Biomedical subjects

E Syvälahti

Publications and source records attributed to E Syvälahti.

At least 19 recordsLinked to original sources

PubMed2003

Ethanol consumption and DRD2 gene TaqI a polymorphism among socially drinking males.

The dopaminergic system in the human brain is thought to play a major role in the development of alcohol consumption habits and alcoholism. It has been reported that homozygous D2-/- knock-out mice lacking D2 receptors consume about 50% to 60% less ethanol than wild-type D2+/+ mice, and heterozygous mice have an intermediate level of alcohol consumption. The DRD2 gene TaqI A polymorphism has been suggested to associate with a low D2 receptor density in post mortem and in vivo measurements. Numerous association studies on this polymorphism and alcoholism have shown most controversial results. We studied whether DRD2 TaqI A genotype affects alcohol consumption in an ethnically homogeneous, representative sample of 1,019 Finnish Caucasian males. After excluding the abstainers from the study, the self-reported alcohol consumption among the remaining 884 non-abstainers was compared in the TaqI A genotype groups (A1/A1, A1/A2, A2/A2). The alcohol consumption of the homozygous A1/A1 group was about 30% lower than in A1/A2 group, and 40% lower than in A2/A2 group (P = 0.042 and 0.041 in a sociodemographic variable-adjusted multivariate model). The results indicate an association between DRD2 genotype and alcohol consumption habits in humans. These results in the large sample of non-alcoholic males are also opposite to some previous findings on the higher A1 allele frequency among alcoholic populations.

Alcohol Drinking↗

PubMed2002

Structural magnetic resonance imaging in patients with first-episode schizophrenia, psychotic and severe non-psychotic depression and healthy controls. Results of the schizophrenia and affective psychoses (SAP) project.

BACKGROUND: Structural brain abnormalities are prevalent in patients with schizophrenia and affective disorders. AIMS: To study how regional brain volumes and their ratios differ between patients with schizophrenia, psychotic depression, severe non-psychotic depression and healthy controls. METHOD: Magnetic resonance imaging scans of the brain on first-episode patients and on healthy controls. RESULTS: Patients with schizophrenia had a smaller left frontal grey matter volume than the other three groups. Patients with psychotic depression had larger ventricular and posterior sulcal cerebrospinal fluid (CSF) volumes than controls. Patients with depression had larger white matter volumes than the other patients. CONCLUSIONS: Left frontal lobe, especially its grey matter volume, seems to be specifically reduced in first-episode schizophrenia. Enlarged cerebral ventricles and sulcal CSF volumes are prevalent in psychotic depression. Preserved or expanded white matter is typical of non-psychotic depression.

Adult↗

PubMed2001

Decreased striatal dopamine transporter binding in vivo in chronic schizophrenia.

We have previously reported that average striatal dopamine transporter (DAT) binding in vivo is unaltered in neuroleptic-naive first-episode schizophrenic patients [Laakso et al., Am. J. Psychiatry 157 (2000) 269]. However, as it has been suggested that some of the brain changes in schizophrenia may vary depending on the illness phase, we studied DAT density in eight stable, medicated chronic schizophrenic patients and eight matched controls using positron emission tomography and [18F]CFT, a marker of dopamine nerve terminals. [18F]CFT binding potentials were significantly lower in chronic schizophrenic patients than in controls, both in the caudate and the putamen (-9 to -16%). Together with the finding of unchanged average striatal DAT levels in first-episode patients and relative insensitivity of striatal [18F]CFT binding to endogenous dopamine and neuroleptic drugs, the result is in line with a relative loss of striatal dopaminergic nerve terminals and/or decreased expression of DAT in a subset of chronic schizophrenic patients.

Adult↗

PubMed2001

A morphometric MRI study of the hippocampus in first-episode, neuroleptic-naïve schizophrenia.

