Biomedical subjects

J Hietala

Publications and source records attributed to J Hietala.

At least 91 records · Page 5Linked to original sources

PubMed1993

Decrease in human striatal dopamine D2 receptor density with age: a PET study with [11C]raclopride.

The effect of age on human striatal dopamine D2 receptors was investigated with positron emission tomography (PET) using [11C]raclopride as a radioligand. Twenty-one healthy volunteers aged from 20 to 81 years were studied. An equilibrium method was applied and two separate PET scans with different specific activities of [11C]raclopride were performed. The maximal number of receptors (Bmax) and their dissociation constant (Kd) were calculated using Scatchard analysis. There was an age-dependent decline in the Bmax (r = -0.49; p = 0.02) of striatal D2 receptors while the Kd remained unchanged. The results show that there is an age-related loss of striatal D2 receptors, which, together with other changes in the brain nigrostriatal dopaminergic system, may contribute to extrapyramidal symptoms associated with aging.

Adult↗

PubMed1993

Chronic clozapine treatment decreases 5-hydroxytryptamine1C receptor density in the rat choroid plexus: comparison with haloperidol.

We studied the effects of chronic treatment (14 days) with clozapine (10 and 25 mg/kg/day s.c.) and haloperidol (0.5 mg/kg/day s.c.) on 5-hydroxytryptamine (5-HT)1C receptor characteristics in the rat choroid plexus. In addition, we measured the effects of these treatments on dopamine D2 receptor characteristics in the rat striatum and determined the brain clozapine concentrations. Finally, the functional role of clozapine at the 5-HT1C receptors was evaluated by using phosphoinositide hydrolysis assay. Chronic administration of clozapine decreased, in a dose-related manner, 5-HT1C receptor density in the choroid plexus (by 49 and 70% with 10- and 25-mg/kg/day dose regimens of clozapine, respectively). The affinity of 5-HT1C receptors was not significantly affected, although there was a tendency toward a higher 5-HT1C receptor KD value in the group of rats treated with the 25-mg/kg/day dose regimen of clozapine. However, no detectable levels of residual clozapine were found in the cortices of rats treated with either clozapine dose regimen. Clozapine did not affect striatal D2 receptor characteristics. In turn, haloperidol, in a dose of 0.5 mg/kg/day that caused dopamine D2 receptor upregulation in the striatum, had no effects on 5-HT1C receptor characteristics in the choroid plexus. Phosphoinositide hydrolysis assays showed that clozapine is a 5-HT1C receptor antagonist. In conclusion, an atypical antipsychotic, clozapine, induced a marked downregulation of 5-HT1C receptors after chronic treatment, whereas a classical antipsychotic, haloperidol, did not. Therefore, we suggest that the decrease in the 5-HT1C receptor density after chronic clozapine treatment may contribute to some of its atypical properties.

Animals↗

PubMed1992

Regulation of dopamine D1 receptors by chronic administration of structurally different D1 receptor antagonists: a quantitative autoradiographic study.

The effects of chronic treatment (18 days) with the novel D1 antagonists, the benzonaphthazepine SCH 39166 (2 mg/kg per day) and the tetrahydroisoquinoline A-69024 (10 mg/kg per day), on D1 and D2 receptor binding in the rat brain were studied by quantitative receptor autoradiography. The benzazepine derivatives, SCH 23390 (0.5 mg/kg per day) and SKF 38393 (20 mg/kg per day), the prototype D1 antagonist and agonist, respectively, were also included in the experiment. Chronic treatment with SCH 23390 increased D1 receptor binding, studied with [3H]SCH 23390, in the nucleus accumbens and in all subregions of the anterior caudatus-putamen. However, chronic treatment with SKF 38393 did not alter D1 receptor binding in the brain areas studied. Interestingly, chronic treatment with SCH 39166 increased D1 receptor binding in the anterior caudatus-putamen but not in the nucleus accumbens. In contrast, chronic treatment with A-69024 did not alter D1 receptor binding in the brain areas studied. Treatment with SCH 23390, SCH 39166, A-69024 or SKF 38393 failed to alter D1 receptor binding in the posterior caudatus-putamen and the tuberculum olfactorium. Neither the D1 antagonists nor the D1 agonist investigated altered D2 receptor binding, studied with [125I]sulpiride, in the caudatus-putamen and nucleus accumbens. In summary, the benzonaphthazepine D1 antagonist, SCH 39166, as well as the benzazepine D1 antagonist, SCH 23390, can increase D1 receptor binding without influencing D2 receptor binding. However, a tetrahydroisoquinoline, A-69024, failed to increase D1 receptor binding, suggesting a differential regulation of D1 receptors after treatment with this putative D1 antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1992

