BMP6/TAZ-Hippo signaling modulates angiogenesis and endothelial cell response to VEGF.

The BMP/TGFß-Smad, Notch and VEGF signaling guides formation of endothelial tip and stalk cells. However, the crosstalk of bone morphogenetic proteins (BMPs) and vascular endothelial growth factor receptor 2 (VEGFR2) signaling has remained largely unknown. We demonstrate that BMP family members regulate VEGFR2 and Notch signaling, and act via TAZ-Hippo signaling pathway. BMPs were found to be regulated after VEGF gene transfer in C57/Bl6 mice and in a porcine myocardial ischemia model. BMPs 2/4/6 were identified as endothelium-specific targets of VEGF. BMP2 modulated VEGF-mediated endothelial sprouting via Delta like Canonical Notch Ligand 4 (DLL4). BMP6 modulated VEGF signaling by regulating VEGFR2 expression and acted via Hippo signaling effector TAZ, known to regulate cell survival/proliferation, and to be dysregulated in cancer. In a matrigel plug assay in nude mice BMP6 was further demonstrated to induce angiogenesis. BMP6 is the first member of BMP family found to directly regulate both Hippo signaling and neovessel formation. It may thus serve as a target in pro/anti-angiogenic therapies.

Suppressed heat shock protein response in the kidney of exercise-trained diabetic rats.

Impaired expression of heat shock proteins (HSPs) and increased oxidative stress may contribute to the pathophysiology of diabetes by disrupted tissue protection. Acute exercise induces oxidative stress, whereas exercise training up-regulates endogenous antioxidant defenses and HSP expression. Although diabetic nephropathy is a major contributor to diabetic morbidity, information regarding the effect of HSPs on kidney protection is limited. This study evaluated the effects of eight-week exercise training on kidney HSP expression and markers of oxidative stress at rest and after acute exercise in rats with or without streptozotocin-induced diabetes. Induction of diabetes increased DNA-binding activity of heat shock factor-1, but decreased the expression of HSP72, HSP60, and HSP90. The inflammatory markers IL-6 and TNF-alpha were increased in the kidney tissue of diabetic animals. Both exercise training and acute exercise increased HSP72 and HSP90 protein levels only in non-diabetic rats. On the other hand, exercise training appeared to reverse the diabetes-induced histological changes together with decreased expression of TGF-beta as a key inducer of glomerulosclerosis, and decreased levels of IL-6 and TNF-alpha. Notably, HSP72 and TGF-beta were negatively correlated. In conclusion, impaired HSP defense seems to contribute to kidney injury vulnerability in diabetes and exercise training does not up-regulate kidney HSP expression despite the improvements in histopathological and inflammatory markers.

Intracellular RNA recognition pathway activates strong anti-viral response in human mast cells.

Mast cells have been implicated in the first line of defence against parasites and bacteria, but less is known about their role in anti-viral responses. Allergic diseases often exacerbate during viral infection, suggesting an increased activation of mast cells in the process. In this study we investigated human mast cell response to double-stranded RNA and viral infection. Cultured human mast cells were incubated with poly(I:C), a synthetic RNA analogue and live Sendai virus as a model of RNA parainfluenza virus infection, and analysed for their anti-viral response. Mast cells responded to intracellular poly(I:C) by inducing type 1 and type 3 interferons and TNF-α. In contrast, extracellular Toll-like receptor 3 (TLR)-3-activating poly(I:C) failed to induce such response. Infection of mast cells with live Sendai virus induced an anti-viral response similar to that of intracellular poly(I:C). Type 1, but not type 3 interferons, up-regulated the expression of melanoma differentiation-associated gene 5 (MDA-5) and retinoic acid-inducible gene-1 (RIG-1), and TLR-3, demonstrating that human mast cells do not express functional receptors for type 3 interferons. Furthermore, virus infection induced the anti-viral proteins MxA and IFIT3 in human mast cells. In conclusion, our results support the notion that mast cells can recognize an invading virus through intracellular virus sensors and produce high amounts of type 1 and type 3 interferons and the anti-viral proteins human myxovirus resistance gene A (MxA) and interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) in response to the virus infection.

Health-related quality of life and cost-effectiveness of treatment in subarachnoid haemorrhage.

