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E Syvälahti

Publications and source records attributed to E Syvälahti.

At least 19 recordsLinked to original sources
PubMed1998

Deramciclane, a putative anxiolytic drug, is a serotonin 5-HT2C receptor inverse agonist but fails to induce 5-HT2C receptor down-regulation.

Deramciclane (EGIS-3886) is a novel anxiolytic agent that binds with high affinity to 5-HT2A/2C receptors. The interactions of deramciclane with the serotonin 5-HT2C receptor were characterized further using receptor phosphoinositide hydrolysis assays and receptor autoradiography. Deramciclane antagonized 5-HT2C receptor mediated 5-HT-stimulated phosphoinositide hydrolysis with an IC50 value of 168 nM. Deramciclane also decreased basal phosphoinositide hydrolysis by up to 33% (EC50 = 93 nM) in a physiological system in the choroid plexus, suggesting that deramciclane possesses inverse agonist properties at this receptor. Administration of single doses of 0.5 mg/kg and 10 mg/kg resulted in a maximal 5-HT2C receptor occupancy of up to 45% and 79%, respectively, in the choroid plexus. Chronic (14 days) treatment with 0.5 mg/kg or 10 mg/kg deramciclane did not alter [125I]DOI (agonist) or [3H]mesulergine (antagonist) binding to 5-HT2C receptors in the choroid plexus compared to saline-treated controls, as determined by quantitative receptor autoradiography. In comparison, the effects of deramciclane on 5-HT2A binding characteristics and receptor occupancy were also studied. Deramciclane treatment resulted in 5-HT2A receptor occupancy of up to 78%, but no significant effect of chronic treatment on 5-HT2A receptor agonist binding levels was found. In conclusion, these data indicate that deramciclane is a 5-HT2C receptor inverse agonist and occupies 5-HT2C receptors during treatment, and that chronic treatment with deramciclane does not lead to 5-HT2C receptor down-regulation.

Animals↗
PubMed1998

Striatal presynaptic dopamine function in type 1 alcoholics measured with positron emission tomography.

Recent in vivo studies have shown low dopamine D2 receptor and dopamine transporter densities among late onset (type 1) alcoholics. We have now studied 6-[18F]-FDOPA (FDOPA) uptake in 10 type 1 alcoholics and eight matched controls to test the hypothesis that striatal presynaptic dopamine function is lower among alcoholics. Markedly low FDOPA uptake (Ki) was observed in the left caudate of two alcoholic patients, but the mean striatal uptake values of the patient group were higher than those of the control group. The greatest difference was observed in the mean FDOPA intake in the left putamen, which was 28% higher in the patient group (t = 3.00, P = 0.008, d.f. = 16, independent samples t-test), and in the right caudate (difference 36%, t = 2.87, P = 0.01). The elevated FDOPA uptake in putamen and caudate correlated with poor Wisconsin Card Sorting Test (WCST) performance (error %) among alcoholics (correlation coefficients from 0.49 to 0.56), which suggests that the magnitude of presynaptic dopamine function alteration correlates with the degree of disability to modify one's behavior. The results do not give support to the hypothesis of generally decreased striatal dopamine turnover in type 1 alcoholism, but on the contrary indicate an increased presynaptic dopamine function. This may represent a compensatory mechanism to low postsynaptic DA function. The low presynaptic DA function observed in the left caudate of two patients suggests that type 1 alcoholism may be a heterogeneous disorder.

Adult↗
PubMed1998

Sex differences in the striatal dopamine D2 receptor binding characteristics in vivo.

OBJECTIVE: The authors investigated whether striatal dopamine D2 receptor binding characteristics in vivo are similar in men and women and whether there are sex-related differences in the decline in D2 receptor density due to aging. METHOD: Striatal D2 receptor density (Bmax), affinity (Kd), and binding potential (Bmax/Kd) were measured with positron emission tomography and [11C]raclopride in 54 healthy subjects (33 men and 21 women). RESULTS: Women had generally lower D2 receptor affinity than men, and this difference was statistically significant in the left striatum. Bmax and Bmax/Kd tended to decline with age twice as fast in men as in women, but the difference did not reach statistical significance. CONCLUSIONS: These results confirm the age-related reduction of D2 receptor density and binding potential in both sexes in vivo. The lower D2 receptor affinity suggests an increased endogenous striatal dopamine concentration in women. This may have implications for the differential vulnerability of men and women to psychiatric disorders like schizophrenia and alcohol and substance dependence.