Magnetic resonance imaging (MRI) studies have frequently, although not unambiguously, reported hippocampal volume deficit in schizophrenia. Data on the hippocampal volumes in first-episode schizophrenia, however, are sparse. In addition, a recent topographic MRI study proposed a regionally specific volume loss in the hippocampus of chronic schizophrenics, but to date no reports have replicated this finding. In this study two-dimensional MRI-based topographic brain mapping was used to study the possibility of regional changes in the hippocampus of 22 controls and 18 patients with first-episode, neuroleptic-naïve schizophrenia. Compared to controls, there were no significant differences between hippocampal volumes, regional volumes, or length of the hippocampus in the patients with schizophrenia. These data are at odds with the previous reports on hippocampal volume loss in first-episode schizophrenia, and with the hypothesis of regionally specific hippocampal volume deficit in schizophrenia.

Adult↗

PubMed2001

The effects of amitriptyline, citalopram and reboxetine on autonomic nervous system. A randomised placebo-controlled study on healthy volunteers.

RATIONALE: In therapeutic use, amitriptyline, reboxetine and citalopram have all been associated with apparent anticholinergic-like side effects (dry mouth, constipation, etc.), despite the very low antimuscarinic activity of reboxetine and citalopram in vitro. OBJECTIVES: We hypothesised that the spectral analysis of heart rate variability (HRV) might detect differences between amitriptyline, citalopram and reboxetine in their anticholinergic activities following a single peroral administration. METHODS: In this double-blind, cross-over study, amitriptyline (75 mg), citalopram (20 mg), reboxetine (4 mg) and placebo were randomly given at 1-week intervals to eight healthy male volunteers. Drug and catecholamine concentrations in plasma were determined repeatedly. The drug effect was assessed with periodic recordings of electrocardiogram (ECG) and blood pressure, and with measurements of salivary secretion. The ECG recordings were subjected to spectral analysis of HRV, in which the high frequency (HF) power of R-R interval (RRI) variability was supposed to reflect cardiac parasympathetic tone. RESULTS: Reboxetine increased heart rate and blood pressure and reduced the HF power of RRI and 3,4-dihydroxyphenylglycol (DHPG) plasma concentrations. Amitriptyline diminished salivary secretion and had a prominent sedative action. Measurements after citalopram did not differ significantly from placebo. CONCLUSIONS: Reboxetine, despite its low antimuscarinic activity in vitro, had distinct effects on the HF power of RRI, consistent with anticholinergic activity in vivo. Amitriptyline had a measurable anticholinergic effect in the salivary glands, but, surprisingly, not in the heart. We suggest that the sedative effect of amitriptyline could alter cardiac sympathovagal balance and, therefore, counteract the anticholinergic drug effect.

Adolescent↗

PubMed2001

Sertindole is a serotonin 5-HT2c inverse agonist and decreases agonist but not antagonist binding to 5-HT2c receptors after chronic treatment.

RATIONALE: Sertindole is a novel antipsychotic drug with high affinity for dopamine D2, alpha-1-adrenoceptors and serotonin 5-HT2A and 5-HT2c receptors. The 5-HT2c receptor component of sertindole may be clinically relevant as this receptor subtype is implicated in regulation of anxiety, cognition/memory and brain plasticity. OBJECTIVE: To characterise the interaction of sertindole with the 5-HT2C receptor using rat choroid plexus as a physiological receptor source. RESULTS: Sertindole had nanomolar affinity for the 5-HT2c receptor in vitro. Sertindole antagonised 5-HT-stimulated phosphoinositide (PI) hydrolysis and, like clozapine, also inhibited basal PI hydrolysis suggesting that sertindole is a 5-HT2C receptor inverse agonist. The effect of repeated sertindole dosing on 5-HT2C receptors was studied in rats treated for 21 days with sertindole (20, 300 and 1250 microg/kg/day). Clozapine (25 mg/kg/day) was used as a comparison drug. 5-HT2C receptor binding in the choroid plexus was measured with antagonist and agonist ligands ([3H]mesulergine and [125I]DOI) using quantitative autoradiography 8 days after withdrawal. Clozapine decreased 5-HT2C receptor antagonist and agonist binding sites equally by 36% and 32%, respectively. Sertindole did not induce significant changes in the total number of 5-HT2C receptors, but the highest dose of sertindole lowered the affinity of [3H]mesulergine for 5-HT2C receptors. This was most likely due to residual sertindole levels in the brain which was supported by direct concentration measurements. In contrast, sertindole induced a highly significant and dose-related decrease in 5-HT2C agonist binding (up to 77%). Neither drug affected striatal D2 receptor binding. CONCLUSIONS: Sertindole, like clozapine, was found to be a serotonin 5-HT2C receptor inverse agonist. The preferential downregulation of 5-HT2C receptor agonist (G-protein-coupled) sites by chronic administration seemed to differentiate sertindole from clozapine at these dose regimens. The 5-HT2c receptor downregulation during repeated dosing may contribute to therapeutic efficacy and/or side effects of sertindole treatment.