Quantification of SCH 39166, a novel selective D1 dopamine receptor antagonist, in rat brain and blood.

A gas chromatographic method for measuring concentrations of a novel D1 antagonist SCH 39166 [(-)-trans-6,7,7a,8,9-13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5- H-benzo[d]naphto(2,1-6)azepine] in rat brain and plasma was developed. The method was applied to descriptive pharmacokinetics of two subcutaneous doses of SCH 39166 (0.25 mg/kg and 2.5 mg/kg). For comparison, concentrations of the "prototype" D1 antagonist SCH 23390 (0.25 mg/kg, SC) [R-(+)-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1-H-3-benzazepine] were also measured in plasma and brain. SCH 23390 (0.25 mg/kg, SC) had a very short elimination half-life of about 30 min in plasma, and disappeared in a slightly slower manner from striatum and cortex. SCH 39166 (0.25 and 2.5 mg/kg, SC), however, had a longer elimination half-life of about 1.5-2.5 h in plasma and brain. Interestingly, the 2.5 mg/kg dose of SCH 39166 produced only two-to five-fold increases in maximum concentrations in plasma and brain compared to the 0.25 mg/kg dose. The reason for this is not clear. The ability of these two doses of SCH 39166 to induce catalepsy in the bar test was also evaluated. It was found that SCH 39166 in these two doses, unlike SCH 23390, was not cataleptic. In conclusion, these pharmacokinetic features of SCH 39166 in the rat should be useful when designing experiments with this novel selective D1 antagonist. Furthermore, the longer elimination half-life of SCH 39166 makes it a more useful probe in pharmacodynamic comparisons of D1 receptor antagonists and classical as well as atypical neuroleptics.

Animals↗

PubMed1992

Chronic clozapine treatment down-regulates serotonin 5-HT-1c receptors in rat brain.

1. The effects of chronic treatment with the atypical antipsychotic, clozapine, and classical antipsychotic, haloperidol, on serotonergic 5-HT-1c and dopamine D2 receptors in rat brain were studied with radioligand binding methods. 2. Two weeks' treatment with clozapine did not alter striatal D2 receptor characteristics measured with 3H-spiperone, but caused a 54% down-regulation of 3H-mesulergine binding to 5-HT-1c receptors in choroid plexus. 3. In contrast, two weeks' treatment with a classical neuroleptic, haloperidol increased significantly D2 receptor number in striatum, but had no effect on 5-HT-1c receptor binding. 4. In conclusion, alterations of 5-HT-1c receptor characteristics after chronic clozapine treatment may represent a mechanism that contributes to the unique clinical profile of this antipsychotic drug.

Animals↗

PubMed1991

Effects of acute administration of SCH 23390 on dopamine and serotonin turnover in major dopaminergic areas and mesencephalic raphe nuclei--comparison with ritanserin.