BACKGROUND: Treatment of aneurysmal subarachnoid haemorrhage (SAH) demands high healthcare resource utilization. Case fatality and disability remain as common outcomes of SAH. The purpose of this study was to perform a treatment cost-effectiveness analysis of patients with SAH. METHODS: We performed a long-term follow-up of the SAH patients treated in our institution over a 3-year period starting February 1998. Outcome 10 years after the SAH and treatment costs were evaluated. The health-related quality of life was evaluated using the EuroQol (EQ-5D) questionnaire and visual-analogue scale (VAS). The cost of a quality-adjusted life year (QALY) was calculated. RESULTS: Median follow-up time of the 178 patients was 10.8 years. Overall mortality rate was 24%. Of the 43 non-survivors, 42% died within 6 months. For the 135 survivors, the median EQ-5D index value was 1.00, which is similar to that for normal population. The median VAS value was 80, which is comparable to normal population's value. Of the survivors, 88% (119/135) were able to live at home and 63% (85/135) returned to work after SAH. The cost of neurosurgical treatment for one QALY was 1700€. CONCLUSION: Long-term outcome of survivors after aneurysmal SAH was relatively good: most of them lived at home, 63% had returned to work and 36% were still working. The quality of life index of the survivors was similar to that of normal populations, and the survivors were as satisfied with their health as people in general are. Cost of neurosurgical treatment and cost of a QALY gained were acceptable.

Mast cells generated from patients with atopic eczema have enhanced levels of granule mediators and an impaired Dectin-1 expression.

BACKGROUND: The disrupted skin barrier of patients with atopic eczema (AE) might facilitate contact between mast cells (MCs) in the skin and environmental triggers of the disease. One such trigger is the skin-colonizing yeast Malassezia sympodialis (M. sympodialis). In this study, we investigated the interaction of MC with M. sympodialis. METHODS: Mast cells were generated from peripheral blood CD34(+) progenitor cells of healthy controls (HC) and M. sympodialis-sensitized AE patients. Biopsy specimens were taken from HC and lesional AE skin for immunohistological stainings. RESULTS: The progenitor-derived MCs expressed the macrophage-inducible C-type lectin receptor Mincle, and exposure of these cells to M. sympodialis induced up-regulation of the mRNA expression of Mincle. Furthermore, we demonstrate that, when compared to HC, the progenitor-derived MCs from AE patients (i) contain more intrinsic granule mediators such as histamine, (ii) exhibit enhanced IL-6 release in response to M. sympodialis exposure, and (iii) have an impaired up-regulation of the fungal recognition receptor Dectin-1. In addition, analysis of skin sections from HC and AE patients revealed MCs as the predominant Dectin-1-expressing cell type in the skin. CONCLUSION: Our data indicate that progenitor-derived MCs from AE patients differ from those from HC. Further investigations with skin-derived MCs are necessary to confirm the observed differences which could provide new insights into the pathogenic mechanisms underlying AE.

Exercise training and experimental diabetes modulate heat shock protein response in brain.

In diabetes, defense systems against cellular stress are impaired. Heat shock proteins (HSPs) function primarily as molecular chaperones. Factors that raise tissue HSP levels may slow progression of diabetes and improve diabetic complications that also affect brain tissue. This study tested the effect of an 8-week exercise training on brain HSP response in rats with or without streptozotocin-induced diabetes (SID). In untrained animals, the HSP levels were not different between SID and non-diabetic groups. Endurance training, however, increased HSP72 and HSP90 protein in non-diabetic rats, whereas SID significantly decreased the effect of training on these HSPs. At the mRNA level, HSP60, HSP90 and GRP75 were increased due to training, whereas HSP72 mRNA was only increased in exercise-trained diabetic animals. Training or diabetes had no effect on protein carbonyl content, a marker of oxidative damage. Altogether, our findings suggest that endurance training increases HSP expression in the brain, and that experimental diabetes is associated with an incomplete HSP response at the protein level.

Stunted growth of pikeperch Sander lucioperca in Lake Sahajärvi, Finland.

Growth of pikeperch Sander lucioperca in the eutrophic and clay-turbid Lake Sahajärvi, Southern Finland, was extremely slow in comparison with other lakes at similar latitudes. The most important food item in July was phantom midge larvae Chaoborus flavicans for all sizes of S. lucioperca (239-423 mm total length L(T)), while later, in August and September, the diet of S. lucioperca (149-407 mm L(T)) consisted of small (30-100 mm L(T)) perch Perca fluviatilis, ruffe Gymnocephalus cernuus and roach Rutilus rutilus.

