Biomedical subjects

M Fillenz

Publications and source records attributed to M Fillenz.

At least 19 recordsLinked to original sources

PubMed1992

Studies on the origin of rat hippocampal dihydroxyphenylacetic acid using microdialysis.

With a dialysis probe implanted in the rat ventral hippocampus we have monitored effects on noradrenaline (NA) and dihydroxyphenylacetic acid (DOPAC) of the infusion through the dialysis probe of drugs acting at dopaminergic and noradrenergic presynaptic autoreceptors; clonidine and idazoxan produced changes in the extracellular concentration of both NA and DOPAC, whereas LY171555 and sulpiride had no effect on NA but produced changes in the concentration of DOPAC. The combined effect of clonidine and LY171555 on DOPAC was additive. Hippocampal DOPAC is therefore derived from both the noradrenergic and the dopaminergic projection to the hippocampus.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1992

Extracellular brain glucose levels reflect local neuronal activity: a microdialysis study in awake, freely moving rats.

The relationship between brain extracellular glucose levels and neuronal activity was evaluated using microdialysis in awake, freely moving rats. The sodium channel blocker tetrodotoxin and the depolarizing agent veratridine were administered through the dialysis probe to provoke local changes in neuronal activity. The extracellular glucose content was significantly increased in the presence of tetrodotoxin and decreased sharply following veratridine application. The systemic injection of a general anaesthetic, chloral hydrate, led to a large and prolonged increase in extracellular glucose levels. The brain extracellular glucose concentration was estimated by comparing dialysate glucose efflux over a range of inlet glucose concentrations. A mean value of 0.47 mM was obtained in five animals. The results are discussed in terms of the coupling between brain glucose supply and metabolism. The changes observed in extracellular glucose levels under various conditions suggest that supply and utilization may be less tightly linked in the awake rat than has previously been postulated.

Animals↗

PubMed1991

Presynaptic adenosine A2 and N-methyl-D-aspartate receptors regulate dopamine synthesis in rat striatal synaptosomes.

Dopamine synthesis rate and cyclic AMP concentration were measured in synaptosomes prepared from rat striatum. Dopamine synthesis rate was decreased by the addition of either adenosine deaminase or 8-phenyltheophylline, an adenosine receptor blocker, and was increased by the addition of 2-chloroadenosine. The addition of L-glutamate in the absence of adenosine deaminase decreased both dopamine synthesis rate and cyclic AMP concentration; in the presence of adenosine deaminase, glutamate had no effect on basal dopamine synthesis, but enhanced K(+)-stimulated synthesis. Both these effects of glutamate were abolished in Ca2(+)-free medium or in the presence of 2-amino-5-phosphonovalerate, an N-methyl-D-aspartate (NMDA) receptor blocker. In Mg2(+)-free medium with adenosine deaminase, glutamate enhanced both basal and K(+)-stimulated synthesis. These results suggest that dopaminergic terminals have A2 adenosine receptors, whose activation can stimulate dopamine synthesis by a cyclic AMP-dependent mechanism, and NMDA receptors, which modulate dopamine synthesis by a Ca2(+)-dependent mechanism.

Adenosine↗

PubMed1991

Anomalously high concentrations of brain extracellular uric acid detected with chronically implanted probes: implications for in vivo sampling techniques.

