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B H Westerink

Publications and source records attributed to B H Westerink.

At least 109 records · Page 6Linked to original sources
PubMed1990

Role of adenylate cyclase in the modulation of the release of dopamine: a microdialysis study in the striatum of the rat.

In the present study, we have applied the brain microdialysis technique to investigate the effect of the stimulation of adenylate cyclase on the extracellular levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in the striatum of freely moving rats. Infusion of 8-bromo-adenosine 3',5'-cyclic monophosphate (8-Br-cAMP), 3-isobutyl-1-methylxanthine, or forskolin produced a significant increase in the release of DA. The effect of 8-Br-cAMP was tetrodotoxin, Ca2+, and dose dependent and was saturable. 8-Br-cAMP also caused an increase in the output of DOPAC and HVA. No effects were seen on the output of 5-HIAA, except at the highest 8-Br-cAMP concentration studied. Infusion of 8-Br-cAMP (25 microM, 1.0 mM, and 3.3 mM) together with infusion of (-)-sulpiride (1 microM) or systemic administration of (+/-)-sulpiride (55 mumol/kg i.p.) produced an additive effect on the release of DA. Infusion or peripheral administration of (-)-N-0437 (1 microM or 1 mumol/kg) both decreased the 8-Br-cAMP-induced increase in the release of DA. These results demonstrate that cyclic AMP may stimulate the release of DA, but it is unlikely that this second messenger is linked to presynaptic D2 receptors controlling the release of DA.

1-Methyl-3-isobutylxanthine↗
PubMed1990

In vivo evidence for the existence of autoreceptors on dopaminergic, serotonergic, and cholinergic neurons in the brain.

Intrastriatal infusions as well as systemic administration of the selective D-2 antagonist (-)-sulpiride caused similar increases in the dialysate levels of dopamine (DA) to about 180% of controls. A similar conclusion was drawn when the selective D-2 agonist (-)-N-0437 was infused intrastriatally or administered systemically: both routes of administration caused a decrease in the release of DA to about 40-50% of controls. In order to evaluate the properties of synthesis-modulating autoreceptors on dopaminergic and serotonergic neurons we have estimated the synthesis rate of serotonin (5-HT) or DA by monitoring the 5-HTP or DOPA formation in the dialysates during infusion of a decarboxylase inhibitor. Infusion of (-)-N-0437 decreased the DOPA formation, whereas infusion of (-)-sulpiride increased the dialysate levels of DOPA; these results indicate that the D-2 receptors controlling the synthesis of DA are localized on nerve terminals. Administration of the selective 5-HT-IA agonist 8-hydroxy-dipropyl-aminotetraline (8-OH-DPAT) resulted in a decrease in the synthesis rate of 5-HT. When 8-OH-DPAT was infused via the dialysis membrane, the agonist was unable to modify the release of 5-HT. The effects of infusion of the muscarinic agonist oxotremorine and the muscarinic antagonist atropine were dependent on the presence of the esterase inhibitor neostigmine in the perfusion fluid. In the absence of neostigmine, oxotremorine caused a pronounced decrease in the output of acetylcholine (ACh), whereas atropine was without effect. In the presence of neostigmine oxotremorine was without effect but infusion of atropine or other anticholinergics caused a pronounced increase in the dialysate levels of ACh. It is concluded that the autoreceptor controlling the release of ACh is of the M3-type and that the receptor is not fully occupied during normal conditions. In conclusion, microdialysis of neurotransmitters is a valuable tool for the study of autoreceptors in vivo. The presented studies provided evidence for the existence of autoreceptors controlling the synthesis and/or release of DA, 5-HT, as well as ACh in the striatum.

Acetylcholine↗
PubMed1989

The enantiomers of the dopamine agonist N-0437: in vivo and in vitro effects on the release of striatal dopamine.

