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Objective: Accumulating evidence implicates immune activation in the development of schizophrenia. Here, monocyte numbers, monocyte chemoattractant protein‐1 (MCP‐1) and chitinase‐3‐like protein 1 (YKL‐40) were investigated in plasma and cerebrospinal fluid (CSF) in first‐episode psychosis (FEP) patients. Method: CSF and blood were sampled from 42 first‐episode psychosis (FEP) patients and 22 healthy controls. The levels of YKL‐40 and MCP‐1 were measured using electrochemiluminescence assay, and blood monocytes were counted using an XN‐9000‐hematology analyzer. Results: We found higher plasma levels of MCP‐1 and YKL‐40 in FEP patients compared with healthy controls, a condition that was unrelated to antipsychotic and/or anxiolytic medication. This was combined with an increased number of blood monocytes and a borderline significant increase in YKL‐40 levels in the CSF of tobacco‐free FEP patients. Plasma or CSF chemokines or blood monocytes did not correlate with the severity of symptoms or the level of functioning. Conclusion: These data demonstrate activation of monocytes in FEP and strengthens the idea of an immune dysfunction of psychotic disorders. Further studies are required to perceive a role of YKL‐40 and MCP‐1 in the initiation and progression of schizophrenia. [ABSTRACT FROM AUTHOR]

Tryptophan degradation along the kynurenine pathway is of central importance for the immune function. Toll-like receptors ( TLRs), representing the first line of immune defence against pathogens, are expressed in various cell types. The most abundant expression is found on monocytes, macrophages and dendritic cells. The aim of this study was to investigate whether stimulation with different TLR ligands induces the kynurenine pathway in human peripheral monocytes. Cell supernatants were analysed using a liquid chromatography/mass spectrometry to measure kynurenine, kynurenic acid ( KYNA), quinolinic acid ( QUIN) and tryptophan. Stimulation of TLR-2, TLR-3, TLR-4, TLR-7/8 and TLR-9 was found to induce the production of kynurenine, but only stimulation of TLR-3 increased levels of further downstream metabolites, such as KYNA and QUIN. Stimulation of TLR-1, TLR-5 and TLR-6 did not induce the kynurenine pathway. Taken together, this study provides novel evidence demonstrating that TLR activation induces a pattern of downstream tryptophan degradation along the kynurenine pathway in monocytes. The results of this study may implicate that TLRs can be used as new drug targets for the regulation of aberrant tryptophan metabolism along this pathway, a potential therapeutic strategy that may be of importance in several disorders. [ABSTRACT FROM AUTHOR]

ABSTRACT Dopamine D2 receptor positron emission tomography (PET) radioligands have proven useful for indirect assessment of the endogenous dopamine concentration in the living brain. On the contrary, dopamine D1 receptor antagonist radioligands have shown no sensitivity to changes in the dopamine concentration. A recent approach to enhance the sensitivity of radioligands to the dopamine concentration has been the development of dopamine D2 receptor agonist radioligands. The aim of this study was to evaluate the dopamine sensitivity of a dopamine D1 receptor agonist radioligand. For this purpose, we developed ( S)-[11C] N-methyl-NNC 01-0259 (( S)-[11C] 1) and characterized the receptor binding of ( S)-[11C] 1 using in vitro receptor binding assays and in vivo PET measurements in monkeys. In vitro, both enantiomers of 1 were partial dopamine D1 receptor agonists, with ( S)- 1 having a 10-50 times higher affinity than ( R)- 1. PET studies in monkey confirmed the stereoselectivity of [11C] 1 in vivo. In monkey, administration of the dopamine D1-like receptor antagonist ( R)-(+)-SCH 23390 decreased the striatal binding potential of ( S)-[11C] 1 by 97%, but administration of the dopamine concentration enhancer d-amphetamine did not affect ( S)-[11C] 1 binding. We conclude that the agonist ( S)-[11C] 1 provides specific binding to dopamine D1-like receptors, possibly representing binding to the high-affinity state of the receptors. The partial dopamine D1 receptor agonist radioligand has, however, no enhanced sensitivity to endogenous dopamine concentrations in comparison with antagonist radioligands. Synapse 67:586-595, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The need for positron emission tomography (PET)-radioligands that are sensitive to changes in endogenous serotonin (5-HT) levels in brain is recognized in experimental and clinical psychiatric research. We recently developed the novel PET radioligand [11C]AZ10419369 that is highly selective for the 5-HT1B receptor. In this PET-study in three cynomolgus monkeys, we examined the sensitivity of [11C]AZ10419369 to altered endogenous 5-HT levels. Fenfluramine-induced 5-HT release decreased radioligand binding in a dose-dependent fashion with a regional average of 27% after 1 mg/kg and 50% after 5 mg/kg. This preliminary study supports that [11C]AZ10419369 is sensitive to endogenous 5-HT levels in vivo and may serve as a tool to examine the pathophysiology and treatment of major psychiatric disorders. Synapse 64:573-577, 2010. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Gulyás B, Halldin C, Sandell J, Karlsson P, Sóvágó J, Kárpáti E, Kiss B, Vas Á, Cselényi Z, Farde L. PET studies on the brain uptake and regional distribution of [11 C]vinpocetine in human subjects. Acta Neurol Scand 2002: 106: 325–332. © Blackwell Munksgaard 2002. Objectives – Vinpocetine is a compound widely used in the prevention and treatment of cerebrovascular diseases. It is still not clear whether the drug has a direct and specific effect on neurotransmission or its effects are due to extracerebral actions, such as changes in cerebral blood flow. The main objective of the present investigation was to determine the global uptake and regional distribution of radiolabelled vinpocetine in the human brain in order to explore whether it may have direct central nervous system effects. Material and methods – Three healthy subjects were examined with positron emission tomography and [11 C]vinpocetine. The regional uptake was determined in anatomically defined volumes-of-interest. The fractions of [11 C]vinpocetine and labelled metabolites in plasma were determined using high pressure liquid chromatography. Results – The uptake of [11 C]vinpocetine in brain was rapid and 3.7% (mean; n =4) of the total radioactivity injected was in brain 2 min after radioligand administration. The uptake was heterogeneously distributed among brain regions. When compared with the cerebellum, an a priori reference region, the highest regional uptake was in the thalamus, upper brain stem, striatum and cortex. Following an initial peak, the total concentration of radioactivity in blood was relatively stable with time, whereas the concentration of the unchanged compound decreased with time in an exponential manner. Conclusion – Vinpocetine, administered intravenously in humans, readily passes the blood–brain barrier and enters the brain. Its regional uptake... [ABSTRACT FROM AUTHOR]

