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Biomedical subjects

M G Feenstra

Publications and source records attributed to M G Feenstra.

At least 19 recordsLinked to original sources
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↗
PubMed1991

Controllable and uncontrollable footshock and monoaminergic activity in the frontal cortex of male and female rats.

Effects of controllable and uncontrollable footshock on monoaminergic activity in the frontal cortex and plasma corticosterone levels were studied in male and female rats. Subjects were exposed to a shuttle-box procedure for a period of either 30 min (60 shocks) or 90 min (180 shocks). A shuttle response ended shock presentation for escape subjects, whereas their yoked, same-sex, counterparts were unable to escape from shock presentation. A third group was exposed to the experimental environment, but did not receive any shocks. Concentrations of noradrenaline, serotonin and dopamine and their major metabolites were measured in the frontal cortex by high performance liquid chromatography with electrochemical detection. Plasma corticosterone was measured by radioimmunoassay. Results of this experiment show that: (1) exposure to the experimental environment without shock already increased the activity of all 3 transmitter systems. In particular, serotonin was very responsive to mere confinement to the shuttle-box. Changes induced by exposure to the experimental environment were similar for males and females. (2) Presentation of footshocks further increased transmitter activity. The activation of noradrenaline and dopamine was larger after uncontrollable shock than after controllable shock. Moreover, uncontrollable shock resulted in higher serotonin levels than controllable shock. (3) Sex-dependent effects of controllability were found for noradrenaline and dopamine, but not for serotonin. Differences in catecholaminergic activity between controllable and uncontrollable shock were larger in females than in males. (4) In both males and females, corticosterone levels in plasma were increased by exposure to the experimental environment. A further elevation was found in response to footshock presentation, which was independent of the controllability of shock.

Animals↗
PubMed1991

Sex- and time-dependent changes in neurochemical and hormonal variables induced by predictable and unpredictable footshock.

Previous experiments have revealed sex-dependent effects of inescapable shock in rats. Behavior of male rats was more severely disrupted by inescapable shock than behavior of female rats. These sex differences were found after 1- and 24-hour intervals but not after a 72-hour interval. The present experiment was designed to study various physiological parameters at 1-, 4- and 24-hour intervals after inescapable footshock. The predictability of shock was manipulated by adding a compound light and tone stimulus that preceded shock presentation for one group but was not correlated with shock presentation for another group of subjects. Noradrenaline, dopamine, serotonin, and metabolites of these 3 transmitters were measured in the frontal cortex. Transient shock-induced increments in dopamine and metabolites of dopamine and serotonin were found, but the sex of the animal did not differentially affect this neurotransmitter response. In addition to neurotransmitter concentrations in the frontal cortex, levels of corticosterone were measured in plasma. The pituitary-adrenal axis was activated for a longer period in females than males after shock. The present data do not provide evidence that behavioral sex differences induced by inescapable shock are paralleled by sex differences in neurotransmitter activity. In addition, sex-dependent effects of predictability of shock on neurotransmitter activity were not detected. The relevance of the observed sex-dependent responses in the pituitary-adrenal system is discussed.

Animals↗
PubMed1991

Chronic propranolol treatment in developing rats: acute and lasting effects on monoamines and beta-adrenergic receptors in the rat brain.

During early postnatal development rat pups were treated twice daily with the beta-adrenergic antagonist propranolol (15 mg/kg) in order to study the acute and long-lasting effects of early blockade of noradrenergic beta-mediated neurotransmission. Treatments from postnatal days 1-10 or days 11-20 did not induce alterations in the number of beta-adrenergic receptors as measured three days after the last injection, nor could lasting effects be shown at 60 days of age. The day 1-10 treatment, however, had a significant effect on the regional brain levels of noradrenaline (NA) and its metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), measured 90 min after the last injection. The metabolite had increased by 40% in all brain regions examined. On day 60, the MHPG concentrations were still increased when compared to postnatally saline-treated animals. Propranolol treatment from day 11-20 only marginally increased MHPG on day 20 and induced no lasting differences. These results suggest that propranolol treatment during the first ten days of life produces a long-lasting increase in NA metabolism, possibly reflecting an increased neuronal NA turnover.

Animals↗
PubMed1991

In vitro and in vivo D2-dopamine receptor binding with [123I]S(-) iodobenzamide ([123I]IBZM) in rat and human brain.