1. The effects of acute administration of SCH 23390 (0.05 and 0.25 mg/kg s.c.), a dopamine D-1 receptor antagonist having also a moderate serotonin-S2 (5-HT-2) receptor blocking activity, and ritanserin (0.5 mg/kg), a specific 5-HT-2 antagonist, on dopamine (DA) and serotonin (5-HT) turnover were investigated in dopaminergic (nucleus caudatus, nucleus accumbens, substantia nigra, A10 area) and serotonergic (nucleus raphe dorsalis and nucleus raphe medialis) rat brain nuclei. 2. Acute SCH 23390 (both doses) increased the metabolism of DA and tended to augment the rate of DA synthesis (accumulation of DOPA after inhibition of aromatic acid decarboxylase) in the nucleus accumbens, but not in the nucleus caudatus. In addition, SCH 23390 had a moderate effect on DA metabolism in substantia nigra. SCH 23390 did not alter the turnover of 5-HT in any of the nuclei studied. 3. Acute administration of ritanserin did not modify 5-HT or DA turnover in any of the nuclei studied. 4. In conclusion, these results suggest that acute SCH 23390 administration preferentially activates the mesolimbic DA system. The lack of effect of ritanserin on DA or 5-HT turnover in nigrostriatal and mesolimbic DAergic areas suggests that under basal conditions the blockade of 5-HT2 receptors do not change monoamine metabolism in these areas. The role of 5-HT-2 blockade in the actions of SCH 23390 on DA turnover appears thus to be of a minor importance.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1991

Chronic D1-receptor blockade: effects on D2-receptor agonist-induced yawning in rats.

The effects of chronic treatment with the selective D1 dopamine receptor antagonist SCH 23390 (0.25 mg kg-1 s.c. twice daily for 18 days, 4 days withdrawal on yawning induced by the D2-receptor agonist quinpirole has been investigated. Low doses of quinpirole (20 and 50 micrograms kg-1 s.c.) induced dose-related yawning behaviour in rats. The yawning response to quinpirole was not significantly different in the presence or absence of SCH 23390 pretreatment. However, chronic treatment with SCH 23390 alone significantly suppressed yawning behaviour. The results suggest that chronic D1-receptor blockade with SCH 23390 does not alter the function of the D2-receptor population mediating yawning behaviour. However, after withdrawal it may result in behavioural activation as seen by suppression of yawning behaviour in the present study.

Animals↗

PubMed1990

Neurochemical effects of chronic co-administration of ritanserin and haloperidol: comparison with clozapine effects.

The effects of chronic treatment with clozapine (20 mg/kg per day), ritanserin (0.5 mg/kg per day), haloperidol (0.5 mg/kg per day), or the combination of haloperidol and ritanserin, on dopamine (DA) and serotonin (5-HT) metabolism were studied. Chronic haloperidol treatment decreased DA metabolism in nucleus caudatus. Chronic ritanserin treatment failed to alter striatal or mesolimbic DA metabolism but decreased the concentrations of 5-HT and 5-hydroxyindoleacetic acid in the nucleus raphe dorsalis. The effects of chronic haloperidol were not altered by concomitant ritanserin administration. In comparison, chronic clozapine treatment affected neither DA nor 5-HT metabolism. These results show that the biochemical effects of chronic haloperidol treatment on the major ascending DA neurons cannot be modulated by concomitant 5-HT2 receptor blockade.

Animals↗

PubMed1990

Effects of chronic SCH 23390 treatment on dopamine autoreceptor function in rat brain.

The effects of chronic treatment with SCH 23390 (0.5 mg/kg per day, 18 days), a selective (DA) D-1 receptor antagonist, on dopamine autoreceptor function in rats were investigated. The decrease of DA metabolism in mesolimbic and nigrostriatal systems and inhibition of spontaneous explorative locomotor activity by low doses of the selective D-2 receptor agonist, quinpirole, were used as behavioral and biochemical indices of DA autoreceptor function. The DA metabolism decreasing effect of quinpirole (20 and 50 micrograms/kg) in mesolimbic or nigrostriatal DA systems was similar in SCH 23390- and vehicle-treated rats. Two-way analysis of variance showed that rats treated chronically with SCH 23390 were significantly more active than vehicle-treated rats. However, there were no statistically significant differences in the quinpirole-induced hypomotility response between these groups. These results indicate that chronic D-1 blockade, unlike classical antipsychotic drugs, does not modulate the biochemical and behavioral indices of DA autoreceptor activation, suggesting a lack of interaction between DA autoreceptors and D-1 receptors in the central nervous system.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1990

Ethanol administration does not alter dopamine D1 and D2 receptor characteristics in rat brain.

