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M G Feenstra

Publications and source records attributed to M G Feenstra.

At least 73 records · Page 4Linked to original sources
PubMed1987

Central noradrenaline depletion during development and its effect on behaviour.

Although early depletion of noradrenaline is known to affect the morphological development of various structures in the brain, it is not clear what implications this has for adult behaviour. In the present study, 6-hydroxydopamine (6OHDA) was injected into the lateral ventricles of 12 day old rats, permanently destroying most of the noradrenergic innervation of the spinal cord and of all the brain areas examined except for the pons/medulla, and reducing the dopamine content of the cerebral cortex considerably. The noradrenaline content of the heart, as well as general developmental parameters such as food intake and body weight, were unaffected. Despite the extensive noradrenaline depletion during development, these rats' spatial memory--as determined in a radial maze task--was no worse than that of controls. In a lever-pressing task the 6OHDA treated rats made no more errors than did controls, but performed more slowly. The results indicate that at least some aspects of learning, memory and sensory-motor ability can develop normally when the noradrenergic innervation of the brain is largely destroyed.

Animals↗
PubMed1987

Effect of noradrenergic denervation on task-related visual evoked potentials in rats.

The present study examines whether destruction of the noradrenergic innervation of the forebrain interferes with the processing of sensory information in a manner that results in impaired selective attention. Electro-cortical responses to task-relevant and irrelevant stimuli were found to be sensitive indicators of the rat's attention to the stimuli. The amplitude of the response to the task-relevant stimulus increased as the rat's performance improved. The response to irrelevant flashes of light depended on the predictability of the flashes and on the rat's level of arousal. Noradrenergic denervation (with the selective neurotoxin DSP4) did not affect either the behavioural response to a visual stimulus which the rat had been trained to respond to for a food reward, or the late positive potential evoked by this stimulus. Neither did it affect the response to continuous (temporally predictable) flashes of light that were irrelevant to the task. Although the response to unpredictable flashes was also largely unaffected, we did find an additional late component in this response after DSP4 treatment. These results show that the noradrenergic innervation of the occipital cortex does not always regulate the extent to which visual stimuli are processed, but that noradrenergic neurotransmission may be activated in order to diminish excessive processing of unexpected stimuli.

Animals↗
PubMed1986

S(-)DP-5,6-ADTN as an in vivo dopamine receptor ligand: relation between displacement by dopamine agonists and their pharmacological effects.

The use of (-)DP-5,6-ADTN as a non-radioactively labeled ligand for an in vivo DA receptor assay is described and compared with racemic DP-5,6-ADTN, previously used for that purpose. The effects of four DA agonists (NPA, bromocriptine, DP-7-OH-ATN and 3-PPP) on the specific (-)DP-5,6-ADTN binding are related to their potencies to decrease striatal HVA concentrations and to induce stereotypy in rats. NPA and DP-7-OH-ATN caused a maximal decrease in HVA levels, when only a fraction of the receptors were occupied, while the occurrence of stereotypy was associated with a high receptor occupation, reflecting the higher affinity of these agonists for presynaptic than for postsynaptic receptors. Bromocriptine did not show this effect, as the dose-response relationships for HVA decrease, for induction of stereotypy and for the decrease in specific (-)DP-5,6-ADTN binding were all virtually equal to each other. While NPA and bromocriptine behaved as full postsynaptic agonists, in that maximal stereotyped behavior was observed after high doses, DP-7-OH-ATN was found to be a partial postsynaptic agonist, as it did not induce maximal stereotypy at a maximal receptor occupation. Racemic 3-PPP only caused a state of hypoactivity, but did neither affect specific (-)DP-5,6-ADTN binding nor striatal HVA levels. Our results are discussed in view of theories on the relation between receptor occupation and pharmacological effects and it is concluded that the in vivo receptor binding method using (-)DP-5,6-ADTN is a very useful tool for such investigations.

Animals↗
PubMed1984

Certain dopamine agonists increase dopamine synthesis in the striatum of rat brain.