Animals↗

PubMed2000

Lack of association between the functional variant of the catechol-o-methyltransferase (COMT) gene and early-onset alcoholism associated with severe antisocial behavior.

Addictive drugs, including ethanol, increase the brain's dopaminergic transmission, and catechol-o-methyltransferase (COMT) enzyme has a crucial role in dopamine inactivation. A common functional polymorphism in the COMT gene results in a three- to four-fold variation in enzyme activity. In a previous study, we found an association between type 1 (with late-onset but without prominent antisocial behavior) alcoholism and the low activity allele of the COMT gene. In this work we analyzed whether the COMT polymorphism has any effect on the development of type 2 (with early-onset and habitual impulsive violent behavior) alcoholism. The COMT genotype was determined in 62 impulsive violent recidivist offenders with early-onset (type 2) alcoholism, 123 late-onset nonviolent (type 1) alcoholics, and 267 race and gender-matched controls. The allele and genotype frequencies of these groups were compared with each other and also with previously published data from 3,140 Finnish blood donors. The type 2 alcoholics did not differ from either the blood donors or the controls. The low activity (L) allele frequency was higher among type 1 alcoholics (chi(2) = 4.98, P = 0.026) when compared with type 2 cases. The odds ratio for type 1 alcoholism as compared with type 2 alcoholism for those subjects with the LL genotype versus the HH genotype was 3.0 (95% confidence interval 1.1-8.4, P = 0.017). The results suggest that COMT genotype has no major role in the development of early-onset alcoholism with severe antisocial behavior.

Adult↗

PubMed2000

Measurement of extrastriatal D2-like receptor binding with [11C]FLB 457--a test-retest analysis.

[11C]FLB 457 is a radioligand for positron emission tomography (PET) that possesses high affinity to D2/D3 receptors. It has been suggested to be useful for quantification of low-density dopamine D2 receptor populations, e.g. in cortical and limbic brain areas. We explored the reproducibility of five methods for measuring extrastriatal D2-like receptor binding potential with [11C]FLB 457. Seven healthy male volunteers were examined twice with [11C]FLB 457 (high specific radioactivity) on the same day, at least 3 h apart. Four brain areas, frontal cortex, nucleus thalamus, temporal cortex and cerebellar cortex, were examined. Binding potentials (BPs) were derived from (1) a target to cerebellum distribution volume ratio, (2/3) two reversible reference tissue compartment models and (4) a transient equilibrium approach. For comparison, BP values were also calculated with the standard three-compartment kinetic model that does not assume a receptor-free reference region. The use of the standard three-compartment model did not result in reproducible BP estimates. The distribution volume (DV) ratio, reference tissue compartment models and the transient equilibrium method all had good to excellent intraclass correlation coefficients (ICCs) in the studied brain areas ranging from 0.56 to 0.93. Absolute variability was also relatively low, ranging from 5.3% to 10.4%. There were no marked differences in the ICC or absolute and relative variability between the four methods based on a reference tissue (cerebellum). In addition, we did not observe systematic differences in the BP between the first and the second scan. These data indicate that the reproducibility of the DV ratio, reference tissue models and the transient equilibrium method is good or excellent. However, each of these methods includes assumptions affecting their validity. Thus, the choice of method will be critically dependent on the purpose of the study.