The effects of 5 weeks' ethanol treatment on the number and affinity of cortical and striatal dopamine D1 receptors and striatal D2 receptors in rat brain were investigated. The ethanol and control diets were carried out using the pair-feeding technique. The number and affinity of dopamine D1 receptor sites in the frontal cortex and caudate-putamen or D2 receptors in the caudate-putamen were not significantly altered by the used ethanol dose regimen. This study demonstrates that if dietary factors related to ethanol consumption are carefully controlled no 'specific' ethanol-induced changes in striatal D1 and D2 or cortical D1 receptor characteristics can be observed after 5 weeks' ethanol consumption. Thus, changes in the central dopamine receptors are not likely to play any significant role in the effects of moderate ethanol consumption on neuronal function.

Animals↗

PubMed1990

Effects of chronic administration of ondansetron (GR38032F), a selective 5-HT3 receptor antagonist, on monoamine metabolism in mesolimbic and nigrostriatal dopaminergic neurons and on striatal D2-receptor binding.

The effects of chronic administration of the selective 5-HT3 receptor antagonist ondansetron (GR38032F) on dopamine (DA) and 5-hydroxytryptamine (5-HT) metabolism in the major ascending dopaminergic neurons and on striatal D2-receptor binding characteristics were investigated. The metabolism of 5-HT was also studied in a number of other brain areas. Chronic ondansetron (0.2 mg/kg/day and 1.0 mg/kg/day SC for 16 days) did not change DA or 5-HT metabolism in the nigrostriatal or mesolimbic dopaminergic areas, although the larger dose of ondansetron slightly and statistically significantly reduced basal concentrations of DA and 5-HT in the nucleus caudatus. D2-receptor binding characteristics were not affected in the caudate-putamen. Ondansetron did not change 5-HT metabolism in the nucleus raphé dorsalis, amygdala, hippocampus or in habenula. It is concluded that chronic administration of ondansetron does not change DA or 5-HT metabolism in the major ascending dopaminergic neurons. This suggest that unlike chronic D2-receptor blockade, chronic blockade of central 5-HT3 receptors does not result in a similar reduction in the activity of nigrostriatal and mesolimbic dopaminergic neurons.

Animals↗

PubMed1990

Dopamine D1 receptor antagonism in schizophrenia: is there reduced risk of extrapyramidal side-effects?

The first selective D1 dopamine receptor antagonist, SCH23390, has been reported to be active in preclinical tests that predict antipsychotic activity in schizophrenic patients. This is particularly exciting because it has been claimed that this compound is 'atypical', in that it has a reduced propensity to induce extrapyramidal side-effects. However, in considering the evidence from preclinical screening tests for antipsychotic activity and extrapyramidal side-effects of potential neuroleptic drugs, Jarmo Hietala and colleagues conclude that the majority of available data is not compatible with the postulated atypical profile of SCH23390.

Basal Ganglia Diseases↗

PubMed1990

5-HT3 receptor antagonist ondansetron does not alter effects of amphetamine on DA metabolism.

The present study was carried out to elucidate the effect of ondansetron, a selective 5-HT3 receptor antagonist, on amphetamine-induced changes in monoamine metabolism in major ascending dopamine (DA) neurons. Amphetamine (2 mg kg-1 s.c.) significantly decreased the concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in nucleus caudatus and nucleus accumbens. Pretreatment with ondansetron (0.1 mg kg-1 and 1 mg kg-1 s.c., 15 min before amphetamine) failed to modify the effects of amphetamine. It is concluded that acute blockade of central 5-HT3 receptors by ondansetron does not prevent amphetamine-induced changes in monoamine metabolism in nigrostriatal or mesolimbic dopaminergic areas.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1990

Chronic treatment with SCH 23390 and haloperidol: effects on dopaminergic and serotonergic mechanisms in rat brain.