N,N-Dipropylamino-5,6-dihydroxytetrahydronaphthalene (DP-5,6-ADTN) induced a rapid and dose-related rise in dopamine (DA) levels in the striatum of rat brain. The increase of DA was less pronounced in the tuberculum olfactorium and there was no change in the frontal cortex. DP-5,6-ADTN and DP-6,7-ADTN also caused a rapid increase in striatal DA synthesis (evaluated from the rise of 3,4-dihydroxyphenylalanine after decarboxylase inhibition) which lasted about 20 min and was followed by a decrease. The increase in DA synthesis rate after the DP-ADTNs was restricted to the striatum, only a decrease was observed in mesolimbic areas and frontal cortex. Dose-effect curves showed that the ED 50% for the stimulation of DA synthesis was somewhat higher (approx. 0.2 mumol/kg) than the ED 50% for the decreasing effect (approx. 0.01 mumol/kg). The increase in striatal DA biosynthesis was not seen after the DA agonists piribedil, TL-99 or apomorphine. Pretreatment of rats with gamma-hydroxybutyrolactone or haloperidol prevented the DP-5,6-ADTN-induced increase in DA synthesis.

4-Butyrolactone↗
PubMed1984

Brain and serum concentrations of dopamine analogues after peripheral administration to rats.

Concentrations of dopamine (DA) analogues were determined in rat brain regions and serum after peripheral administration of the drugs. The time course of the concentrations of four N,N-dialkylated DA derivatives is reported in relation to the simultaneously measured effects on DA metabolism. Maximum brain concentrations were reached at about 10 min after injection, followed by a rapid elimination of the parent compounds. O-Methylation was found to be of major importance in this early disappearance. The 3-O-methyl metabolite of N,N-dipropyl-DA (DiPr-DA) was very rapidly formed and was eliminated much more slowly than the parent compound. Inhibition of O-methylation as well as subcutaneous, instead of intraperitoneal (ip), administration resulted in higher brain and serum levels of DiPr-DA. Brain concentrations of 11 DA analogues were determined 10 min after ip injection and were compared with their octanol/water (pH 7.4) partition coefficients. Within one group of compounds with a similar metabolic profile the brain concentrations and partition coefficients showed a good correlation.

Animals↗
PubMed1983

Inhibition of rat brain monoamine oxidase type A by 2-aminotetralin and tetrahydroisoquinoline analogues of dopamine.

The in vitro inhibition of rat brain monoamine oxidase type A (MAO-A) by various dopamine analogues is reported and compared to some established inhibitors of the enzyme. The estimated IC50's were found to be in the range 10(-5)-10(-3) mol/l. This makes these compounds more than 10 000 times less potent than the selective MAO-A inhibitor harmaline and more than 10 times less potent than the selective MAO-B inhibitors pargyline and deprenyl. When the brain concentrations that are reached after peripheral administration of these drugs are taken into account it is unlikely that inhibition of MAO is relevant to their effects as has been suggested. Also the endogenous brain concentrations of some tetrahydroisoquinolines are probably too low to produce an inhibition of the enzyme.

Animals↗
PubMed1983

In vivo dopamine receptor agonist binding in rat brain: relation with pharmacological effects.

The relation between in vivo rat striatal dopamine (DA) receptor binding of N,N-dipropyl-2-amino-5,6-dihydroxytetralin (DiPr-5,6-ADTN) and the dopaminergic effects of this compound was studied. The results indicate that maximal stereotyped biting and gnawing was associated with maximal saturable binding. At doses which maximally decreased striatal acidic DA metabolite concentrations a 25% or less occupation of binding sites was found. It is suggested that total in vivo binding is associated with stereotypy but not with the biochemical effects.

Animals↗
PubMed1983

In vivo dopamine receptor binding studies with a non-radioactively labeled agonist, dipropyl-5,6-ADTN.

Evidence is presented that a low dose of peripherally administered N,N-dipropylamino-5,6-dihydroxytetralin (DiPr-5,6-ADTN) specifically labels dopamine (DA) receptors in rat brain. Concentrations of this potent DA receptor agonist were determined by a highly selective method using reversed phase liquid chromatography and amperometric detection. The binding characteristics satisfy all criteria regarding saturability, stereospecificity, regional distribution and relation with pharmacological effects that are associated with DA receptor interactions. A rough estimation of the density of binding sites in the striatum resulted in values of 60-70 pmol/g. Lesioning the nigrostriatal pathway does not significantly alter the amount of ligand bound, nor do pretreatments with serotonergic, alpha-adrenergic or beta-adrenergic antagonists. DiPr-5,6-ADTN has thus been shown to be a useful ligand for labeling central DA receptors and a powerful tool in the study of DA-ergic mechanisms.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1983

Amperometric detection of low concentrations of dopamine receptor agonists after liquid chromatographic on-column sample enrichment: effect of o-methylation on brain concentrations of dipropyl-5,6-ADTN and dipropyl-6,7-ADTN.