Adult↗
PubMed1997

Antagonist binding characteristics of the Ser311-->Cys variant of human dopamine D2 receptor in vivo and in vitro.

We report in vivo and in vitro antagonist binding characteristics of the naturally occurring Ser311-->Cys variant of the human D2 dopamine receptor. Striatal receptor binding characteristics in vivo were measured with positron emission tomography and the D2 antagonist [11C]raclopride. The in vitro affinity of raclopride for the Ser311-->Cys variant and the wild type receptor was studied in membrane binding assays from stably transfected cell lines. One healthy male carrying the heterozygous Ser311-->Cys (TCC-->TGC) substitution was identified with denaturing gradient gel electrophoresis and DNA sequencing. The striatal D2 receptor binding characteristics in vivo in this subject were normal. This was supported by the in vitro data as the Ki values of raclopride for the Ser311-->Cys variant and the wild type receptor were identical. Our data suggest that the Ser311-->Cys variant of the human D2 receptor does not influence antagonist-receptor recognition in vivo or in vitro.

Adult↗
PubMed1997

Effect of smoking on neuroleptics in schizophrenia.

OBJECTIVE: The effect of smoking on daily doses and plasma levels of neuroleptics prescribed for schizophrenic patients was studied. METHODS: 90 outpatients with schizophrenic disorder (DSM-III-R) who were on a stable regimen of psychotropic medication and showed a stable clinical state were included in a double-blind placebo-controlled trial. Data were collected and blood tests taken at the baseline interview. The plasma levels were obtained for 52 patients. RESULTS: Daily neuroleptic doses converted to chlorpromazine equivalents correlated significantly (r = 0.436) with the plasma levels of their unmetabolised fractions. The neuroleptic doses increased with age in smokers, while in nonsmokers they decreased. Neither sex, age nor smoking had a significant association with the neuroleptic plasma levels. CONCLUSIONS: Smoking seems to lead to increased neuroleptic dosages in postmenopausal schizophrenics by increasing hepatic metabolism and renal excretion of the drugs and possibly enhancing dopamine release. It is also possible that older smoking patients form a selected group of heavy smoker and they, therefore, need exceptionally high neuroleptic doses.

Adult↗
PubMed1997

Effects of lorazepam administration on striatal dopamine D2 receptor binding characteristics in man--a positron emission tomography study.

Lorazepam is a widely used benzodiazepine class anxiolytic drug. It is known to enhance GABAergic neurotransmission in the brain, but the actions of benzodiazepines on other neurotransmitter systems are largely unknown. We studied the effects of 1 week's administration with lorazepam (2 mg daily, PO) or placebo on striatal D2 dopamine receptors in four healthy male volunteers using a double-blind randomized cross-over design. D2 receptor density and affinity as well as binding potential (Bmax/Kd) were measured with [11C]-raclopride and positron emission tomography. Although the individual responses varied, lorazepam did not significantly affect D2 receptor binding characteristics, nor did the average effect sizes exceed test-retest variability of the method. In conclusion, the results suggest that striatal D2 dopamine receptor characteristics are not affected by the clinically relevant lorazepam treatment regimen used.

Adult↗
PubMed1997

Citalopram as an adjuvant in schizophrenia: further evidence for a serotonergic dimension in schizophrenia.

There is increasing evidence suggesting that symptoms of depression and anxiety may also be associated with serotonergic dysfunction in schizophrenic patients. The effect of the adjuvant selective serotonin reuptake inhibitor citalopram was assessed regarding the symptom dimensions of schizophrenia measured with the Positive and Negative Syndrome Scale (PANSS) and with the Hamilton Rating Scale for Depression (HRSD). Citalopram alleviated symptoms of the depression/anxiety dimension of the PANSS, but not the symptoms of the four other PANSS domains or depressive symptoms measured with the HRSD. The results support the hypothesis of a serotonergic dimension in schizophrenia.

Adult↗
PubMed1997

Allelic association between D2 but not D1 dopamine receptor gene and alcoholism in Finland.