The enantiomers of the potent and selective dopamine (DA) D-2 receptor agonist 2-(N-propyl-N-2-thienylethyl-amino)-5-hydroxytetralin, N-0437, were tested for their pharmacological actions on DA D-2 autoreceptors in vivo, by measuring DA release by microdialysis during local administration of both drugs and in vitro, by measuring their effects on the electrically stimulated release of [3H]DA from striatal slices. In both experimental situations (-)-N-0437, at low doses, acted as an agonist on receptors controlling DA release. However, in vivo at a concentration of 10 microM (-)-N-0437 induced a short-lasting increase in DA release and in vitro the inhibitory effect of (-)-N-0437 was significantly less pronounced at higher concentrations (1-10 microM). (+)-N-0437 (0.1-10 microM) showed an antagonistic action both in vivo and in vitro. Following inhibition of the neuronal impulse flow with tetrodotoxin, (+)-N-0437 failed to increase DA release suggesting the effect of this enantiomer is not associated with an amphetamine-like action on the nerve terminal. The use of the DA re-uptake inhibitor GBR 12909 confirmed the antagonism of (+)-N-0437 towards DA receptors. Since it is known that (+)-N-0437 acts as an agonist on DA D-2 autoreceptors controlling the synthesis of DA, these results provide additional evidence for the existence of distinct DA D-2 autoreceptor populations involved in the release and synthesis of DA. The differential actions of (-)- and (+)-N-0437 gave rise to mutual antagonism of the actions of the enantiomers both in vivo and in vitro, thus providing a strong argument for using the enantiomers instead of the racemate in clinical situations.

Animals↗
PubMed1989

On the mechanism of neuroleptic induced increase in striatal dopamine release: brain dialysis provides direct evidence for mediation by autoreceptors localized on nerve terminals.

The influence of sulpiride on the in vivo release of dopamine and DOPAC from the rat striatum was investigated by microdialysis. Racemic sulpiride was administered systemically (i.p.) to control rats and to rats in which a striatum was pretreated by kainic acid. In addition various concentrations (10(-8) to 10(-5) M) of the two enantiomers of sulpiride were infused into the striatum and the effects on the release of dopamine were recorded. Infusion as well as systemic administration of sulpiride caused a maximal increase in the release of dopamine of about 180-190% of basal values. A similar increase was seen in kainic acid-pretreated rats. The rises in dopamine seen after systemic administration or infusion of sulpiride were not additive, suggesting that similar mechanisms were involved. DOPAC dialysate levels also increased during infusion of the neuroleptic but the rise was significantly less when sulpiride was administered i.p. to kainic acid pretreated rats. It is concluded that the rise in dopamine release seen after neuroleptics is mediated by autoreceptors localized on nerve terminals. This implies that the well-known increase in electrical activity of dopaminergic neurons during neuroleptic treatment, is not responsible for the increased release of the transmitter.

Animals↗
PubMed1989

Microdialysis and striatal dopamine release: stereoselective actions of the enantiomers of N-0437.

An intracerebral dialysis method was used to test both enantiomers of the very potent and selective dopamine (DA) D-2 agonist 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin, N-0437, for their actions on DA receptors in the striatum of the rat. (-)N-0437 induced a 60% decrease in DA release, which was independent of the presence or absence of a kainic acid lesion placed unilaterally in the striatum. Stereotyped behaviour was apparent following administration of the (-) enantiomer. Thus, (-)N-0437 displayed an agonistic action on both pre- and postsynaptic D-2 receptors. (+)N-0437 did not induce any effect in the release model after peripheral administration nor did it induce any form of stereotypy. A comparison between the effects of (-)N-0437 after oral (10 mumol/kg) and transdermal (10 mumol/kg) administration showed the advantages of the latter mode of administration. Transdermal application induced a much longer duration of action of the drug (13 h) in comparison with the oral mode (5 h). Thus, transdermal administration may be a very useful method of drug application for therapeutic use.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

On the origin of extracellular GABA collected by brain microdialysis and assayed by a simplified on-line method.