Effects of chronic administration (18 days) with SCH 23390 (0.1 or 0.5 mg/kg/day s.c.) and haloperidol (1 mg/kg/day s.c.) on dopamine and serotonin synthesis and metabolism in discrete dopaminergic and serotonergic nuclei of rat brain were studied. Additionally, the effects of these treatments on dopamine D-1 and D-2 receptor characteristics in rat caudate-putamen were investigated. Chronic administration with both dose regimens of SCH 23390 decreased DA metabolism significantly (basal homovanillic acid concentrations) in nucleus caudatus. In another set of experiments dopamine synthesis (rate of accumulation of 3,4-dihydroxyphenylalanine after 3,4-dihydroxyphenylalanine-decarboxylase inhibition) was reduced significantly only in nucleus accumbens after the higher SCH 23390 dose regimen. In turn, chronic administration with haloperidol decreased basal dopamine metabolism and synthesis in nucleus caudatus and nucleus accumbens. Chronic haloperidol, but not SCH 23390, treatment induced a clear-cut increase in [3H]spiperone binding in caudate-putamen. Interestingly, neither SCH 23390 nor haloperidol treatments affected [3H]SCH 23390 binding in caudate-putamen. SCH 23390 and haloperidol had no significant effects on serotonin synthesis and metabolism in serotonergic and dopaminergic areas. In conclusion, the classical antipsychotic drug, haloperidol, clearly decreases dopamine turnover in nigrostriatal and mesolimbic dopaminergic systems. The D-1 antagonist, SCH 23390, also decreases dopaminergic activity in nigrostriatal and mesolimbic systems although DA synthesis and metabolism are affected to different degrees in nucleus caudatus and nucleus accumbens. Therefore, we suggest that if D-1 antagonists such as SCH 23390 show antipsychotic activity in clinical studies, they may not be free of extrapyramidal side-effects.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1989

Maturation of immunoglobulin G avidity after rubella vaccination studied by an enzyme linked immunosorbent assay (avidity-ELISA) and by haemolysis typing.

Two tests were introduced recently for assessment of the avidity of rubella immunoglobulin antibodies. In the quantitative test--avidity-enzyme linked immunosorbent assay (ELISA)--IgG antibodies obtained from individuals shortly after primary infection with rubella virus are distinguished from those with past immunity by their antigen-elution characteristics. This method uses agents that disrupt hydrophobic bonds in proteins [Kamoun PP (1988): Denaturation of globular proteins by urea: Breakdown of hydrophobic bonds? Trends in Biological Sciences 13:424-425.]. In the semiquantitative, presumptive test--haemolysis typing--the low-avidity rubella-IgG antibodies are distinguished from the high-avidity antibodies by the quality of their haemolytic zones in a radial haemolysis test. In the present study, both tests were applied to sera taken before and after vaccination with two different strains (Cendehill or RA 27/3) of live attenuated rubella virus. It was found that after vaccination of previously nonimmune subjects, IgG synthesized during the first 2 months had a very low avidity; IgG avidity increased dramatically during the subsequent 4 months and less markedly between 6 and 12 months after vaccination. On the contrary, the initially high IgG avidity of previous immune vaccinees remained at an elevated level postvaccination. These results provide a basis for identification of recent primary rubella virus infections, or vaccination reactions, by the avidity of specific IgG and also for their separation from rubella reinfections.

Adult↗

PubMed1989

Differential tolerance to cataleptic effects of SCH 23390 and haloperidol after repeated administration.

