Biomedical subjects

A C Linthorst

Publications and source records attributed to A C Linthorst.

28 records · Page 2Linked to original sources

PubMed1995

Effect of bacterial endotoxin and interleukin-1 beta on hippocampal serotonergic neurotransmission, behavioral activity, and free corticosterone levels: an in vivo microdialysis study.

In this study the effect of immune system stimulation and intracerebroventricular (i.c.v.) administration of interleukin-1 beta (IL-1 beta) on hippocampal serotonergic neurotransmission, behavioral activity, and the hypothalamic-pituitary-adrenocortical (HPA) axis is described. An in vivo microdialysis method was used to measure hippocampal extracellular concentrations of serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in conscious, freely moving rats. In addition, we established a method to continuously monitor free corticosterone levels in dialysates. Behavioral activity was scored by measuring the time during which rats were active (locomotion, grooming, eating, drinking). We found a significant, positive relationship between behavioral activity and hippocampal extracellular concentrations of 5-HT. Intraperitoneal (i.p.) administration of the bacterial endotoxin lipopolysaccharide (LPS; 30, 100, and 300 micrograms/kg body weight) produced an increase in the extracellular concentrations of 5-HT and 5-HIAA in the hippocampus, which was paralleled by a significant decline in behavioral activity and a marked increase in extracellular corticosterone levels. Thus, the close correlation between hippocampal extracellular 5-HT levels and behavioral activity observed in control rats was disrupted in the LPS-treated animals. The effects of i.p. LPS could be mimicked by i.c.v. application of recombinant human IL-1 beta (hIL-1 beta; 100 ng). i.c.v. pretreatment with the IL-1 receptor antagonist (IL-1ra; 10 micrograms) antagonized the hIL-1 beta-induced effects. IL-1ra showed no intrinsic effects. Furthermore, it was found that i.c.v. pretreatment with IL-1ra (10 micrograms) significantly attenuated the i.p. LPS-induced (100 micrograms/kg body weight) rise in hippocampal extracellular 5-HT levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

The nigrostriatal dopamine system and the development of hypertension in the spontaneously hypertensive rat.

Several observations reported in the literature reveal a role of brain catecholaminergic systems in the development of hypertension in spontaneously hypertensive rats (SHR). As reviewed here, our results obtained with intracerebroventricular injections of 6-hydroxydopamine in your SHR point in particular to the involvement of the nigrostriatal dopamine system. The electrically stimulated release of radiolabeled dopamine in vitro from caudate nucleus slices of SHR was lower than that in slices of normotensive Wistar-Kyoto rats (WKY). Using an in vivo microdialysis method, we found that the extracellular concentration of dopamine and the metabolite DOPAC was lower in the caudate nucleus of conscious SHR than in that of WKY. We also studied the effects of lesions of the pars compacta of the substantia nigra of 4 week-old SHR and WKY, 1) on blood pressure and heart rate, 2) on the concentrations of dopamine and metabolites in the caudate nucleus and 3) on the release of radiolabeled dopamine from caudate nucleus slices using an in vitro superfusion method, 6 weeks following lesioning. Substantia nigra lesions caused a profound attenuation of the development of hypertension in SHR, with no effect on heart rate. The ratios DOPAC/dopamine and HVA/dopamine were lower in sham-treated SHR than in sham-treated WKY pointing to a lower turnover of dopamine in SHR. Six weeks after lesioning, the concentrations of dopamine were decreased in the caudate nucleus of both strains. At this time, the stimulus-evoked release of dopamine from the remaining terminals was significantly increased in caudate nucleus slices of SHR but not in slices of WKY. Thus, whereas the release of dopamine from caudata nucleus slices is lower in sham-treated SHR than in sham-treated WKY, lesioning of the substantia nigra results in a similar release of dopamine from caudate nucleus slices of lesioned SHR and sham-treated WKY. This normalization of dopaminergic activity may be the causal factor underlying the attenuation of the development of hypertension in SHR after bilateral lesioning of the pars compacta, of the substantia nigra.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

The nigrostriatal dopamine system: role in the development of hypertension in spontaneously hypertensive rats.