Central D2-dopamine receptor occupancy determined by positron emission tomography (PET) during neuroleptic drug treatment may be a useful measure for optimal dose finding in schizophrenic patients. The clinical benefit is dependent on the reliability of such determinations. The ratio of radioactivity in the striatum to that of the cerebellum is widely used for calculation of D2-receptor occupancy and as an index of D2-dopamine receptor density. To test the reliability of such ratios a test-retest analysis was performed in a series of healthy subjects. The reliability was very high, both when experiments were repeated on the same day and after time intervals of months to years. A group of subjects were examined twice using PET camera systems with different resolution. The striatum to cerebellum ratios obtained from the high-resolution PET camera system were significantly higher than ratios from the camera with lower resolution. The age effect on the striatum to cerebellum ratio was examined in 25 healthy young adults and in 18 neuroleptic-naive schizophrenic patients. A statistically significant decline was found both in the healthy controls and in the schizophrenic patients. The results do not support the view that there is a lack of age effect on the D2-dopamine receptor density in schizophrenia. [ABSTRACT FROM AUTHOR]

The stereoenantiomers of piquindone (Ro 22-1319), a new antipsychotic pyrroloisoquinoline derivative, were labelled with the positron-emitting isotope "C. Only the (-) enantiomer inherits most of the biological activity of racemic piquindone, the Compounds were examined by positron emission tomography (PET) for dopamine-D2 receptor binding in the living brain of Cynomolgus monkeys and healthy human subjects after i.v. administration of tracer doses the (-) enantiomer but not the (+) enantiomer was show to accumulate markedly in the dopamine D2 receptor rich caudate/putamen, and the putamen/cerebellar activity ratio increased to about 2 during the hour when radioactivity could be followed (-) 11C piquindone binding in the monkey putamen was not ealisly displaceable by receptors in the living human brain. The results are compatible with the view that clinical adminstration of piquindone produces a long-lasting effect on central dopamine-D2 receptors (-)"C piquindone is a useful ligand effects of piquindone and blcokade of specific binding sites in the brain of schizophrenic patients. [ABSTRACT FROM AUTHOR]

Objectives: Assess pharmacokinetics, dopamine D2 and serotonin 5-HT2A receptor occupancy of paliperidone immediate-release 1mg (paliperidone IR; Study 1) and paliperidone extended-release tablets 6mg (paliperidone ER; Study 2).Methods: Blood samples were collected pre-dose and ≤24h (Study 1) and ≤48h (Study 2). Striatal D2 receptor binding was measured using PET and 11C-raclopride pre-dose and post-dose at 2.5h (Study 1) and at 22h and 46h (predicted Cmax; Study 2). Frontal cortex 5-HT2A receptor occupancy (Study 1) was assessed using[11C]M100,907 ≥1 week pre-dose and 4.5h post-dose (Cmax). The apparent dissociation constant (KDapp=plasma concentration at which 50% of target receptor is occupied) was estimated using an Emax model.Results: Formulation differences were reflected in tmax and Cmax. Paliperidone ER 6mg corresponds to median D2 occupancy of 64% at 22h post-dose. Using the KDapp, plasma concentrations corresponding to 70-80% D2 occupancy were estimated: 15-25ng/mL (Study 1); 10-17ng/mL (Study 2). Using pooled data from both studies the in vivo KDapp is estimated to be 4.9ng/mL.Conclusion: Paliperidone occupies central D2 and 5HT2A receptors. D2 receptor occupancy with paliperidone ER suggests 6mg will be an effective dose in the treatment of schizophrenia. (See Table)Clinical Pharmacology & Therapeutics (2005) 79, P74–P74; doi: 10.1016/j.clpt.2005.12.265 [ABSTRACT FROM AUTHOR]