A sensitive and selective method of determination of N,N-dipropylamino-5, 6-dihydroxytetralin and its 6,7-dihydroxy isomer in rat plasma and brain tissue is described. The method is based on isolation of these dopamine receptor agonists from the biological samples on small Sephadex G-10 columns, followed by reversed phase high performance liquid chromatography with amperometric detection. Large volume (2 ml) injections result in on-column sample enrichment without a subsequent loss in column efficiency. Using this method the very low detection limit of 4 pmol/g was achieved in brain tissue. It was found that the lower in vivo potency as a centrally acting dopamine agonist of the 6,7-compared with the 5,6-isomer is almost entirely due to the lower brain concentrations achieved after peripheral administration of equimolar doses. This difference is mainly caused by different rates of O-methylation by catechol-O-methyltransferase, which follows from the fact that inhibition of this enzyme by tropolone leads to almost equal brain concentrations of the two isomers.

Animals↗
PubMed1983

A comparison of the potencies of various dopamine receptor agonists in models for pre- and postsynaptic receptor activity.

Several dopamine (DA) receptor agonists, notably N,N-dipropyl-2-aminotetralin analogues differing in the number and position of phenolic hydroxyl groups, were evaluated in model systems for pre- and postsynaptic dopaminergic activity. Apomorphine, piribedil and pergolide were included for comparison. All compounds inhibited the gamma-butyrolactone (GBL)-induced increase in DA concentrations in the rat striatum and olfactory tubercle, although a dose-dependency could not be demonstrated for one of the compounds, i.e. N,N-dipropyl-2-amino-5,6-dihydroxy-tetralin. In addition to the reversal of the DA-increase all compounds decreased the HVA and DOPAC levels in a dose-dependent manner, in much the same way as in normal, non GBL-pretreated rats. The potencies of the drugs to decrease HVA in normal rats and to inhibit the DA-increase and to decrease HVA in GBL-pretreated rats, both in the striatum and the olfactory tubercle were compared with each other and with the potencies to induce stereotyped behaviour. It may be concluded that (1) N,N-dipropyl-2-amino-7-hydroxytetralin shows the largest difference in activity in the biochemical and the behavioural models, suggesting a selective presynaptic activity. This was corroborated by the appearance of a marked hypomotility after low doses of this compound; (2) The potencies to decrease striatal HVA concentrations are generally somewhat different from the potencies to inhibit GBL-induced DA-increases, but appear to be comparable to the potencies to inhibit GBL-induced dihydroxyphenylalanine (DOPA)-increases; (3) There is no indication that the DA agonists in general are more potent at presynaptic receptors in the tubercle than in the striatum.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1982

Reversed-phase liquid chromatography with amperometric detection of lipophilic dopamine analogues and determination of brain and serum concentrations after sample clean-up on small sephadex G-10 columns.

The liquid chromatographic determination of N-alkylated analogues of dopamine is described. The retention of these compounds, ranging from dopamine to N,N-dibutyl-dopamine, was studied on four bonded-phase columns, of which Nucleosil 5 C18 was chosen for routine use. The compounds were detected by a rotating disc amperometric detector. Samples of rat brain and serum were taken through a clean-up step on small Sephadex G-10 columns from which the dopamine analogues eluted in the same fraction as dopamine. The overall recovery was 70--90% from brain tissue and 60--70% from serum or plasma. The limit of detection for the catechol-containing compounds in tissue was 40--100 pg, for O-methylated ones 100--200 pg. The method is applied to the determination of dopamine analogues in rat brain after peripheral administration.

Animals↗
PubMed1980

The significance of COMT activity in controlling dopamine agonist levels in brain and serum: studies with a prodrug and a metabolite of 6,7-ADTN.