The effects of lesions in the pars compacta of the substantia nigra of 4-week-old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) were studied on (a) changes in blood pressure during a period of 6 weeks following lesioning, and (b) dopamine and metabolite concentrations in the caudate nucleus and (c) the in vitro release of [3H]dopamine from caudate nucleus slices 6 weeks after the lesioning. We report here that substantia nigra lesions caused a profound attenuation of the development of hypertension in SHR. No effect on heart rate was observed. Whereas the concentrations of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) in the caudate nucleus were not different, the amount of homovanillic acid (HVA) and the ratios DOPAC/dopamine and HVA/dopamine were lower in sham-treated SHR than in sham-treated WKY, indicating a lower turnover of dopamine in SHR. Six weeks after lesioning, the concentrations of dopamine, DOPAC and HVA were decreased in the caudate nucleus (46-66%) of both strains, whereas DOPAC/dopamine and HVA/dopamine ratios tended to be increased in both SHR and WKY. Using an in vitro superfusion method, it was found, that the electrically stimulated release of [3H]dopamine from caudate nucleus slices of sham-treated SHR was lower than from slices of sham-treated WKY at the age of 10 weeks. Six weeks after lesioning, the stimulus-evoked release of [3H]dopamine from the remaining terminals was significantly increased in caudate nucleus slices of SHR, whereas the difference did not reach statistical significance in WKY.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

Prenatal immune challenge alters the hypothalamic-pituitary-adrenocortical axis in adult rats.

We investigated whether non-abortive maternal infections would compromise fetal brain development and alter hypothalamic-pituitary-adrenocortical (HPA) axis functioning when adult. To study putative teratogenic effects of a T cell-mediated immune response versus an endotoxic challenge, 10-d-pregnant rats received a single intraperitoneal injection of 5 x 10(8) human red blood cells (HRBC) or gram-negative bacterial endotoxin (Escherichia coli LPS: 30 micrograms/kg). The adult male progeny (3 mo old) of both experimental groups showed increased basal plasma corticosterone levels. In addition, after novelty stress the HRBC group, but not the LPS group, showed increased ACTH and corticosterone levels. Both groups showed substantial decreases in mineralocorticoid (MR) and glucocorticoid receptor (GR) levels in the hippocampus, a limbic brain structure critical for HPA axis regulation, whereas GR concentrations in the hypothalamus were unchanged and in anterior pituitary were slightly increased. HRBC and LPS indeed stimulated the maternal immune system as revealed by specific anti-HRBC antibody production and enhanced IL-1 beta mRNA expression in splenocytes, respectively. This study demonstrates that a T cell-mediated immune response as well as an endotoxic challenge during pregnancy can induce anomalies in HPA axis function in adulthood. Clinically, it may be postulated that disturbed fetal brain development due to prenatal immune challenge increases the vulnerability to develop mental illness involving inadequate responses to stress.

Animals↗

PubMed1994

Local administration of recombinant human interleukin-1 beta in the rat hippocampus increases serotonergic neurotransmission, hypothalamic-pituitary-adrenocortical axis activity, and body temperature.