The present study describes a simplified on-line system for determination of GABA in brain dialysates. GABA was determined with an isocratic HPLC method after derivatization with o-phthaldialdehyde. One peristaltic pump was sufficient to transport both the perfusion fluid and the derivatizing reagent. The basal release of GABA was stimulated by infusion with either elevated K+ or the GABA uptake inhibitor (-)-nipecotic acid. Basal as well as stimulated GABA release were investigated for possible calcium-dependency by infusing submmolar amounts of the potent calcium antagonist cadmium. Infusion of cadmium did not modify the dialysate concentrations of GABA. In addition basal as well as nipecotic acid enhanced release of GABA dialysate concentrations were investigated for nerve-impulse dependency by infusing mumolar amounts of tetrodotoxin. No change in the GABA output was observed during infusion of TTX. From these results it is concluded that the basal as well as the nipecotic acid induced release of GABA did not fulfill the criteria for classic exocytotic release. Possible explanations for these unexpected findings are discussed.

Animals↗
PubMed1989

Effect of ouabain applied by intrastriatal microdialysis on the in vivo release of dopamine, acetylcholine, and amino acids in the brain of conscious rats.

In the present study we have applied a brain microdialysis technique to investigate the effects of ouabain infusion on the release of dopamine, acetylcholine, and amino acids from striatal neurons in freely moving rats. Ouabain caused an increase in the dialysate levels of dopamine; its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC); and the amino acids glutamate, aspartate, taurine, glycine, alanine, serine, asparagine, and threonine. The ouabain-induced increase in dopamine was dose dependent and explosive (100-fold at an infusion concentration of 1 mmol/L) and contrasted strongly with the small effect of the glycoside on the output of DOPAC. We investigated the nature of ouabain-induced transmitter release by determining its sensitivity to coinfusion with tetrodotoxin or the calcium antagonist Mg2+. In the case of dopamine two mechanisms of ouabain-induced release could be established. At lower infusion concentrations ouabain induced an exocytotic type of release whereas at higher concentrations the release was probably carrier mediated. In the case of amino acids we noticed a calcium-independent release which was nerve impulse flow dependent in the case of glutamate and aspartate and impulse flow independent in the case of alanine, serine, glycine, threonine, and asparagine. Ouabain induced a decrease in the release of acetylcholine and glutamine.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Use of calcium antagonism for the characterization of drug-evoked dopamine release from the brain of conscious rats determined by microdialysis.

Dopamine was determined by microdialysis of the striatum of conscious rats. We investigated whether the release of dopamine, induced by nine different pharmacological treatments, was sensitive to calcium antagonism. Calcium antagonism was determined by Mg2+ or Cd2+ infusion. The following conditions were investigated: haloperidol, haloperidol plus GBR 12909, nomifensine, (+)-amphetamine (all administered intraperitoneally), KCl, 1-methyl-4-phenyl-pyridinium ion (MPP+), glutamate, ouabain, and 120 mmol/L magnesium (all applied by infusion through the dialysis membrane). The results on calcium antagonism were combined with data on tetrodotoxin (TTX) sensitivity. With the combined data, three different types of dopamine release were characterized. First, action potential-dependent dopamine release was observed in animals treated with saline, haloperidol, haloperidol plus GBR 12909, nomifensine, and ouabain. Second, action potential-independent release was established in the case of (+)-amphetamine, glutamate, MPP+, and 120 mmol/L Mg2+. Finally, K+-induced dopamine release was classified as TTX independent and calcium dependent. It is concluded that brain dialysis is a powerful method for differentiating between different types of neurotransmitter release.

1-Methyl-4-phenylpyridinium↗
PubMed1988

Dopamine release in the nucleus accumbens of freely moving rats determined by on-line dialysis: effects of apomorphine and the neuroleptic-like peptide desenkephalin-gamma-endorphin.

This study examined the effects of apomorphine, sulpiride, desenkephalin-gamma-endorphin (DE gamma E) and a combination of DE gamma E with apomorphine on the release of dopamine (DA) and its main metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens of freely moving rats. A fully automated on-line brain dialysis system was used. A small dose of s.c. administered apomorphine induced a decrease in the output of DA and DOPAC. Sulpiride, infused into the nucleus accumbens, induced a 2-fold increase in the output of DA, DOPAC and HVA. DE gamma E hardly modified either the basal release of DA, DOPAC and HVA or the apomorphine-induced attenuation of the release of DA and DOPAC. These results indicate a dissociation between the behavioural effects of DE gamma E and its effect on the release of DA in vivo.