After i.p. administration of the dibenzoylester of 2-amino-6,7-dihydroxytetralin (DB-6,7-ADTN) a metabolite was found in rat brain and serum, which was identified as 2-amino-6-hydroxy-7-methoxytetralin (7-O-MeADTN). By means of HPLC coupled with amperometric detection, time-concentration curves of 7-O-MeADTN in rat brain and serum were determined after 100 mumol/kg DB-6,7-ADTN. These showed a rapid formation and homogeneous distribution of high peak levels (4 nmol/g) of 7-O-MeATN. Brain and serum concentrations of 6,7-ADTN after 100 mumol/kg DB-6,7-ADTN, determined during catechol-O-methyltransferase (COMT) inhibition by tropolone, were 5--7 times higher than those during normal COMT activity, thus equalling 5,6-ADTN concentrations after 100 mumol/kg DB-5,6-ADTN. The greater susceptibility of 6,7-ADTN to metabolic degradation by COMT was confirmed by preliminary results of in vitro studies, which showed that two methoxy derivatives are formed from 6,7-ADTN and one, in very small amounts, from 5,6-ADTN. 7-O-MeADTN had no dopaminergic activity of its own, as after i.p. injection of 100 mumol/kg it was devoid of behavioural and biochemical effects typical for DA agonists. A homogeneous distribution and high peak concentrations (20 nmol/g after 15 min) were found in rat brain after this dose of the metabolite. The results indicate that a substantial amount of 6,7-ADTN, in contrast to 5,6-ADTN, is metabolized by COMT and that differences between brain concentrations of both isomers are almost exclusively due to differences in susceptibility for COMT. This has implications for the design of new DA agonists.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1980

Selective storage in vivo of 5,6-ADTN in dopamine-rich areas of the rat brain.

This study investigates the mechanism of the selective storage of the dopamine agonist 2-amino-5,6-dihydroxytetrahydronaphthalene (5,6-ADTN, used as the esterified prodrug) in densely innervated dopaminergic brain structures. The accumulation of 5,6-ADTN in dopamine-rich areas appeared to be non-saturable at the doses studied. In rats with a unilateral 6-OHDA lesion there was a corresponding unilateral decrease in 5,6-ADTN concentrations which suggests that the agonist interacts with dopamine uptake or storage mechanisms. Apart from an initial decreased penetration in the brain, reserpine-induced depletion of dopamine stores did not influence the accumulation of 5,6-ADTN in dopamine-rich areas, which suggests that 5,6-ADTN is taken up in the so-called 'non-reserpine sensitive DA-pool'. Unexpectedly, reserpine pretreatment caused a long-lasting (at least 170 h) decrease of 5,6-ADTN distribution in non-dopaminergic structures. 5,6-ADTN (used as the prodrug) could have a role to play in the elucidation of the significance of the various dopamine pools.

Animals↗
PubMed1980

Effect of non-catecholic 2-aminotetralin derivatives on dopamine metabolism in the rat striatum.

The concentrations of dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured in the striatum of rats after i.p. injection of dipropyl-2-aminotetralin and the four positional isomers of monohydroxy-dipropyl-2-aminotetralin. All compounds except 8-OH dipropylaminotetralin caused a decrease in DOPAC- and HVA-concentrations. In addition, 5-OH-dipropylaminotetralin produced a small elevation in DA concentrations. In contrast, 7-OH dipropylaminotetralin, in doses of 100 mumol/kg and more, decreased DA to 50% and initially increased HVA and DOPAC to about 200%, after which the concentrations of the metabolites fell to 30% or less. The 5-OH isomer was found to be the most potent compound, decreasing HVA concentrations to 70% at a dose of 0.14 mumol/kg. The potencies are compared to those of catechol-group containing DA-agonists such as apomorphine and N,N-dipropyl-5,6-dihydroxy-2-aminotetralin. In addition, a comparison is made with reported behavioural data. It is suggested that the more active N-alkylated 2-aminotetralins have a conformation which corresponds to that of the alpha rotamer of dopamine.

2-Naphthylamine↗
PubMedDate not supplied

R(-)-baclofen: focal epilepsy after intracortical administration in the rat.

R(-)- or S(+)-baclofen were injected into lamina IV-V of the sensorimotor cortex of the rat. Clinical observation and ECoG registration revealed that partial epilepsy with focal motor symptoms developed following injection of R(-)-baclofen, with an ED50 of 0.25 nmoles, a mean latency of 17 min independent of the dose, and a duration of more than 5 h at a dose of 5 nmoles. S(+)-Baclofen was ineffective at doses of up to 5 nmoles (2 x ED100 (-)-baclofen), indicating a stereoselective action of the (-)-isomer.

Animals↗