An association study between two missense variations of the benzodiazepine receptor (peripheral) gene and schizophrenia in a Japanese sample

Kurumaji, Akeo; Nomoto, Hitoshi; Yoshikawa, Takeo; Okubo, Yoshiro; Toru, Michio

doi:10.1007/s007020070090

Cited by 22 publications

(12 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This strongly supports the assumption that progesterone-derived neuroactive steroids contribute to the actions of olanzapine but not of risperidone and haloperidol (Barbaccia et al, 2001;Marx et al, 2000Marx et al, , 2003. The recent reports support our observation that levels of GABAergic neuroactive steroid are significantly lower in schizophrenics (Kurumaji et al, 1997(Kurumaji et al, , 2000. Moreover, numerous evidences suggest that variations in the steady-state level of neuroactive steroids, especially ALLO in brain, may be relevant to pathophysiology of a range of psychiatric disorders (Guidotti et al, 2000(Guidotti et al, , 2001.…”

Section: Discussionsupporting

confidence: 90%

Role of Neuroactive Steroid Allopregnanolone in Antipsychotic-like Action of Olanzapine in Rodents

Ugale

Hirani

Morelli

et al. 2004

Neuropsychopharmacol

View full text Add to dashboard Cite

Olanzapine increases brain allopregnanolone (ALLO) levels sufficiently to modulate neuronal activity by allosterically regulating GABA A receptors. Recently, we reported the antipsychotic-like profile of ALLO in rodents. The present study examined the hypothesis that olanzapine-induced elevation of endogenous neurosteroid ALLO is vital for its neuroleptic-like action. The conditioned avoidance response (CAR) and apomorphine-induced climbing behavioral paradigms were used in rodents. Administration of ALLO (1 mg, intracerebroventricular (i.c.v.)) or neurosteroidogenic agents such as the mitochondrial diazepam binding inhibitor receptor agonist, FGIN 1-27 (0.5 mg, i.c.v.) or the ALLO precursor, progesterone (10 mg/kg, i.p.) significantly potentiated olanzapine-induced blockade of CAR and apomorphine-induced climbing. In contrast, these agents failed to alter the antipsychotic-like effect of risperidone and haloperidol. On the other hand, inhibition of the endogenous biosynthesis of neurosteroids by the 3b-hydroxysteroid dehydrogenase inhibitor, trilostane (30 mg/kg, i.p.), the 3a-hydroxysteroid oxidoreductase inhibitor, indomethacin (5 mg/kg, i.p.), or the GABA A receptor antagonist bicuculline (1 mg/kg, i.p.) and dehydroepiandrosterone sulfate (DHEAS) (1 mg/kg, i.p.) blocked the effect of olanzapine, but not of risperidone and haloperidol. Socially isolated animals, known to exhibit decreased brain ALLO and GABA A receptor functions, displayed a shortening in the muscimol-induced loss of righting reflex and an increased susceptibility to apomorphine-induced climbing. Administration of olanzapine, but not of haloperidol and risperidone, normalized the duration of muscimol-elicited loss of righting reflex. Although all three antipsychotics proved capable of antagonizing the apomorphine-induced climbing, a dose almost five times higher of olanzapine was required in socially isolated animals. The data obtained suggest that enhancement of the GABAergic tone plays a key role in the antipsychotic-like effect exerted by olanzapine in rodents, likely as a consequence of augmented levels of neuroactive steroids, in particular ALLO, in the brain. The present findings provide the first specific behavioral evidence in support of the hypothesis that neuroactive steroid ALLO-mediated GABAergic modulation is essential for the antipsychotic-like action of olanzapine.

show abstract

Section: Discussionsupporting

confidence: 90%

Role of Neuroactive Steroid Allopregnanolone in Antipsychotic-like Action of Olanzapine in Rodents

Ugale

Hirani

Morelli

et al. 2004

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

“…Furthermore, the urine of both subjects was negative for common drugs of abuse. To explore possible causes of the unusual brain uptake, we plan to examine polymorphisms of the PBR gene including those reported (Kurumaji et al, 2000) and also perform in vitro binding to PBRs located on white blood cells.…”

Section: Nonbindersmentioning

confidence: 99%

Kinetic analysis in healthy humans of a novel positron emission tomography radioligand to image the peripheral benzodiazepine receptor, a potential biomarker for inflammation

et al. 2008

View full text Add to dashboard Cite

The peripheral benzodiazepine receptor (PBR) is upregulated on activated microglia and macrophages and thereby is a useful biomarker of inflammation. We developed a novel PET radioligand, [ 11 C]PBR28, that was able to image and quantify PBRs in healthy monkeys and in a rat model of stroke. The objective of this study was to evaluate the ability of [ 11 C]PBR28 to quantify PBRs in brain of healthy human subjects. Twelve subjects had PET scans of 120 to 180 min duration as well as serial sampling of arterial plasma to measure the concentration of unchanged parent radioligand. One-and two-tissue compartmental analyses were performed. To obtain stable estimates of distribution volume, which is a summation of B max /K D and nondisplaceable activity, 90 min of brain imaging was required. Distribution volumes in human were only ∼5% of those in monkey. This comparatively low amount of receptor binding required a two-rather than a one-compartment model, suggesting that nonspecific binding was a sizeable percentage compared to specific binding. The time-activity curves in two of the twelve subjects appeared as if they had no PBR binding -i.e., rapid peak of uptake and fast washout from brain. The cause(s) of these unusual findings are unknown, but both subjects were also found to lack binding to PBRs in peripheral organs such as lung and kidney. In conclusion, with the exception of those subjects who appeared to have no PBR binding, [ 11 C]PBR28 is a promising ligand to quantify PBRs and localize inflammation associated with increased densities of PBRs.

show abstract

“…We have reported the two missense polymorphisms of the nucleotide sequence in the exon 4, i.e., Ala147Thr and His162Arg [Kurumaji et al, 2000]. Several studies have reported some evidence for linkage between the mood disorders and a genetic marker located on 22q11-q13 [DeteraWadleigh et al, 1999;Edenberg et al, 1997;Lachman et al, 1997].…”

Section: Introductionmentioning

confidence: 97%

No association of two missense variations of the benzodiazepine receptor (peripheral) gene and mood disorders in a Japanese sample

et al. 2001

View full text Add to dashboard Cite

The benzodiazepine receptor (peripheral) (BZRP) plays an important role in the steroid syntheses of the adrenal glands and brain, which is possibly involved in the pathophysiology of mood disorders. We evaluated an association study between two missense variations of the BZRP gene and mood disorders in a Japanese sample. However, no statistically significant associations with either bipolar disorders or depressive disorders were observed in the allele frequencies, genotype counts, or haplotype distributions for the two variations, although the present sample size had a moderate power (0.46-0.86). These results do not suggest that the BZRP gene plays a role in the genetic predisposition of affective disorders.

show abstract

An association study between two missense variations of the benzodiazepine receptor (peripheral) gene and schizophrenia in a Japanese sample

Cited by 22 publications

References 22 publications

Role of Neuroactive Steroid Allopregnanolone in Antipsychotic-like Action of Olanzapine in Rodents

Role of Neuroactive Steroid Allopregnanolone in Antipsychotic-like Action of Olanzapine in Rodents

Kinetic analysis in healthy humans of a novel positron emission tomography radioligand to image the peripheral benzodiazepine receptor, a potential biomarker for inflammation

No association of two missense variations of the benzodiazepine receptor (peripheral) gene and mood disorders in a Japanese sample

Contact Info

Product

Resources

About