In this study, we equipped rats with a microdialysis probe in the hippocampus, which enabled stress-free intrahippocampal administration of recombinant human IL-1 beta (hIL-1 beta). Perfusion of the probes was conducted with a Ringer's solution containing 0.1 or 1.0 microM hIL-1 beta or without hIL-1 beta, usually for 6 h. Time-dependent changes in serotonergic neurotransmission and hypothalamic-pituitary-adrenocortical activity were simultaneously monitored by measuring serotonin [5-hydroxytryptamine (5-HT)], 5-hydroxyindoleacetic acid, and corticosterone concentrations in the dialysates. In control rats, there was a clear relationship between extracellular 5-HT concentrations in the hippocampus and behavioral activity. Extracellular 5-HT levels were up to twice as high in behaviorally active rats compared to those in resting or sleeping animals. Intrahippocampal administration of hIL-1 beta markedly increased extracellular 5-HT concentrations in the hippocampus and induced a significant decrease in behavioral activity, thereby uncoupling the parallelism between changes in 5-HT and changes in behavioral activity observed in control rats. Perfusion with 0.1 microM hIL-1 beta, but not with 1 microM hIL-1 beta, produced a decrease in 5-hydroxyindoleacetic acid levels, followed by a return to preinfusion levels. Moreover, intrahippocampal administration of hIL-1 beta increased hypothalamic-pituitary-adrenocortical axis activity, as evidenced by marked increases in both plasma ACTH and plasma and dialysate corticosterone levels. In addition, a rise in body temperature by approximately 2 C was observed at time points at which the effects of hIL-1 beta on 5-HT and corticosterone levels were (near-)maximal. hIL-1 beta-treated rats displayed typical characteristics of sickness behavior, such as immobility, piloerection, and a curled-up body posture. Most importantly, no effects were found either with heat-inactivated hIL-1 beta or when hIL-1 beta was administered via a probe implanted in the neocortex. Based on these results, we postulate that the hippocampal IL-1 system may play an important role in the coordination of neuroendocrine, autonomic, and behavioral responses after an immune challenge.

Adrenal Cortex↗

PubMed1993

Dopamine D1 and D2 receptors in the caudate nucleus of spontaneously hypertensive rats and normotensive Wistar-Kyoto rats.

A series of studies was carried out to characterize the binding properties of dopamine D1 and D2 receptors in membrane homogenates of the caudate nucleus of spontaneously hypertensive rats (SHR). Binding in SHR was studied at the age of 4 weeks when the rats were still in the prehypertensive phase, and at the age of 8 weeks, during the phase in which blood pressure is increasing dramatically; age-matched normotensive Wistar-Kyoto rats (WKY) were used as controls. Binding to dopamine D1 receptors was studied using [3H]SCH 23390. Antagonist binding of dopamine D2 receptors was performed with [3H]spiperone. At both ages no differences were found between SHR and WKY in affinity (Kd) or concentration (Bmax) of dopamine D1 and D2 receptors. Binding to the high affinity state of the dopamine D2 receptor was measured using the agonist [3H]N-n-propylnorapomorphine (NPA). No differences in Bmax or Kd were found between SHR and WKY at both ages studied, indicating that the ratio between dopamine D2 receptors in the high and in the low affinity state is not altered in spontaneous hypertension. Although the results do not reveal differences in affinities or concentrations of dopamine D1 or D2 receptors in the caudate nucleus between SHR and WKY, a role in the development of hypertension for the here described lack of receptor up-regulation in connection with our previous observation of lower release of dopamine in the caudate nucleus of SHR, cannot be excluded.

Animals↗

PubMed1992

Effect of SCH 23390 and quinpirole on novelty-induced grooming behaviour in spontaneously hypertensive rats and Wistar-Kyoto rats.

Grooming behaviour induced by exposure to a novel environment was studied in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). The dopamine D1 receptor antagonist, SCH 23390, and the dopamine D2 receptor agonist, quinpirole, were used to study brain dopamine systems in these rat strains, via their effects on grooming behaviour. The total grooming behaviour displayed in a 50-min observation period was significantly lower in SHR than in WKY. Except for the paw licking component no differences between the two strains were observed in the separate behavioural elements of grooming behaviour. SCH 23390 and quinpirole were found to suppress novelty-induced grooming behaviour of both strains. In SHR, grooming behaviour was less suppressed by SCH 23390, whereas the suppression by quinpirole was more pronounced than in WKY. These results indicate that there are alterations in central dopamine systems in SHR, probably involving changes both in dopamine D1 and D2 receptor mechanisms in the brain.

Animals↗

PubMed1991

Effect of the dopamine D2 receptor agonist quinpirole on the in vivo release of dopamine in the caudate nucleus of hypertensive rats.