We studied the relationship of D2 and D1 receptor gene polymorphisms and alcoholism in male Finnish alcoholics and assessed male controls. Seventy alcoholics entering a detoxification programme and 50 control individuals were recruited. Forty-three per cent of the alcoholic patients, but only 22% of controls, had the D2 receptor gene TaqI A restriction fragment length polymorphism A1 allele. The frequency of the A1 allele was significantly higher in alcoholics (p = 0.039). In comparison, no association between alcoholism and the D1 receptor gene EcoRI restriction fragment length polymorphism alleles was found. A logistic regression analysis of the alcoholic population failed to support the idea that the presence of the A1 allele would be linked to estimates of alcohol dependence severity rated with the Severity of Alcohol Dependence Questionnaire or the Michigan Alcoholism Screening Test. In conclusion, allelic association between the D2 but not D1 receptor gene and alcoholism in a genetically relatively homogenous population of male Finns was found. The results are in agreement with the view that the D2 receptor locus is involved in genetic susceptibility to alcoholism but does not give support to a special association of severe alcohol dependence and the A1 allele of the D2 receptor gene.

Alcoholism↗
PubMed1996

Effects of clozapine metabolites and chronic clozapine treatment on rat brain GABAA receptors.

Similarly to clozapine, a clozapine metabolite, N-desmethylclozapine, but not clozapine N-oxide, antagonized brain gamma-aminobutyric acid type A (GABAA) receptors at high micromolar concentrations. However, daily subcutaneous injections of clozapine (10 and 25 mg/kg) and haloperidol (0.5 mg/kg) for 14 days failed to alter the modulation by GABA of rat cerebrocortical and cerebellar benzodiazepine ([3H]flunitrazepam) or convulsant (t-[35S]bicyclophosphorothionate) binding sites of the GABAA receptor. The results thus suggest that the GABAA receptor antagonism exerted by chronic in vivo clozapine treatment is weak as compared to this treatment's actions on certain monoamine receptors and is unlikely to be involved in the therapeutic actions of clozapine.

Animals↗
PubMed1996

Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2c receptor.

Interactions of the selective serotonin reuptake inhibitors (SSRIs) citalopram, fluoxetine and its main metabolite norfluoxetine, and the tricyclic antidepressant (TCA) imipramine with the rat serotonin 5-HT2C receptor in a clonal cell line and in the rat choroid plexus were investigated by radioligand binding and phosphoinositide (PI) hydrolysis assays. For comparison, the affinities of a variety of other antidepressants of different chemical classes for the cloned rat 5-HT2C and 5-HT2A receptors were also determined by radioligand binding assays. Fluoxetine displayed relatively high affinity for the 5-HT2C receptor in the choroid plexus, with a Ki value for inhibition of [3H]mesulergine binding of 55.4 nM. The Ki values for imipramine, norfluoxetine and citalopram were 136 nM, 203 nM, and 298 nM, respectively. Similar rank order of potency was detected in PI hydrolysis assays, which showed that these drugs are antagonists at the 5-HT2C receptor without exhibiting inverse agonist activity. [3H]Ketanserin (5-HT2A) binding assays revealed that the SSRIs fluoxetine, norfluoxetine and citalopram show 10- to 23-fold selectivity for the 5-HT2C receptor in vitro, whereas the TCA imipramine does not. Many other TCAs also had high to intermediate affinity for both 5-HT2A and 5-HT2C receptors. The present data provide evidence that fluoxetine, norfluoxetine and citalopram, along with many other antidepressant compounds, interact directly with the 5-HT2C receptor.

Animals↗
PubMed1996

Serotonergic modulation of striatal D2 dopamine receptor binding in humans measured with positron emission tomography.

The modulating effect of serotonergic drugs on the striatal dopamine neurotransmission has remained controversial, and there are no published data on serotonin-dopamine interaction obtained from living human brain. Citalopram is a selective serotonin reuptake inhibitor widely used in the treatment of depression (20-40 mg/day). We measured the effects of acute (20 mg, per os) and chronic (20 mg/day for 14 days) doses of citalopram and placebo intake on [11C]-raclopride binding to striatal D2-receptors in eight healthy volunteers by using positron emission tomography. Although the effect magnitude was not large, the results indicate that chronic citalopram intake slightly decreases the raclopride binding which may reflect increased dopamine release in the striatum. In addition, after 14 days there was a high correlation between the citalopam plasma levels and the decrease in the [11C]-raclopride binding in both the caudate and the putamen, although statistically significant effect in the raclopride binding potential was more pronounced in the putamen. This report suggests functional interaction of brain dopaminergic and serotonergic systems in vivo in man.