The development of tolerance to the cataleptic effect of the selective D-1 antagonist SCH 23390 (0.5 mg/kg/day SC or 0.1 mg/kg/day SC) and haloperidol (1 mg/kg/day SC) during repeated administration was investigated. Catalepsy in rats was measured using the horizontal bar method. SCH 23390 induced a dose-related cataleptic effect of short duration, whereas the cataleptic effect of haloperidol appeared more slowly and lasted longer. Marked tolerance to the cataleptic effect of haloperidol developed already 6 days from the beginning of the treatment. The cataleptic effect of the higher dose regimen of SCH 23390 was also significantly reduced after 6 days' treatment. However, unlike haloperidol, this subacute tolerance was gradually reversed and was no longer significant after 12 and 18 days. The cataleptic response to the lower dose of SCH 23390 (0.1 mg/kg/day) was not significantly altered during the treatment and no initial catalepsy tolerance was observed with this dose regimen. These results suggest that different mechanisms are involved in the expression of cataleptic behaviour during chronic treatment with SCH 23390 and classical antipsychotics, such as haloperidol.

Animals↗

PubMed1989

Dopamine D2 and muscarinic receptor binding characteristics in rat brain after withdrawal of subchronic fluphenazine and sulpiride treatment.

1. The effects of subchronic (10 days) treatment with two antischizophrenic drugs, fluphenazine and sulpiride, on rat brain dopamine and muscarinic receptor sites were studied at various time points after withdrawal from the drug treatments. Striatal D-2 dopamine receptors and cortical muscarinic receptors were characterized with the radioligands 3H-spiperone and 3H-quinuclidinyl benzilate (3H-QNB), respectively. 2. Neither drug treatment affected significantly the number or affinity of cortical muscarinic receptors during the withdrawal time of 18 days. 3. The number of D-2 receptors in striatum was not altered after 4 or 8 fluphenazine-free days, but after 18 days fluphenazine caused an increase of 55% in the density of D-2 receptors. Sulpiride caused a slight increase in Bmax of striatal D-2 receptors after 4 and 8 withdrawal days but the maximum increase of 29% was observed after 18 withdrawal days. 4. Fluphenazine treatment caused an increase in the apparent dissociation constant 4 days after the termination of the treatment suggesting that residual neuroleptic levels may have been retained after this dose regimen, since the Kd returned near control levels as the withdrawal time passed. Sulpiride, however, caused a moderate increase in Kd throughout the withdrawal time. 5. In conclusion, these results suggest that even a rather short treatment with fluphenazine or sulpiride, a classical and an atypical neuroleptic, respectively, can induce pronounced changes in striatal dopamine receptor characteristics after a drug washout period of almost three weeks. Thus, possible delayed actions of classical as well as novel neuroleptic drugs on neurotransmitter function should be considered in studies examining the neuroleptic withdrawal effects.

Animals↗

PubMed1989

Mixed bacterial and viral infections are common in children.

Acute phase and convalescent sera from 51 pediatric patients who had a documented viral infection and no obvious culture-confirmed bacterial infection such as meningitis, otitis media or urinary tract infection were tested by enzyme immunoassay for antibodies to Haemophilus influenzae and Branhamella catarrhalis and by the latex agglutination test for pneumococcal antigens to evaluate the frequency of mixed bacterial and viral infections. A mixed bacterial and viral infection was documented in 19 patients (37%). Seven patients (14%) showed a diagnostic rise in antibodies to H. influenzae and 8 patients (16%) showed an antibody elevation to B. catarrhalis in their paired sera; pneumococcal antigen was detected in acute phase serum from 4 patients (8%). The rate of mixed infections in patients having respiratory symptoms was 52%. High serum C-reactive protein values and white blood cell counts were found significantly more often in those with mixed infections than in those who had viral infections. The results indicate that mixed bacterial and viral infections occur more frequently in children than one could anticipate on the basis of the earlier reports. Mixed bacterial and viral etiology is highly probable in a child who has a defined viral infection with high C-reactive protein and white blood cell count values, especially in the presence of respiratory symptoms.

Adolescent↗