The height of peak 2, h2, recorded using linear sweep voltammetry with 350-micron-diameter carbon paste electrodes in rat striatum was measured from the day of implantation (day 0) to 4 months after surgery. The value of h2 was at a minimum on day 0 (0.6 +/- 0.2 nA; n = 20), rose sharply to a maximum on day 2 (6.3 +/- 0.9 nA; n = 12), and decreased to a stable level by day 7 (3.3 +/- 0.7 nA; n = 16), which lasted for 4 months (3.2 +/- 0.6 nA; n = 9). These changes were shown by microinfusion of uricase to be due to variations in the concentrations of extracellular uric acid, although h2 appears to have a small baseline contribution of approximately 0.3 nA from 5-hydroxyindoleacetic acid. The stable value of h2 recorded under chronic conditions was estimated to correspond to a minimal uric acid concentration of 50 mumol/L, which represents a 10-fold increase in the extracellular level of this purine metabolite compared with the initial (acute) value. Very similar results were obtained using a microdialysis technique that detected uric acid directly. These estimates of striatal uric acid concentration are in marked contrast to those obtained using 40-micron diameter carbon fiber electrodes, which showed a decrease from the acute preparation to less than 1 mumol/L under chronic conditions. Large values of h2 were also recorded with chronically implanted paste electrodes in the hippocampus and frontal cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Adenosine agonists can both inhibit and enhance in vivo striatal dopamine release.

The effects on striatal dopamine (DA) release and metabolism by local administration of adenosine analogues with different affinities for the A1 and A2 adenosine receptors, were investigated using the technique of microdialysis. 2-Chloroadenosine (2-CADO), decreased levels of both dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in striatal dialysates at concentrations of 1-10 microM; a similar effect was also seen after administration of N6-(2-phenylisopropyl)adenosine (R(-)-PIA) and 5'-N-ethylcarboxamido-adenosine (NECA) at a concentration of 10 microM. The inhibitory action of 2-CADO on DA release and metabolism was blocked by the selective A1 antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT), suggesting mediation by A1 receptors. 2-CADO at a concentration of 100 microM increased levels of both DA and DOPAC in striatal perfusates, an effect which was not inhibited by CPT. This stimulatory action on extracellular DA concentration in striatum was also seen with 10 microM 5'-(N-cyclopropyl)-carboxamidoadenosine (CPCA) a relatively selective A2 adenosine agonist. These results suggest that adenosine agonists enhance or depress striatal DA release depending on the nature and concentration of the drug.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1990

Effect of diazepam on behaviour and associated changes in ascorbate concentration in rat brain areas: striatum, n. accumbens and hippocampus.

The effect of diazepam on spontaneous and tail-pinch-induced behaviour was monitored together with the measurement of extracellular ascorbate using constant potential voltammetry with carbon paste electrodes. Diazepam (3 mg/kg) was followed by eating during the 1st hour after administration in non-food-deprived rats and a reduction in the behaviour triggered by a mild tail-pinch 90 min after drug administration. There was no change in ascorbate concentration in parallel with the spontaneous eating; however, the brisk increase in ascorbate concentration in striatum, nucleus accumbens and hippocampus, which accompanies the tail-pinch, was decreased in size and duration after diazepam. This effect was blocked by the central benzodiazepine receptor antagonist Ro15 1788 (5 mg/kg).

Animals↗

PubMed1990

Local administration of flurazepam has different effects on dopamine release in striatum and nucleus accumbens: a microdialysis study.

The action of local administration of flurazepam on extracellular levels of dopamine (DA) and its metabolites 3,4 dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA) in the anterior striatum and medial nucleus accumbens have been investigated using microdialysis. Flurazepam (10 microM), administered through the perfusion medium for 20 min, reduced levels of DA in dialysates from the nucleus accumbens by 60% while the same concentration of the drug had no effect on levels of DA in perfusates from the striatum. Pretreatment with the benzodiazepine antagonist Ro 15-1788 (flumazenil) or with picrotoxin, a drug which blocks the GABAA receptor-associated chloride channel, inhibited the effect of flurazepam on levels of DA in the nucleus accumbens, which suggests that the effect was mediated by the multimolecular GABAA/benzodiazepine receptor complex. Administration of flurazepam had little effect on the two metabolites of DA, DOPAC and HVA, in either the nucleus accumbens or striatum. The inverse partial benzodiazepine agonist, FG 7142, had no significant action on the release of DA in the nucleus accumbens. These results suggest that the dopaminergic projection to the nucleus accumbens is more sensitive to benzodiazepine-induced inhibition than the projection to the striatum.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1990

In vivo neurochemical effects of tail pinch.