Size-dependent optical properties of BaTiO3-SrTiO3 superlattices.

Artificial BaTiO(3)-SrTiO(3) superlattices with stacking periodicity varying between 27 and 1670 A in separate films were grown on MgO substrates by pulsed laser deposition. Both the static and active optical properties were found to be sensitive on the stacking periodicity. Birefringence decreased with increasing individual layer thickness due to relaxation of the interface originated stress. The electro-optic response also showed a layer thickness dependence, reaching a maximum at an individual layer thickness of 13 unit cells.

Interventions for preventing injuries in the construction industry.

BACKGROUND: Construction workers are frequently exposed to various types of injury-inducing hazards. A number of injury prevention interventions have been proposed, yet the effectiveness of these is uncertain. OBJECTIVES: To assess the effects of interventions for preventing injuries among workers at construction sites. SEARCH STRATEGY: We searched the Cochrane Injuries Group's specialised register, CENTRAL, MEDLINE, EMBASE, PsycINFO, OSH-ROM (including NIOSHTIC and HSELINE), EI Compendex. The reference lists of relevant papers, reviews and websites were also searched. The searches were not restricted by language or publication status. All databases were searched up to June 2006. SELECTION CRITERIA: Randomized controlled trials, controlled before-after studies and interrupted time series of all types of interventions for preventing fatal and non-fatal injuries among workers at construction sites. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed study quality. For interrupted time series, we reanalysed the studies and used an initial effect, measured as the change in injury-rate in the year after the intervention, as well as a sustained effect, measured as the change in time trend before and after the intervention. MAIN RESULTS: Five interrupted time series studies met the inclusion criteria. Three studies evaluated the effect of regulations, one evaluated a safety campaign, and one a drug-free workplace program on fatal or non-fatal injuries compared to no drug-free workplace program. The overall methodological quality was low. The regulatory interventions did not show either an initial or sustained effect on fatal or non-fatal injuries, with effect sizes of 0.69 (95% confidence interval (CI) -1.70 to 3.09) and 0.28 (95% CI 0.05 to 0.51). The safety campaign did have an initial and sustained effect, reducing non-fatal injuries with effect sizes of -1.82 (95% CI -2.90 to -0.75) and -1.30 (95% CI -1.79 to -0.80) respectively. The drug-free workplace program did have an initial and sustained effect, reducing non-fatal injuries compared to no intervention, with effect sizes of -6.74 (95% CI -10.02 to -3.54) and -1.76 (95% CI -3.11 to -0.41) respectively. AUTHORS' CONCLUSIONS: The vast majority of technical, human factors and organisational interventions which are recommended by standard texts of safety, consultants and safety courses, have not been adequately evaluated. There is no evidence that regulations for reducing fatal and non-fatal injuries are effective. There is limited evidence that a multifaceted safety campaign and a multifaceted drug program can reduce non-fatal injuries in the construction industry.

Population Exposure-Response Modeling of Naloxegol in Patients With Noncancer-Related Pain and Opioid-Induced Constipation.

Naloxegol is a polyethylene glycol derivative of naloxone approved in the US as a once-daily oral treatment for opioid-induced constipation (OIC) in adults with chronic noncancer pain. Population exposure-response models were constructed based on data from two phase III studies comprising 1,331 adults with noncancer pain and OIC. In order to characterize the protocol-defined naloxegol responder rate, the number of daily spontaneous bowel movements (SBMs) was characterized by a longitudinal ordinal nonlinear mixed-effects logistic regression dose-response model, and the incidence of diary entry discontinuation was described by a time-to-event model. The mean number of SBMs per week increased with increasing naloxegol dose. The predicted placebo-adjusted responder rates (90% confidence interval) were 10.4% (4.6-13.4%) and 11.1% (4.8-14.4%) for naloxegol 12.5 and 25 mg/day, respectively. Model-predicted response to naloxegol was influenced by the baseline SBM frequency and characteristics of the opioid treatment.

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.

Linkage of antisocial alcoholism to the serotonin 5-HT1B receptor gene in 2 populations.

