta-antagonist propranolol in particular, and are summarized here.

Humans↗