Adult↗
PubMed1996

Chronic citalopram and fluoxetine treatments upregulate 5-HT2c receptors in the rat choroid plexus.

The effects of chronic (for 14 days) citalopram and fluoxetine treatments with three doses (2.5, 10, and 20 mg/kg) and withdrawal times (24 hours, 68 hours, and 14 days) on 5-HT2C (formerly 5-HT1C) receptors in the rat brain choroid plexus were studied with quantitative receptor autoradiography in two separate experiments. Chronic citalopram treatment caused a consistent and dose-related increase in the density of 5-HT2C receptors (up to 90%). This effect was slightly more pronounced when measured with an antagonist ligand ([3H]mesulergine) than with an agonist ligand [(+/-)-1-(2,5-dimethoxy-4-[125I]iodophenyl)-2-aminopropane ([125I]DOI)]. The upregulation was most evident 24 hours after the last dose and disappeared thereafter rather rapidly. Chronic fluoxetine treatment also increased the density of 5-HT2C receptors 24 hours from the last dose, but the increase was accompanied by a reduced affinity and was less marked than that observed with citalopram. The changes in receptor characteristics were not observed consistently after the 68-hour withdrawal from fluoxetine. Furthermore, the upregulation of fluoxetine appeared not to be dose related or reflected by an increase in agonist binding. In conclusion, the results show that chronic citalopram and fluoxetine treatments induce an increase of choroid plexus 5-HT2C receptor density, but the effect is more marked with citalopram. These differences in the regulation of the 5-HT2C receptors may lead to pharmacodynamic differences between chronic citalopram and fluoxetine treatments.

Amphetamines↗
PubMed1996

Citalopram as an adjuvant in chronic schizophrenia: a double-blind placebo-controlled study.

The effects of citalopram--the most selective serotonin reuptake inhibitor on the market--on psychopathological symptoms were studied in chronic schizophrenic patients on a stable regimen of neuroleptic medication. Outpatients suffering from schizophrenic disorder (DSM-III-R) with Positive and Negative Symptom Scale (PANSS) scores higher than 50 were included in a double-blind placebo-controlled add-on study. The daily dose of citalopram was 20 mg in the first week and 40 mg for the remaining period. A total of 90 patients (45 patients receiving citalopram and 45 receiving placebo) completed the 12-week trial. There were no changes in neuroleptic plasma levels during the trial. There was a significant decrease in total PANNS scores during the trial, although no statistically significant differences between the citalopram group and the placebo group were revealed. The number of responders in terms of severity of illness (CGI) was higher and the increase in subjective well-being (VAS) was greater in patients on citalopram than in those receiving placebo. There were no significant differences in the occurrence of side-effects. It is concluded that, in chronic schizophrenic out-patients, citalopram has no clear effect on the psychopathological symptoms; it may improve the general clinical condition, and it appears to increase the subjective well-being of these patients. Citalopram appears to be safe when used to treat schizophrenic patients who are receiving concomitant neuroleptic treatment.

Adolescent↗
PubMed1996

Dopamine in schizophrenia.

The DA hypothesis of schizophrenia is one of the oldest biological hypotheses of schizophrenia with many revised versions. However, it is unlikely that any single neurotransmitter hypothesis is able to explain the biological basis of such a highly heterogenous disorder as schizophrenia in a satisfactory way. Rather, it is evident that the biological vulnerability factors and the 'acute neurophysiology' of schizophrenic symptoms involve a complex set of imbalances of aberrant connections in neuronal circuits in the brain. Dopamine is likely to be one of the transmitter substances involved, as evidenced by recent neuroimaging studies in neuroleptic-naive schizophrenia. Regardless of whether the DA hypothesis of schizophrenia is true or not, the DA hypothesis of neuroleptic drug action still has a relatively solid basis. The DA D2 receptor blockade remains the best characterized clinically useful mechanism of drug action to alleviate psychotic symptoms. The ongoing and future work on the precise role of DA in schizophrenia should focus on first-episode/admission neuroleptic-naive schizophrenic patients. Such studies represent the best opportunity of finding out specific changes in the dopaminergic pathways and relating them in a meaningful way to various dimensions of psychopathology seen in schizophrenic patients.