Adult↗

PubMed2000

Two-year outcome in first-episode psychosis treated according to an integrated model. Is immediate neuroleptisation always needed?

In this multicentre study the two-year outcome of two groups of consecutive patients (total N = 106) with first-episode functional non-affective psychosis, both treated according to the 'need-specific Finnish model', which stresses teamwork, patient and family participation and basic psychotherapeutic attitudes, was compared. No alternative treatment facilities were available in the study sites. The two study groups differed in the use of neuroleptics: three of the sites (the experimental group) used a minimal neuroleptic regime whilst the other three (the control group) used neuroleptics according to the usual practice. Total time spent in hospital, occurrence of psychotic symptoms during the last follow-up year, employment, GAS score and the Grip on Life assessment were used as outcome measures. In the experimental group 42.9% of the patients did not receive neuroleptics at all during the whole two-year period, while the corresponding proportion in the control group was 5.9%. The overall outcome of the whole group could be seen as rather favourable. The main result was that the outcome of the experimental group was equal or even somewhat better than that of the control group, also after controlling for age, gender and diagnosis. This indicates that an integrated approach, stressing intensive psychosocial measures, is recommended in the treatment of acute first-episode psychosis.

Adolescent↗

PubMed2000

Striatal dopamine transporter binding in neuroleptic-naive patients with schizophrenia studied with positron emission tomography.

OBJECTIVE: Recent in vivo imaging studies indicate a dysregulated presynaptic function of the striatal dopaminergic system in patients with schizophrenia. To further explore the basis of this phenomenon, the authors studied brain dopamine transporter binding in vivo in patients with first-episode, never-medicated schizophrenia. METHOD: Nine patients with schizophrenia and nine healthy matched comparison subjects were recruited. Striatal dopamine transporter binding was measured with positron emission tomography and a specific dopamine transporter ligand, [(18)F]CFT, a radiolabeled form of 2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane. RESULTS: Average caudate and putamen dopamine transporter binding potentials were almost identical in the patients and comparison subjects, but the patients lacked the right-left asymmetry of the caudate dopamine transporter binding seen in the comparison group. CONCLUSIONS: Average striatal dopamine transporter density is unaltered in neuroleptic-naive patients with schizophrenia. However, patients lack asymmetry in caudate dopamine transporter binding, which conforms with disrupted brain lateralization in this disorder.

Adult↗

PubMed2000

High levels of dopamine activity in the basal ganglia of cigarette smokers.

OBJECTIVE: The authors' goal was to study presynaptic dopamine activity in smoking and nonsmoking human subjects in vivo. METHOD: [(18)F]Fluorodopa ([(18)F]DOPA) uptake K(i) values in the basal ganglia of nine smoking and 10 nonsmoking healthy men were measured with positron emission tomography. RESULTS: Significantly higher [(18)F]DOPA uptake was observed in both the putamen (average 17.3% higher) and the caudate (average 30.4% higher) of smokers than in those of nonsmokers. CONCLUSIONS: Smoking is related to greater dopamine activity in the human basal ganglia. Nicotine-induced dopamine activity may be a relevant mechanism in dependence on cigarette smoking.

Adult↗

PubMed1999

Depressive symptoms and presynaptic dopamine function in neuroleptic-naive schizophrenia.

We have previously reported aberrations in the striatal presynaptic dopamine function in neuroleptic-naive schizophrenic patients compared to healthy controls (Hietala, J., Syvälahti, E., Vuorio, K. et al., 1995. Lancet 346, 1130-1131). In this extended study we explore whether the altered presynaptic dopamine function correlates with the clinical symptomatology in schizophrenia. Striatal dopamine synthesis capacity (6-[18F]fluorodopa (FDOPA) uptake, Ki values) was studied with positron emission tomography in 10 neuroleptic-naive schizophrenic patients and 13 healthy controls. The clinical symptomatology was characterized with the Positive and Negative Symptom Scale (PANSS). The patients had an increased FDOPA uptake in striatum and lacked the asymmetry in caudate FDOPA uptake (p = 0.0005), confirming our earlier results. Left striatal FDOPA uptake (Ki) values correlated negatively with depressive symptoms in a highly significant manner. On the other hand, paranoid symptomatology correlated positively with right putamen FDOPA uptake at a trend level (rho = 0.73, p < 0.02). The lack of asymmetry in caudate Ki values did not associate with any dimension of psychopathology. The major finding in this study is that depressive symptoms in neuroleptic-naive first-admission schizophrenia are associated with low presynaptic dopamine function. This link appears to be hemisphere-related and may have drug-treatment implications, e.g., in prediction of response to D2 receptor blocking antipsychotic drugs. A possible connection between paranoid symptomatology and subcortical hyperdopaminergia is suggested, but this remains to be further verified.