Tail pinch in the rat gives rise to a well characterised pattern of behaviour which includes gnawing, licking and eating. We have used both in vivo voltammetry and microdialysis to monitor neurochemical changes which accompany the behavioural response to a 5-min tail pinch. Tail pinch resulted in a increase of extracellular 5-hydroxytryptamine and a smaller and more delayed increase of 5-hydroxyindole acetic acid in the hippocampus. In the striatum there was a rise of both extracellular dopamine and ascorbate. With a recently developed constant potential voltammetric technique we can continuously monitor changes in extracellular ascorbate. Using this technique we found a very rapid rise in ascorbate current during a 5-min tail pinch; the current began to decline as soon as the clip was removed. The high time resolution of the technique also allowed us to record similar ascorbate changes during a 0.5-s tail pinch.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1990

Tail pinch-induced changes in the turnover and release of dopamine and 5-hydroxytryptamine in different brain regions of the rat.

Tail pinch was administered through a paper clip attached to the rat's tail. The ex vivo changes in the metabolite/transmitter ratio were used as a measure of changes in the turnover of dopamine and 5-hydroxytryptamine. After a 2-min tail pinch dopamine turnover was increased in the striatum but not in the frontal cortex, hypothalamus or olfactory tubercle; 5-hydroxytryptamine turnover was increased in frontal cortex and hippocampus and was unchanged in striatum, hypothalamus and olfactory tubercle. Microdialysis was used to monitor the changes in extracellular neurotransmitter and metabolite concentrations during and after tail pinch. A 5-min tail pinch caused a rapid rise of both dopamine in the striatum and 5-hydroxytryptamine in the hippocampus. There was a smaller increase in the 5-hydroxytryptamine metabolite 5-hydroxyindoleacetic acid and only a non-significant increase in the dopamine metabolite 3,4-dihydroxyphenylacetic acid.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1989

The effects of anxiolytic and anxiogenic benzodiazepine receptor ligands on motor activity and levels of ascorbic acid in the nucleus accumbens and striatum of the rat.

The effects of the anxiolytic benzodiazepine flurazepam and the anxiogenic beta-carboline N-methyl-beta-carboline-3-carboxylate (FG 7142) were measured in unanaesthetised rats. Changes in motor activity, using a Doppler-shift microwave device, and in the extracellular concentration of ascorbate in the striatum and nucleus accumbens, using linear sweep voltammetry with carbon paste electrodes, were monitored continuously over a period of 7 days. Both motor activity and release of ascorbate were greater during the dark than the light period; regression analysis showed a high correlation coefficient for motor activity vs release of ascorbate. The two drugs caused similar changes in this diurnal pattern. A single intraperitoneal injection of either flurazepam or FG 7142 at the end of the light period was followed by a reduction in the nocturnal rise of motor activity and of levels of ascorbate in both the nucleus accumbens and striatum. However, whereas the correlation coefficient for motor activity vs the level of ascorbate in both the nucleus accumbens and striatum remained high after the injection of flurazepam, there was a breakdown of the correlation on the day after the injection of FG 7142, followed by recovery.

Animals↗

PubMed1989

Both systemic and local administration of benzodiazepine agonists inhibit the in vivo release of 5-HT from ventral hippocampus.