Animals↗
PubMed1988

The effect of systemically applied cholinergic drugs on the striatal release of dopamine and its metabolites, as determined by automated brain dialysis in conscious rats.

The effects of cholinergic drugs on the in vivo release of dopamine (DA) and its metabolites were studied in the striatum of freely moving rats. The endogenous compounds were sampled by microdialysis and analysed by on-line HPLC. High doses of oxotremorine (5 mumol/kg), physostigmine (3.6 mumol/kg), nicotine (3 mumol/kg) and atropine (10 mumol/kg) were injected i.p. Oxotremorine, physostigmine and atropine failed to modify the release of DA, while nicotine induced a slight (30%) but significant increase in the release of the transmitter. In contrast, oxotremorine and physostigmine did produce a significant rise of the dialysate contents of the DA metabolites. Thus, these data demonstrate clearly that changes in DA metabolism do not necessarily reflect changes in the release of DA. The most interesting findings of the present study is the fact that muscarinic receptor stimulation or blockade does not modify the release of DA from the rat striatum, while nicotine receptor stimulation may exert some stimulatory effect on the release of DA. This conclusion does not support the concept that the mode of action of anticholinergic drugs used in the treatment of parkinsonism, can be ascribed to a modulation of striatal dopaminergic activity.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

Scheduled eating increases dopamine release in the nucleus accumbens of food-deprived rats as assessed with on-line brain dialysis.

This study examined the effect of scheduled eating on the in vivo release of dopamine (DA) in the nucleus accumbens of rats that were maintained on a food deprivation schedule. DA release was measured by means of a fully automated on-line brain dialysis system. The initiation of eating increased the release of DA, which remained elevated during the entire eating period. Termination of eating caused a gradual decrease of the release of DA to basal values. Increased motor activities did not change the release of DA. These results indicate a link between eating and DA release and demonstrate the suitability of on-line brain dialysis for behavioural experiments.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

Differential effects of 4-aminopyridine and 2,4-diaminopyridine on the in vivo release of acetylcholine and dopamine in freely moving rats measured by intrastriatal dialysis.

The central effects of 4-aminopyridine (4-AP), a blocking agent of voltage-dependent potassium channels, and its more polar analogue, 2,4-diaminopyridine (2,4-DAP), were studied after i.p. injection and direct intrastriatal administration in rats. The effects of the drugs on the release of acetylcholine (ACh) and dopamine (DA) were quantified by means of an in vivo microdialysis sampling technique. Both neurotransmitters were determined by on-line HPLC analysis. Both aminopyridines increased the release of ACh dose dependently when administered intrastriatally. After peripheral administration, however, 4-AP but not 2,4-DAP induced an increase in the release of ACh. These results are interpreted as being due to the greater lipid solubility of 4-AP compared to 2,4-DAP and hence its better penetration through the blood-brain barrier. Intrastriatal administration of 4-AP induced a much lower increase in the release of DA compared to ACh, whereas there was no change in the release of DA after peripheral administration. These results indicate that the sensitivity of excitable membranes to the releasing effects of 4-AP is not the same for DA- and ACh-containing neurotransmitter systems.

4-Aminopyridine↗
PubMed1988

The significance of extracellular calcium for the release of dopamine, acetylcholine and amino acids in conscious rats, evaluated by brain microdialysis.

The influence of the calcium concentration of the perfusion fluid on the release of striatal dopamine recorded by brain dialysis was investigated. The release of dopamine appeared very sensitive to the calcium concentration of the Ringer. Next we studied whether three different methods known to antagonize the effects of calcium entry, were able to affect the release of dopamine. The conditions investigated were: the use of calcium-free Ringer, infusion of magnesium, and infusion of the calcium-antagonist verapamil. Calcium-antagonism was studied on the day of implantation of the cannula as well as on several days thereafter. It appeared that magnesium infusion was the most effective condition to antagonize the effects of calcium on the release of dopamine. Magnesium infusion was also most effective in preventing drug-evoked voltage-dependent dopamine release (induced by coadministration of haloperidol and GBR 12909). In addition magnesium infusion appeared a potent antagonist of acetylcholine release. In contrast, the dialysate content of aminoacids was not influenced by magnesium infusion.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

Basal acetylcholine release in freely moving rats detected by on-line trans-striatal dialysis: pharmacological aspects.