Adolescent↗

PubMed1999

Brain 5-HT2A receptor occupancy of deramciclane in humans after a single oral administration--a positron emission tomography study.

RATIONALE: Deramciclane fumarate is a new 5-HT2A and 5-HT2C receptor antagonist with putative anxiolytic effects. In the present study the binding of deramciclane to serotonin 5-HT2A receptors in frontal cortex of healthy male volunteers was studied using [11C]-N-methyl spiperone ([11C]-NMSP) and positron emission tomography. METHODS: The receptor occupancy percentage was assessed by the means of inhibition of [11C]-NMSP from the 5-HT2A receptors in the frontal cortex. Single oral doses of 20, 50 and 150 mg deramciclane were given to three subjects at each dose level (total n = 9). The receptor occupancy was measured before deramciclane and at 3 and 6 h post-dosing except at the 20 mg dose level where only the 3-h measurement was done. The occupancy percentage was calculated with the ratio method using cerebellum as a reference area. RESULTS: Deramciclane inhibited [11C]-NMSP binding dose and concentration dependently. However, deramasciclane inhibited maximally only 52% of the [11C]-NMSP binding in the frontal cortex, indicating a non-5-HT2A receptor binding component of this radioligand in frontal cortex. On average, specific [11C]-NMSP binding cerebellum ratios below 0.355 were not possible to achieve in this population. The 52% inhibition was regarded to represent near 100% 5-HT2A receptor occupancy. The 50 and 90% receptor occupancies were reached at deramciclane plasma concentrations of 21 ng/ml and 70 ng/ml, respectively. CONCLUSIONS: Deramciclane penetrates the blood-brain barrier in humans. Deramciclane binds to the 5-HT2A receptors in the frontal cortex in a saturable manner in vivo. Consequently, the increase in deramciclane concentration in plasma above 70 ng/ml will not result in major increase in the 5-HT2A receptor occupancy in the brain.

Administration, Oral↗

PubMed1999

Association between the functional variant of the catechol-O-methyltransferase (COMT) gene and type 1 alcoholism.

Catechol-O-methyltransferase (COMT) is an enzyme which has a crucial role in the metabolism of dopamine. It has been suggested that a common functional genetic polymorphism in the COMT gene, which results in 3 to 4-fold difference in COMT enzyme activity, may contribute to the etiology of mental disorders such as bipolar disorder and alcoholism. Since ethanol-induced euphoria is associated with the rapid release of dopamine in limbic areas, it is conceivable that subjects who inherit the allele encoding the low activity COMT variant would have a relatively low dopamine inactivation rate, and therefore would be more vulnerable to the development of ethanol dependence. The aim of this study was to test this hypothesis among type 1 (late-onset) alcoholics. The COMT polymorphism was determined in two independent male late onset (type 1) alcoholic populations in Turku (n = 67) and Kuopio (n = 56). The high (H) and low (L) activity COMT genotype and allele frequencies were compared with previously published data from 3140 Finnish blood donors (general population) and 267 race- and gender-matched controls. The frequency of low activity allele (L) was markedly higher among the patients both in Turku (P = 0.023) and in Kuopio (P = 0.005) when compared with the general population. When all patients were compared with the general population (blood donors), the difference was even more significant (P = 0.0004). When genotypes of all alcoholics (n = 123) were compared with genotypes of matched controls, the odds ratio (OR) for alcoholism for those subjects having the LL genotype vs those with HH genotype was 2.51, 95% CI 1.22-5.19, P = 0.006. Also, L allele frequency was significantly higher among alcoholics when compared with controls (P = 0.009). The estimate for population etiological (attributable) fraction for the LL genotype in alcoholism was 13.3% (95% CI 2.3-25.7%). The results indicate that the COMT polymorphism contributes significantly to the development of late-onset alcoholism.