BACKGROUND: In mice, quantitative trait locus studies and behavioral evaluation of animals deleted for 5-HT1B have implicated this serotonin autoreceptor in alcohol consumption and aggressive behavior. We therefore investigated whether the 5-HT1B gene (HTR1B) is linked to alcoholism with aggressive and impulsive behavior in the human, as represented by 2 psychiatric diagnoses: antisocial personality disorder and intermittent explosive disorder comorbid with alcoholism. METHODS: Linkage was first tested in 640 Finnish subjects, including 166 alcoholic criminal offenders, 261 relatives, and 213 healthy controls. This was followed by a study in a large multigenerational family derived from a Southwestern American Indian tribe (n=418) with a high rate of alcoholism. All subjects were psychiatrically interviewed, blind-rated for psychiatric diagnoses, and typed for a HTR1B G861C polymorphism and for a closely linked short-tandem repeat locus, D6S284. Linkage was evaluated in sib pairs, and by using an association approach in which pedigree randomization corrects for nonindependence of observations on related subjects. RESULTS: In Finnish sib pairs, antisocial alcoholism showed significant evidence of linkage to HTR1B G861C (P=.04) and weak evidence with D6S284 (P=.06). By association analysis, the 183 Finnish antisocial alcoholics had a significantly higher HTR1B-861C allele frequency than the other 457 Finns we studied (P=.005). In the Southwestern American Indian tribe, significant sib pair linkage of antisocial alcoholism to HTR1B G861C (P=.01) was again observed, and there was also significant linkage to D6S284 (P=.01). CONCLUSION: These results suggest that a locus predisposing to antisocial alcoholism may be linked to HTR1B at 6q13-15.

Role of the serotonin transporter promoter polymorphism in anxiety-related traits.

BACKGROUND: The heritability of interindividual variation in anxiety and other aspects of personality establishes that variants of genes influence these traits. A functional polymorphism in the promoter of the human serotonin transporter gene (SLC6A4*C) was identified and found to be linked to an anxiety-related personality trait, Neuroticism. The polymorphism affects gene transcription and, ultimately, gene function. We have attempted to confirm the role of SLC6A4*C in anxiety-related personality traits by sibpair analysis and association studies. METHODS: Sibpair linkage analysis and association study were performed in 655 Finns. The index cases were 182 alcoholic criminal offenders, through which 258 relatives were ascertained to obtain 366 sibpairs. In addition, 215 unrelated population controls were collected. Each individual was psychiatrically interviewed, blind-rated for DSM-III-R diagnoses, and assessed with the Tridimensional Personality Questionnaire. RESULTS: The sibpair analysis revealed a positive linkage between SLC6A4*C and the 2 anxiety-related subdimensions of Harm Avoidance: HA1 (Anticipatory Worry) and HA2 (Fear of Uncertainty) (P = .003). However, there was no consistent association between SLC6A4*C and any Tridimensional Personality Questionnaire trait. CONCLUSIONS: In the present study we replicated the relationship of SLC6A4*C to anxiety by sibpair linkage analysis but found no evidence of association, raising the question of whether SLC6A4*C locus is itself affecting anxiety or is linked to another still unknown functional variant.

A tryptophan hydroxylase gene marker for suicidality and alcoholism.

BACKGROUND: Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of serotonin. Low turnover rate of this monoamine neurotransmitter is associated with impaired impulse control. We previously reported that, in Finns, TPH genotype was associated with suicidality, a pathophysiological mechanism that may involve impaired impulse control. METHODS: Association and sib-pair linkage analyses of a polymorphism in intron 7 of the TPH gene with suicidality, alcoholism, and the Karolinska Scales of Personality were conducted in 804 Finnish alcoholic offenders, controls, and their relatives, in a sample that included 369 sib pairs. RESULTS: The association of the TPH 17 779C (L) allele to suicidality in impulsive offenders reported previously was replicated in a new group of Finnish offenders (P=.001, n=122). The intron 7 variant in the TPH gene showed significant evidence for linkage to suicidality (P=.006 in unaffected sib pairs), severe suicide attempts (P=.006 in unaffected sib pairs; regression: P=.01), alcoholism (P=.003 in unaffected sib-pairs; regression: P=.02), and Karolinska Scales of Personality socialization score (regression: P=.002). CONCLUSIONS: The status of the TPH A779C allele as a marker for suicidality was replicated and linkage with alcoholism and Karolinska Scales of Personality socialization score was also observed. A functional variant(s) in or close to the TPH gene may predispose individuals to suicidality and other behaviors thought to be influenced by serotonin.

HTR2C Cys23Ser polymorphism in relation to CSF monoamine metabolite concentrations and DSM-III-R psychiatric diagnoses.