As a promising dopamine D2-receptor imaging agent for single photon emission computerized tomography (SPECT), [123I](S)-(-)-2-hydroxy-3-iodo-6-methoxy-N [(1-ethyl-2-pyrrolidinyl)methyl]benzamide ([123I]IBZM) has recently been synthesized in a modified way along with its precursor, S(-)BZM, and the stereoisomer R(+)BZM. The present study applied this new product to investigate in vitro and in vivo D2-receptor binding in rat brain and in postmortem human brain. In vitro saturation binding curves with [123I]IBZM for rat crude striatal membrane preparations yielded an affinity constant (Kd) of 0.28 nM confirming data in the literature. Displacement curves revealed an order of increasing potency as follows: R(+)BZM less than S(-)sulpiride = less than S(-)BZM less than S(-)IBZM. A similar order was obtained when [3H]spiperone was used as ligand. For human putamen and caudate nucleus membranes slightly higher Kd values (0.49 nM) were obtained. Rank order of displacing potency for the various drugs was similar to that found in the rat preparations. In vivo uptake of [123I]IBZM in rat brain following injection of 50 microCi (12-16 pmol) in the tail vein revealed an increase in the striatum-to-cerebellum ratio from 1.5 at 5 min to 6.9 at 2 h. The olfactory tubercle-to-cerebellum ratio was also raised from 1.6 to 3.3. Other brain regions tested failed to show statistically significant enhancements. Coinjection of 40 nmol S(-)IBZM, 4 mumol S(-)BZM or 200 nmol haloperidol displaced [123I]IBMZ when tested at 90 min. The use of 4 mumol R(+)BZM resulted in minor displacement only, demonstrating that stereospecificity of the displacement was present in vivo and in vitro. Displacements were also observed in substantia nigra and pons-medulla oblongata, but not in hippocampus or frontal and occipital cortex. The data provide the required background needed in order to initiate in vivo binding studies for D2-receptors in basal ganglia of human patients using [123I]IBZM in SPECT analyses.

Animals↗
PubMed1991

Pre- and postnatal developmental changes of adrenoceptor subtypes in rat brain.

beta-Adrenergic receptor subtypes, beta 1 and beta 2, were studied during pre- and postnatal development in the rat brain. [125I]Iodocyanopindolol (6-300 pmol/L) binding assays in the presence of 5-hydroxytryptamine (0.6-6 mumol/L) were used to measure exclusively beta-adrenergic receptors. In forebrain tissue, saturable and stereoselective binding was detected on gestational day 13. The amount of beta-adrenergic binding increased until postnatal day 23, when adult values were reached. The dissociation constants of [125I]iodocyanopindolol binding remained the same throughout development, as did the affinity of several beta-adrenergic and non-beta-adrenergic compounds. The proportion of the beta 2-adrenergic receptors was determined using the beta 1-selective antagonist ICI-89406 (7-150 nmol/L) and was found to change from 65% in prenatal forebrain tissue to 28% in adulthood. In cerebellum/medulla pons tissue, however, the proportion of beta 2-receptor binding (80%) remained unchanged during the whole developmental period.

Adrenergic beta-Antagonists↗
PubMed1990

Microdialysis studies on cortical noradrenaline release: basic characteristics, significance of extracellular calcium and massive post-mortem increase.

Extracellular noradrenaline was measured on-line in the cerebral cortex of the freely moving rat by microdialysis coupled to high performance liquid chromatography and electrochemical detection. High potassium concentrations in the perfusion fluid led to a strong increase, whereas tetrodotoxin led to almost undetectable levels of noradrenaline. This shows that noradrenaline in the dialysate was directly derived from active neuronal release. Noradrenaline levels were sensitive to calcium concentrations in the perfusion fluid: from 10% in calcium-free medium to 200% for 10 mM calcium. An overdose of anesthetic caused a 60-fold increase of noradrenaline post-mortem.

Animals↗
PubMed1990

Widespread alterations in central noradrenaline, dopamine, and serotonin systems in the Brattleboro rat not related to the local absence of vasopressin.

A comprehensive study of monoamine transmitter and metabolite concentrations measured by HPLC was undertaken in female (vasopressin-deficient) Brattleboro rats as compared to Long Evans rats. Noradrenaline was significantly increased in 8 out of 13 dissected brain regions, whereas concentrations of the metabolite 3-methoxy-4-hydroxyphenylglycol were not altered. The increases were not restricted to areas which are normally innervated by vasopressin-containing neurons. Serotonin was increased in 6 and dopamine in 4 regions and this was accompanied in some areas by increases in the metabolites 5-hydroxyindolacetic acid and dihydroxyphenylacetic acid. Only in the striatum, cerebellum, and the medulla-pons no changes could be detected in any of the compounds of interest. These results show that the long term absence of vasopressin in Brattleboro rats appears to be associated with increases in monoamine transmitter contents and decreased metabolite/transmitter ratios. The regional distribution of these changes does not bear any relationship to the regional distribution of vasopressin cell bodies or nerve endings.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Sex differences in the effects of inescapable footshock on central catecholaminergic and serotonergic activity.