The effects of benzodiazepine- and GABAA-receptor agonists and antagonists on the release and metabolism of 5-HT were measured in the ventral hippocampus of freely moving rats using microdialysis. Systemic injections of the benzodiazepine agonists, flurazepam and diazepam reduced the levels of 5-HT while the partial inverse agonist, FG 7142 (N-methyl-beta-carboline-3-carboxamide), had no effect. Local perfusion of flurazepam through the dialysis probe also decreased the release of 5-HT in the ventral hippocampus, an effect which was completely blocked by the benzodiazepine antagonist, Ro15-1788 (flumazenil). Local application of the GABAA agonist muscimol had no effect on the release of 5-HT, while the antagonist picrotoxin, administered locally, caused a 4-fold enhancement of release of 5-HT. Picrotoxin also resulted in a complete block of the inhibitory effect of flurazepam on release of 5-HT. None of these drugs caused significant changes in the levels of the metabolite of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) in the ventral hippocampus. These results suggest that the inhibitory effect of flurazepam on the release of 5-HT is mediated by benzodiazepine/GABAA receptors in the hippocampus and that GABA exerts a tonic inhibitory effect on the release of 5-HT in the region of the brain.

Animals↗

PubMed1989

Rapid changes in striatal ascorbate in response to tail-pinch monitored by constant potential voltammetry.

The first peak in the voltammogram recorded with linear sweep and a carbon paste electrode implanted in the rat striatum is due to the oxidation of ascorbic acid. When the potential is held at a level slightly positive to this peak a current is recorded which is abolished by the microinjection of ascorbic acid oxidase in the vicinity of the electrode; this suggests that it is due to the oxidation of ascorbate. This current shows the same diurnal variation as the size of the ascorbate peak and its rise and fall coincides with the onset and offset of motor activity. A tail-pinch applied through a paper clip causes an immediate rise in the ascorbate current which begins to fall as soon as the paper clip is removed. Measurement of the ascorbate current at constant potential provides a technique for monitoring rapid changes in extracellular brain ascorbate in response to physiological stimuli.

Animals↗

PubMed1988

Dopamine in the basal ganglia and benzodiazepine-induced sedation.

The effects of the anxiolytic benzodiazepine flurazepam on motor activity and the turnover of dopamine were measured in rats. Changes in motor activity were measured using a doppler-shift device; changes in extracellular homovanillic acid (HVA), monitored by linear sweep voltammetry with carbon paste electrodes implanted in the striatum and nucleus accumbens and ex vivo measurements of changes in 3,4-dihydroxyphenylacetic acid/dopamine (DOPAC/DA) ratios in the striatum and nucleus accumbens were used as indices of changes in the turnover of dopamine. Injection of vehicle increased the nocturnal rise in the concentration of HVA and the ex vivo DOPAC/DA ratio in the nucleus accumbens. Injection of flurazepam decreased the nocturnal rise in HVA and DOPAC/DA ratio in the nucleus accumbens below control levels. There was also a decrease in the nocturnal rise in motor activity. Neither injection of vehicle nor injection of flurazepam caused changes in either the concentration of HVA or the DOPAC/DA ratio in the striatum. The correlation coefficient for motor activity compared to concentration of HVA remained high for the nucleus accumbens but was reduced for the striatum after administration of flurazepam. The results suggest that the sedative effect of flurazepam may be due to an action on the mesolimbic but not the nigrostriatal dopaminergic pathway.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1988

K+-dependent stimulation of dopamine synthesis in striatal synaptosomes is mediated by protein kinase C.

Dopamine synthesis rate was measured in striatal synaptosomes. Removal of Na+ increased synthesis rate; this was blocked in Ca2+-free medium and by addition of the Ca2+/calmodulin inhibitor N-6-aminohexyl-5-chloro-1-naphthalenesulfonamide (W7). The increase in dopamine synthesis rate caused by the addition of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) was blocked by the protein kinase C inhibitor polymyxin B. K+-stimulated synthesis was unchanged in Ca2+-free medium or by addition of W7; it was blocked by polymyxin B. The effect of 50 mM K+ was additive with that of 8-Br cyclic AMP and of Na+ removal; the combined effect of 50 mM K+ and TPA was no greater than that of either alone. These results suggest that stimulation of dopamine synthesis in striatal synaptosomes by 50 mM K+ is mediated by protein kinase C.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1987

Protein kinase C mediates the stimulation by somatostatin of dopamine synthesis in the rat striatum and nucleus accumbens.