The basal release of acetylcholine (without the use of an esterase inhibitor) from brain tissue was quantified by means of transversal striatal dialysis in freely moving rats, coupled on-line to an HPLC analysis system. Basal release of acetylcholine was shown to be fully calcium dependent and tetrodotoxin sensitive. A comparison between a U-shaped and a transversally localized dialysis probe was made and some important differences were noticed. The use of a transversal probe resulted in a 20 times higher recovery when compared with the U-shaped cannula. The effect of the cholinomimetic oxotremorine and the anticholinergic atropine on the basal acetylcholine output was determined. Atropine increased the output of acetylcholine, whereas oxotremorine induced a decrease in the output of the transmitter. Application of various degrees of esterase inhibition (by addition of neostigmine to the perfusion fluid) did not qualitatively interfere with the effects of oxotremorine or atropine on the release of acetylcholine.

Acetylcholine↗
PubMed1988

The use of in vivo brain dialysis of dopamine, acetylcholine, amino acids and lactic acid in studies on the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

The use of intracerebral brain dialysis in freely moving rats in neurochemical and neurotoxicological research is discussed and exemplified by studies on the neurotoxin MPTP. Intrastriatal administration of its toxic metabolite MPP+, via the dialysis tube, induced massive changes in the release of neurotransmitters and metabolites. Release enhancing effects could not be repeated by a second MPP+ perfusion and decreases in neurotransmitter or metabolite output were persistent. This indicates that MPP+ has irreversible, toxic effects on various neuortransmitter systems. The MPP+-induced release of DA has been characterized by studying the effect of pretreatment with various drugs, as well by comparison of the time courses of MPP+-induced DA release with those of amphetamine-induced DA release and of MPP+-induced lactate overflow.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1988

Characterization of in vivo dopamine release as determined by brain microdialysis after acute and subchronic implantations: methodological aspects.

Infusion of tetrodotoxin (TTX) through the dialysis membrane and perfusion with calcium-free Ringer solution (calcium depletion) were used to evaluate the dopamine release determined by in vivo brain dialysis. Several hours after implantation, the dopamine release recorded by the U-shaped cannula did not respond to calcium depletion and was only partly (approximately 50%) TTX dependent. The half-life of the TTX-independent dopamine overflow was determined to be 2 h. In contrast, when a transstriatal cannula was used, the dopamine output displayed calcium and TTX dependency. Differences in the dimensions of the two types of probes are a likely explanation for the observed effects. Twenty-four hours after implantation, both types of cannula fulfilled the criteria of calcium and TTX dependency. The results indicate that infusion of TTX-containing or calcium-free Ringer solution can be used to estimate the functional damage caused by the implantation of the cannula.

Animals↗
PubMed1987

Scope and limitations of in vivo brain dialysis: a comparison of its application to various neurotransmitter systems.

Brain dialysis is rapidly becoming a routine research method with a wide range of applications. Since 1982 this sampling technique is frequently used as a method to study the in vivo release of endogenous neurotransmitters such as dopamine, noradrenaline, serotonin, acetylcholine and certain amino acids. In this review most of the studies that have appeared in this field, are evaluated. Special attention was given to the question whether the neurotransmitter content in the dialysate is related to neurotransmission. Criteria such as the presence of a high tissue/dialysate concentration ratio, the sensitivity of the transmitters to membrane active compounds and the occurrence of receptor-mediated effects, are discussed. It is concluded that dopamine, noradrenaline and acetylcholine found in the dialysate are directly derived from neurotransmission, whereas the overflow of excitatory amino acid neurotransmitters is related to neurogenic as well as to metabolic events.

Acetylcholine↗