In two experiments sex differences in changes in central noradrenergic, dopaminergic and serotonergic activity were measured immediately after a 30-min session of inescapable footshocks. In Experiment 1 concentrations of noradrenaline, dopamine, serotonin and their major metabolites were determined in the frontal cortex, hypothalamus, amygdala, striatum, mesencephalon and the medulla-pons area. Inescapable shock increased the activity of all 3 transmitter systems, as evidence by increased metabolite concentrations in specific brain areas. Shock-induced increments in metabolite levels were larger in females than in males, especially for the serotonergic system. In addition, shock presentation resulted in a decrement in the noradrenaline content in most areas studied. In the frontal cortex, noradrenaline was reduced by inescapable shock in males but not in females. In Experiment 2, sex-dependent neurochemical consequences of predictable versus unpredictable shocks were studied in the frontal cortex and the medulla-pons area. Similar to Experiment 1, both brain parts showed large shock-induced increments in the activity of the catecholaminergic systems. Differential effects of predictable and unpredictable shock were not found (frontal cortex) or were rather small (medulla-pons) and appeared sex-dependent for serotonin in this area. The sex differences in neurochemical change found in the first experiment were largely replicated in the second experiment. The relevance of the observed sex differences in central neurotransmitter reactivity for sex differences in behavior is discussed.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Central monoamine metabolism in the male Brown-Norway rat in relation to aging and testosterone.

Concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), noradrenaline (NA), free 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were determined in brain regions of 5-, 20-, and 32-month-old male Brown-Norway rats using high pressure liquid chromatography. In view of the activating effects of sex steroids on peptide and monoamine transmitter systems and the declining plasma testosterone levels with aging, the effects of testosterone supplementation on age-related changes in central monoamine metabolism were also studied. Age-related decreases in monoamine metabolism were observed in nigrostriatal, mesocortical and coeruleohippocampal systems. Marked reductions in DOPAC (35%) and HVA (50%) occurred in the ventral tegmental area between 20 and 32 months of age. 5-HT and 5-HIAA levels showed reductions and increases depending on the brain region. Testosterone administration resulted in elevations of HVA in the substantia nigra and MHPG in the locus coeruleus and hippocampus, which were most pronounced in young animals. It is concluded that there are marked differences in age-related changes between nigrostriatal, mesocortical and coeruleohippocampal systems and that testosterone exerts a stimulatory influence on some aspects of monoamine metabolism in young but not in aged animals.

Aging↗
PubMed1990

Folates: epileptogenic effects and enhancing effects on [3H]TBOB binding to the GABAA-receptor complex.

The biochemical mechanism responsible for the convulsive effects of folates was investigated. The epileptogenic effects of folates were determined in vivo by quantification of the seizures following intracortical application in rats. The rank order of epileptogenic effects is: folic acid greater than or equal to 5-HCO-H4 folate greater than H2 folate greater than 5-CH3-H4 folate. This sequence of epileptogenicity in vivo is compared to the rank order of the effects of folates on radioligand binding to the GABAA-receptor complex in vitro. The inhibitory potencies of folates on [3H]muscimol and [3H]diazepam bindings did not correlate with their epileptogenic effects. However, folates reverse the inhibiting effect of GABA on the binding of the cage convulsant [3H]TBOB [( 3H]t-butylbicycloorthobenzoate). The rank order of this in vitro effect (folic acid greater than 5-HCO-H4 folate greater than H2 folate = 5-CH3-H4 folate) resembles the rank order of epileptogenicity determined in vivo. A relationship between the in vivo and in vitro effects is therefore suggested.

Animals↗
PubMed1990

Lasting effects of early noradrenergic receptor occupation on brain noradrenaline turnover and on beta-receptors.

Neuroactive substances reaching the developing brain can affect the formation of the functionality of nervous circuitry. To explain this so-called functional neuroteratology it has been proposed that neurotransmission has persistently been altered. Pharmacological interference with the developing central noradrenergic system in the rat by means of drugs like clonidine, yohimbine and propranolol, indeed revealed lasting changes in the turnover of noradrenaline in several brain areas, but no changes were found in beta-receptor density. It is assumed that either alpha-receptor density is affected or that signal transduction is altered, since electrophysiologically a persistent supersensitivity was found for the noradrenaline-evoked depression of glutamate-evoked firing in e.g. CA1 pyramidal cells of the hippocampus. Elucidation of the underlying neurochemical mechanisms of such lasting effects of perinatal exposure to noradrenergic drugs aims at establishing the role of noradrenaline in development, but also to provide physicians with the possibility to better assess the advantages and disadvantages of drugs to be prescribed during reproduction and, hence, to make the best choice of treatment.

Animals↗