BACKGROUND: Heritable variation in brain monoaminergic activity has been suggested to lead to interindividual differences in vulnerability to alcoholism, and many other behavioral disorders. We evaluated if a functional Cys23Ser polymorphism in the 5-HT2C receptor gene, the principal serotonin receptor in the brain, contributes to variation in serotonin, norepinephrine and dopamine activity, as indexed by their major metabolite concentrations in cerebrospinal fluid (CSF). Genotype-monoamine metabolite concentration associations were subsequently correlated to risk for alcoholism. METHODS: The study sample consisted of unrelated Finnish males, including 214 alcoholic, violent offenders and 222 population controls who were interviewed using the Structured Clinical Interview for DSM-III-R, blind rated for psychiatric diagnoses and typed for the HTR2C Cys23Ser polymorphism. CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of serotonin, 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), the major metabolite of norepinephrine, and homovanillic acid (HVA), the major metabolite of dopamine were available from 195 individuals. RESULTS: The major finding in this study was that HTR2C CysSer23 significantly contributed to CSF MHPG concentrations (p = .012). Higher concentrations of CSF MHPG were observed both in alcoholic violent offenders and population controls with HTR2C Ser23 genotype. Despite the association of Cys23Ser to CSF MHPG, HTR2C genotype was not associated with alcoholism, nor with other psychiatric disorders present in this sample. CONCLUSIONS: We conclude that a functional HTR2C Cys23Ser polymorphism contributes to the interindividual genetic variation of CSF MHPG explaining 3% of the total variance. This finding suggests that 5-HT2C receptors are involved in the regulation of norepinephrine turnover in humans; however, HTR2C Cys23Ser does not appear to contribute to the risk of alcoholism, or its contribution to this complex and heterogenous disorder is too small to be detected by a sample of this size and structure.

Two naturally occurring amino acid substitutions of the 5-HT2A receptor: similar prevalence in patients with seasonal affective disorder and controls.

We screened the 5-HT2A receptor gene coding region in 50 patients with seasonal affective disorder (SAD) using a single strand conformational polymorphism analysis and estimated the frequencies of two synonymous and two non-synonymous substitutions we detected in 70 Centre d'Etude du Polymorphism Humain (CEPH) population controls and 62 normal controls. Both of the amino acid substitutions: Ala447-Val447 and His452-Tyr452, were located within the cytoplasmic. C-terminal tail of the receptor. Rarer allele frequencies in CEPH were 0.7% and 9.3% for Val447 and Tyr452, respectively. Allele frequencies of all four polymorphisms, including the two amino acid substitutions, were not significantly different in SAD patients as compared to CEPH and normal controls. Lack of association of Val447 and Tyr452 to SAD is consistent with observations showing normal 5-HT2A receptor Ca2+ response in platelets with this disorder, however, the two 5-HT2A amino acid substitutions may lead to differences in behavioral phenotypes.

Mapping of the serotonin 5-HT1D beta autoreceptor gene on chromosome 6 and direct analysis for sequence variants.

Abnormal brain serotonin function may be characteristic of several neuropsychiatric disorders. Thus, it is important to identify polymorphic genes and screen for functional variants at loci coding for genes that control normal serotonin functions. 5-HT1D beta is a terminal serotonin autoreceptor which may play a role in regulating serotonin synthesis and release. Using an SSCP technique we screened for 5-HT1D beta coding sequence variants in psychiatrically interviewed populations, which included controls, alcoholics, and alcoholic arsonists and alcoholic violent offenders with low CSF concentrations of the main serotonin metabolite 5-HIAA. A common polymorphism was identified in the 5-HT1D beta gene with allele frequencies of 0.72 and 0.28. The SSCP variant was caused by a silent G to C substitution at nucleotide 861 of the coding region. This polymorphism could also be detected as a HincII RFLP of amplified DNA. DNAs from informative CEPH families were typed for the HincII RFLP and analyzed with respect to 20 linked markers on chromosome 6. Multipoint analysis placed the 5-HT1D beta receptor gene between markers D6S286 and D6S275. A maximum two-point lod score of 10.90 was obtained to D6S26, which had been previously localized on 6q14-15. Chromosomal aberrations involving this region have been previously shown to cause retinal anomalies, developmental delay, and abnormal brain development. This region also contains the gene for North Carolina-type macular dystrophy.

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.

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.

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.