Dopamine↗
PubMed1995

Presynaptic dopamine function in striatum of neuroleptic-naive schizophrenic patients.

Presynaptic dopamine function (6-[18F]-fluorodopa uptake) in the brains of seven neuroleptic-naive first-admission schizophrenic patients and eight healthy controls was studied with positron emission tomography. The fluorodopa influx constant (Ki) in putamen was higher in the patients than in controls (average mean: 0.0149 vs 0.0129, p = 0.034). The changes in caudate were smaller but significantly lateralised to the left caudate. There was one catatonic schizophrenic patient in our sample. This patient had lower striatal Ki than any control. Alterations in striatal presynaptic dopamine function may constitute a part of disrupted neural circuits that predispose to schizophrenic psychosis.

Adult↗
PubMed1995

Differential regulation of rat 5-HT2A and 5-HT2C receptors after chronic treatment with clozapine, chlorpromazine and three putative atypical antipsychotic drugs.

Interactions with 5-HT2A and 5-HT2C receptors may be important for the actions of atypical antipsychotic drugs, such as clozapine (CLOZ). In this study we characterized the interaction of chlorpromazine (CPZ) and three putative atypical antipsychotic drugs, risperidone (RIS), amperozide (AMP), and ORG 5222 (ORG) with the 5-HT2A and the 5-HT2C receptor. CLOZ was used as a reference agent. These agents had 5-HT2C receptor-binding affinities (Ki values) in the following rank order: ORG (0.9 nM) > CLOZ (13.2 nM) > or = CPZ (27.1 nM) > RIS (112 nM) > > AMP (2580 nM). RIS (1.9 nM) and AMP (75.6 nM) had clearly higher affinities for the 5-HT2A than the 5-HT2C receptor; otherwise the 5-HT2A and 5-HT2C receptor affinities were approximately the same. Phosphoinositide hydrolysis studies in the rat choroid plexus revealed that all these agents were 5-HT2C receptor antagonists, with an approximately similar rank order of potency compared to the 5-HT2C receptor-binding data. Quantitative receptor autoradiography was used to study the regulation of 5-HT2A and 5-HT2C receptors after chronic treatment (14 days, SC injections once a day) with CLOZ (25 mg/kg), CPZ (15 mg/kg), RIS (0.3 mg/kg), AMP (5 mg/kg), and ORG (0.1 mg/kg). In the doses used, CLOZ, CPZ, and ORG decreased the frontal cortical 5-HT2A receptor binding of [3H]ketanserin and [125I]DOI by 40% to 60%. AMP also significantly decreased 5-HT2A receptor [3H]ketanserin binding by 30%, whereas RIS did not affect 5-HT2A receptor binding. In contrast to 5-HT2A receptors, only CLOZ significantly (by about 50%) decreased 5-HT2C receptor [3H]mesulergine and [125I]DOI binding in the choroid plexus. For comparison, CPZ was the only drug to significantly upregulate striatal D2 receptor-binding sites, whereas none of the drugs affected striatal D1 receptors. The main finding in this study is that 5-HT2A and 5-HT2C receptors are differentially regulated after chronic treatment with CLOZ, CPZ, RIS, AMP, and ORG.

Animals↗
PubMed1995

Maximum recommended doses of lignocaine are not toxic.

The maximum recommended doses of lignocaine are frequently exceeded in clinical practice as some blocks may need more lignocaine to produce adequate anaesthesia. We have examined the success rate of brachial plexus block, possible toxic symptoms after a dose of lignocaine 900 mg with adrenaline, and the maximum plasma concentration of lignocaine produced in 17 adult patients. In all patients, the block was excellent and no toxic symptoms were encountered. The highest mean lignocaine plasma concentration was 2.9 micrograms ml-1 45 min after the block. We conclude that in brachial plexus block, the dose of lignocaine with adrenaline can be as high as 900 mg without fear of toxic symptoms.

Adolescent↗