In experiments using a synaptosomal preparation from the striatum and nucleus accumbens, somatostatin caused a dose-dependent increase in dopamine synthesis. This increase was additive with that produced by 8-BrcAMP but not with that produced by the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA), and was blocked by the protein kinase C inhibitor polymyxin B (PMB). These findings suggest that stimulation of dopamine synthesis by somatostatin is mediated by activation of protein kinase C.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1987

Cholecystokinin stimulates dopamine synthesis in synaptosomes by a cyclic AMP-dependent mechanism.

The effects of different fragments of cholecystokinin (CCK) on dopamine synthesis were studied in synaptosomal preparations from the striatum, substantia nigra, and frontal cortex. In striatal synaptosomes, dopamine synthesis rate measured by dopamine accumulation was 12.5% lower than that measured by 3,4-dihydroxyphenylalanine (DOPA) accumulation; however, K+-accelerated synthesis was the same for both methods. Synthesis rate was independent of exogenous tyrosine levels. In the three regions studied, the combined stimulatory effects of 8-Br-cyclic AMP and high K+ were additive. CCK-5, CCK-3, CCK-27-33, and CCK-8 (sulphated) enhanced synthesis, CCK-5 being the most potent fragment. The nonsulphated octapeptide had no effect. In all three regions, CCK-5 and high K+ had an additive effect on dopamine synthesis; CCK-5 and 8-Br-cyclic AMP together produced the same enhancement of synthesis as CCK-5 alone. CCK-5 produced similar dose-dependent increases in dopamine synthesis and cyclic AMP accumulation in striatal synaptosomes, and both effects were blocked by the CCK antagonist proglumide.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1987

Effects of an anxiogenic benzodiazepine receptor ligand on motor activity and dopamine release in nucleus accumbens and striatum in the rat.

The effects of the anxiogenic beta-carboline FG 7142 (N-methyl-beta-carboline-3-carboxylate) on motor activity and dopamine release in nucleus accumbens and striatum were measured in the rat. Changes in extracellular homovanillic acid (HVA) concentration, monitored by computer-controlled linear sweep voltammetry with carbon-paste electrodes, were used as an index of changes in dopamine release. An intraperitoneal injection of FG 7142 was followed by an inhibition of the nocturnal rise in motor activity and in dopamine release in nucleus accumbens, but not striatum. Two days after the drug injection, dopamine release in nucleus accumbens returned to control level and then increased on days 3-6 after the injection; there was no delayed change in motor activity or in striatal dopamine release. In parallel experiments using ex vivo changes in the ratio of 3,4-dihydroxyphenylacetic acid (DOPAC) to dopamine as an index of changes in dopamine turnover, a similar early depression and delayed increase of dopamine turnover in nucleus accumbens, with no change in striatum, was found after an intraperitoneal injection of FG 7142. Regression analysis of motor activity versus dopamine release showed a decrease in correlation between these 2 parameters for nucleus accumbens but not striatum after FG 7142 injection. These results suggest that the inverse benzodiazepine receptor agonist FG 7142 has a biphasic effect on dopamine release from mesolimbic neurons and support the hypothesis that dopamine release in nucleus accumbens and striatum has a modulatory effect on the control of motor activity but does not play a determining role in the regulation of movement.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1986

An amperometric enzyme electrode for monitoring brain glucose in the freely moving rat.

Brain glucose concentration was measured with an amperometric enzyme electrode using glucose oxidase (EC 1.1.3.4) irreversibly adsorbed onto an organic conducting salt. The responses of the electrode and its stability both in vitro and in vivo are described. Parellel changes in brain glucose and blood glucose (measured in samples from an implanted intra-atrial cannula) following injections of insulin are reported.

Animals↗