Using an in vivo microdialysis method, we found that the extracellular concentrations of dopamine and its main metabolite dihydroxyphenylacetic acid (DOPAC) were lower in the caudate nucleus of 8-week-old spontaneously hypertensive rats (SHR) than in the same area of age-matched normotensive Wistar-Kyoto rats (WKY). No differences in the extracellular concentrations of dopamine and DOPAC were found between renal and deoxycorticosterone acetate (DOCA)-salt hypertensive rats when compared to their respective controls. After subcutaneous administration of the dopamine D2 receptor agonist quinpirole (10, 33 and 100 micrograms/kg), the amount of dopamine and DOPAC in the dialysates was diminished dose dependently. The quinpirole-mediated inhibition of dopamine release was more pronounced in SHR than in WKY, whereas inhibition of the extracellular DOPAC concentration was not different. Compared to WKY, the dose-response curve for the inhibition of dopamine release by quinpirole was shifted to the left in SHR and the maximal inhibition in response to the highest dose was significantly greater. Renal and DOCA-salt hypertensive rats showed no differences in the quinpirole-induced inhibition of the extracellular concentrations of striatal dopamine and DOPAC compared to their controls. The present findings on changes in dopaminergic neurotransmission and D2 autoreceptor-mediated modulation of dopamine release in genetically hypertensive rats but not in rats with experimentally induced hypertension provide further evidence for the hypothesis that alterations in the nigrostriatal dopamine system may be involved in the initiation of the development of spontaneous hypertension.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1991

Role of brain dopamine systems in the development of hypertension in the spontaneously hypertensive rat.

We studied the role of central dopamine in the development of hypertension. Earlier work had shown that depletion of brain dopamine can inhibit the age-related rise in blood pressure in spontaneously hypertensive rats (SHR). In an open-field test, locomotor activity of Wistar-Kyoto controls was inhibited by haloperidol, apomorphine and sulpiride, but these drugs had less effect in SHR. The stimulation-evoked release of [3H]-dopamine from slices of the striatum of SHR was smaller than that from slices of WKY. The inhibition of the stimulation-evoked release of [3H]-dopamine by quinpirole was greater in SHR than in WKY. The results from the lesion experiments and from the behavioural activity studies would suggest an enhanced release of central dopamine in SHR, which might contribute to the development of hypertension in these animals. However, the in vitro release experiments (and subsequent in vivo microdialysis experiments) do not support such an enhanced release but rather showed decreased release of striatal dopamine in SHR.

Animals↗

PubMed1990

Electrically stimulated [3H]dopamine and [14C]acetylcholine release from nucleus caudatus slices: differences between spontaneously hypertensive rats and Wistar-Kyoto rats.

Using an in vitro superfusion method it was found that nucleus caudatus slices of 8- and 12-week-old spontaneously hypertensive rats (SHR) release significantly less [3H]dopamine and [14C]acetylcholine upon electrical stimulation than do slices of normotensive Wistar-Kyoto rats (WKY) at all frequencies tested. At 4 weeks similar trends were seen, but the difference in [14C]acetylcholine release was not significant. That the difference in release of dopamine was already present prior to the onset of the development of hypertension, i.e. at the age of 4 weeks, indicates that it is probably not a consequence of, but rather associated with the development of hypertension. Addition of the dopamine uptake inhibitor nomifensine to the superfusion medium caused an increase in the net release of [3H]dopamine by inhibiting re-uptake, but did not influence the difference in release between SHR and WKY. The release of labelled dopamine and acetylcholine was inhibited in the presence of the dopamine D2 receptor agonist quinpirole. The concentration-response curve for the inhibition of the release of [3H]dopamine, but not that of [14C]acetylcholine, by quinpirole was shifted to the left and the maximum inhibition was higher for SHR than for WKY. These results suggest that the difference in stimulus-evoked release of labelled dopamine in the nucleus caudatus is not the consequence of changes in the uptake mechanism of dopamine, but is associated with differences between SHR and WKY in dopamine D2 autoreceptor regulation.

Acetylcholine↗