Background and Aims: Whereas striatal dopamine D2 receptor (D2R) availability has shown to be altered in individuals with alcohol use disorder (AUD) and in healthy individuals with a family history of AUD, the role of D2R in the development of AUD is unknown. In this positron emission tomography (PET) study, we measured whether D2R availability is associated with subsequent alcohol use and alcohol-related factors, at a follow-up 8 to 16 years post-PET scan, in social drinkers., Design: Longitudinal study investigating the association between PET data and later self-report measures in healthy individuals., Setting: Academic research imaging centre in Stockholm, Sweden., Participants: There were 71 individuals (68 of whom had evaluable PET data, 5 females, 42.0 years mean age) from a series of previous PET studies., Measurements: One PET examination with the D2R antagonist radioligand [ 11 C]raclopride at baseline and self-report measures assessing alcohol use, drug use, impulsivity, reward sensitivity and family history of alcohol or substance use disorder at follow-up., Findings: We found no evidence for an association between D2R availability and later alcohol use (B = -0.019, B 95% CI = -0.043 to -0.006, P = 0.147) nor for the majority of the alcohol-related factors (B 95% CI = -0.034 to 0.004, P = 0.273-0.288). A negative association with a small effect size was found between D2R availability and later impulsivity (B = -0.017, B 95% CI = -0.034 to -0.001, P = 0.046)., Conclusions: Low striatal dopamine D2 receptor availability may not be a strong predictor in the development of alcohol use disorder., (© 2023 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Antipsychotic drugs were introduced in the early 50s on the basis of clinical observations in patients with schizophrenia. Experimental studies later revealed that antagonism at the D(2) dopamine receptor is a common characteristic of all antipsychotic drugs. In the 80s, the advent of brain imaging technologies such as positron emission tomography (PET) allowed for direct noninvasive studies of drug binding in treated patients. The concept receptor occupancy is defined as the fraction (%) of a receptor population that is occupied during treatment with an unlabelled drug. With regard to antipsychotic drugs, the radioligand [(11) C]-raclopride has been the most widely used for binding to the D(2) /D(3) -dopamine receptors. The present review discusses the contribution from molecular imaging to the current understanding of mechanism of action (MoA) of antipsychotic drugs. Consistent initial PET-findings of high D2-receptor occupancy in the striatum of patients responding to different antipsychotic drug treatments provided clinical support for the dopamine hypothesis of antipsychotic drug action. It has subsequently been demonstrated that patients with extrapyramidal syndromes (EPS) have higher occupancy (above 80%) than patients with good response but no EPS (65-80%). The PET-defined interval for optimal antipsychotic drug treatment has been implemented in the evolvement of dose recommendations for classical as well as more recently developed drugs. Another consistent finding is lower D(2) -occupancy during treatment with the prototype atypical antipsychotic clozapine. The MoA of clozapine remains to be fully understood and may include nondopaminergic mechanisms. A general limitation is that currently available PET-radioligands are not selective for any of the five dopamine receptor subtypes. Current attempts at developing such ligands may provide the tools required to refine further the MoA of antipsychotic drugs.

We have previously identified mutations in exon three in NURR1 (NR4A2) in two patients with schizophrenia (SZ) and one patient with bipolar disease with psychotic symptoms. In the present study we analyzed the promoter region of NURR1 and identified five polymorphic sites: three were found to be in strong linkage disequilibrium with a previously identified polymorphic site in the sixth intron. One polymorphism of this haplotype and the two other independent polymorphisms were investigated for their possible association with SZ and Parkinson's disease (PD) by comparing their frequencies in a Swedish material consisting of 134 subjects with SZ and 207 matched controls and 108 subjects with PD and 125 matched controls. Exon 1 was also investigated in our Parkinson and control material but no variances were found. The distributions of the two most informative polymorphisms in the promoter were investigated in an American material as well consisting of 141 subjects with SZ and 139 matched controls. Furthermore, the identified markers were screened for association with putative endophenotypes of SZ in the Swedish material. The distribution of sequence variants among the Swedish controls matched for SZ was investigated with regard to personality. No significant genotype or allelic association of the three sequence variants with SZ or PD was found. Several comparisons regarding endophenotypes or personality indicated association at the 5% confidence level, although correction for multiple testing rendered none of these findings significant. We conclude that the identified polymorphic sites in the human NURR1 are unlikely to be involved in conferring susceptibility for SZ or PD in our patient material., (Copyright 2003 Wiley-Liss, Inc.)

Positron emission tomography and 11-C-labelled raclopride was used to determine central D2-dopamine receptor occupancy in three melperone treated patients. Treatment with melperone in daily doses of 250 and 300 mg for 3 to 6 weeks, resulted in a receptor occupancy above 70%. Thus, clinical doses of melperone as we previously demonstrated for several classical neuroleptics cause a substantial D2-dopamine receptor blockade in the human brain in vivo.