Adult↗

PubMed1999

Association between low activity serotonin transporter promoter genotype and early onset alcoholism with habitual impulsive violent behavior.

A common 44-base pair insertion/deletion polymorphism in the promoter region of the human serotonin transporter (5-HTT) gene has been observed to be associated with affective illness and anxiety-related traits. This biallelic functional polymorphism, designated long (L) and short (S), affects 5-HTT gene expression since the S promoter is less active than the L promoter. Since there is strong evidence of a disturbance in brain serotonergic transmission among antisocial, impulsive, and violent type 2 alcoholic subjects, we decided to test the hypothesis that the frequency of the S allele, which is associated with reduced 5-HTT gene expression, is higher among habitually violent type 2 alcoholics when compared with race and gender-matched healthy controls and non-violent late-onset (type 1) alcoholics. The 5-HTT promoter genotype was determined by a PCR-based method in 114 late onset (type 1) non-violent alcoholics, 51 impulsive violent recidivistic offenders with early onset alcoholism (type 2), and 54 healthy controls. All index subjects and controls were white Caucasian males of Finnish origin. The S allele frequency was higher among type 2 alcoholics compared with type 1 alcoholics (chi2 = 4.86, P = 0.028) and healthy controls (chi2 = 8.24, P = 0.004). The odds ratio for SS genotype vs LL genotype was 3.90, 95% Cl 1.37-11.11, P = 0.011 when type 2 alcoholics were compared with healthy controls. The results suggest that the 5-HTT 'S' promoter polymorphism is associated with an increased risk for early onset alcoholism associated with antisocial personality disorder and impulsive, habitually violent behavior.

Adult↗

PubMed1999

Measurement of striatal D2 dopamine receptor density and affinity with [11C]-raclopride in vivo: a test-retest analysis.

Subacute and long-term stability of measurements of D2 dopamine receptor density (Bmax), affinity (Kd) was studied with positron emission tomography in eight healthy male volunteers. [11C]-Raclopride and the transient equilibrium method were used to measure D2 receptor characteristics. The interval between measurements (scan pairs) was 3 to 7 weeks (subacute) for four subjects and 6 to 11 months (long-term) for four subjects. A test-retest analysis of quantitative measurements of D2 receptor Bmax and Kd was compared with that done on binding potential (BP, Bmax/Kd) measures. In addition, the effect of error in defining the transient equilibrium time (tmax) in the parameter estimation procedure was explored with simulations. The subacute test-retest indicates good reproducibility of D2 receptor density, affinity, and BP ratio measurements with intraclass correlation coefficients of 0.90, 0.96, and 0.86, respectively. The variability of the measurements after 6 to 11 months was slightly higher than that seen in a subacute testing for Kd and more clearly so for binding potential and Bmax. The absolute variability in Bmax (14.5%) measurements was consistently higher than that of Kd (8.4%) or BP (7.9%) both in subacute and long-term measurements. Simulations indicated that the Bmax and Kd estimation procedure is more sensitive to error in the tmax than that for the BP. The results indicate a good overall stability of the equilibrium method with [11C]raclopride for measuring dopamine D2 receptor binding characteristics in the striatum. The BP approach is more stable than Kd and especially Bmax measurements. Error in defining the tmax in particular in the low specific radioactivity scan may be one source of greater variability in Bmax versus BP. However, a higher intraindividual variability in measurements of the D2 receptor Bmax also may include a component of continuous regulation of this parameter over time. These methodologic aspects should be considered in the design and interpretation of longitudinal studies on D2 dopamine receptor characteristics with [11C]-raclopride.

Adult↗

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↗