Characterization of [3H]clozapine binding sites in rat brain

Kusumi, Ichiro; Matsubara, Shin; Takahashi, Yasuhiro; Ishikane, T.; Koyama, Tsukasa

doi:10.1007/bf01271545

Cited by 11 publications

(8 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It binds to dopaminergic, serotonergic, H1 histaminergic, muscarinic acethylcholine, and α1-and α2-adrenergic receptors (King and Waddington, 2004;Leysen, 2000). Clozapine has relatively low affinity for the D2 receptors in the striatum (Xiberas et al, 2001), while its in vitro affinity for the D4 receptors is much higher than that for D1, D2, D3, and D5 receptors (Coward, 1992;Kusumi et al, 1995). This accounts for the efficacy of clozapine in alleviating the symptoms of schizophrenia without causing extra pyramidal side effects (Farde et al, 1992), because D4 receptor density is high in the frontal cortex and amygdala but relatively low in the basal ganglia (De La Garza and Madras, 2000;Tarazi et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Effect of clozapine on interval timing and working memory for time in the peak-interval procedure with gaps

Buhusi

Meck

2007

Behavioural Processes

View full text Add to dashboard Cite

Previous research indicates that dopamine controls both the speed of an internal clock (Maricq and Church, 1983) and sharing of resources between the timer and other cognitive processes (Buhusi, 2003). For example, dopamine agonist methamphetamine increases the speed of an internal clock and resets timing after a gap, while dopamine antagonist haloperidol decreases the speed of an internal clock and stops timing during a gap (Buhusi and Meck, 2002a). Using a 20-s peak-interval procedure with gaps we examined the acute effects of clozapine (2.0 mg/kg i.p.), which exerts differential effects on dopamine and serotonin in the cortex and striatum, two brain areas involved in interval timing and working memory. Relative to saline, clozapine injections shifted the response functions leftward both in trials with and without gaps, suggesting that clozapine increased the speed of an internal clock and facilitated the maintenance of the pre-gap interval in working memory. These results suggest that clozapine exerts effects in different brain areas in a manner that allows for the pharmacological separation of clock speed and working memory as a function of peak trials without and with gaps.

show abstract

Section: Discussionmentioning

confidence: 99%

Effect of clozapine on interval timing and working memory for time in the peak-interval procedure with gaps

Buhusi

Meck

2007

Behavioural Processes

View full text Add to dashboard Cite

show abstract

“…P450 26B1 and the recently described P450 46B1 are involved in the metabolism of the endogenous substances all-trans retinoic acid and cholesterol, respectively (Bogdanovic et al, 2001;Trofimova-Griffin and Juchau, 2002;Mast et al, 2003). Drugs used in treatment of common neurological and mental diseases (e.g., clozapine, phenytoin, and antidepressants) exhibit specific function in certain brain regions (Kusumi et al, 1995;Riedl et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

mRNA Distribution and Heterologous Expression of Orphan Cytochrome P450 20A1

Stark

Wu²,

Bartleson³

et al. 2008

Drug Metabolism and Disposition

View full text Add to dashboard Cite

ABSTRACT:Cytochrome P450 (P450) 20A1 is one of the so-called "orphan" P450s without assigned biological function. mRNA expression was detected in human liver, and extrahepatic expression was noted in several human brain regions, including substantia nigra, hippocampus, and amygdala, using conventional polymerase chain reaction and RNA dot blot analysis. Adult human liver contained 3-fold higher overall mRNA levels than whole brain, although specific regions (i.e., hippocampus and substantia nigra) exhibited higher mRNA expression levels than liver. Orthologous full-length and truncated transcripts of P450 20A1 were transcribed and sequenced from rat liver, heart, and brain. In rat, the concentrations of full-length transcripts were 3-to 4-fold higher in brain and heart than in liver. In situ hybridization of rat whole brain sections showed an mRNA expression pattern similar to that observed for human P450 20A1, indicating expression in substantia nigra, hippocampus, and amygdala. A number of N-terminal modifications of the codon-optimized human P450 20A1 sequence were prepared and expressed in Escherichia coli, and two of the truncated derivatives showed characteristic P450 spectra (200-280 nmol of P450/ l). Although the recombinant enzyme system oxidized NADPH, no catalytic activity was observed with the heterologously expressed protein when a number of potential steroids and biogenic amines were surveyed as potential substrates. The function of P450 20A1 remains unknown; however, the sites of mRNA expression in human brain and the conservation among species may suggest possible neurophysiological function.P450 monooxygenases catalyze the introduction of oxygen into a vast range of molecules and are known to have diverse functions in endogenous and exogenous metabolism (Ortiz de Montellano, 2005). Cytochromes P450 (P450s) in families 1 to 3 are involved primarily in the metabolism of exogenous compounds, i.e., drugs and environmental pollutants, whereas families 4 to 51 consist of enzymes involved primarily in the bioconversion of endogenous compounds, i.e., steroids, fatty acids, vitamins, and eicosanoids (Guengerich, 2005). To date 57 human P450 (CYP or P450, P450 indicating the nucleotide or protein and CYP indicating the gene in question) genes are known (http://drnelson.utmem.edu/CytochromeP450.html). The P450s can be divided into six major groups based on their main substrates: steroids, vitamins, fatty acids, eicosanoids, xenobiotics, and unknown (Nelson et al., 1996;Guengerich et al., 2005). It is noteworthy, however, that a number of known P450s have assigned substrates in more than one of these groups, and some substrates cannot be assumed to be true physiological substrates based only on their conversion rates (e.g., testosterone 6␤-hydroxylation for hepatic P450 3A4), in the absence of other evidence of function. Although extensive research efforts have been directed to elucidating the endogenous and exogenous functions of individual P450s, one-fourth of the human P450s still have not been assigned ...

show abstract

“…The method for membrane processing and for each receptor binding assay was reported previously (Meltzer et al, 1989;Kusumi et al, 1995). Briefly, the tissue was homogenized in 50mM Tris-HC1 buffer (pH 7.7 at 25~ containing 5mM EDTA using a Polytron (setting 6, 20 sec).…”

Section: Receptor Binding Assaymentioning

confidence: 99%

“…We have previously reported that the D 4 receptor binding sites can be detected in rat frontal cortex by means of a [3H]clozapine binding method (Kusumi et al, 1995). Since no D 4 specific radioligand is presently available, the D 4 receptor component is measured indirectly from displacement experiments using nemonapride.…”

Section: Introductionmentioning

confidence: 99%

Long-term treatment with haloperidol or clozapine does not affect dopamine D4 receptors in rat frontal cortex

Kusumi

Ishikane

Matsubara³

et al. 1995

J. Neural Transmission

Self Cite

View full text Add to dashboard Cite

We examined the effects of long-term treatment with haloperidol and clozapine on dopamine D4 receptors in rat frontal cortex. Dopamine D4 receptor binding sites were indirectly determined from the displacement experiments of [3H]clozapine binding using nemonapride. Three-weeks administration of haloperidol (0.5 mg/kg) or clozapine (10 mg/kg) did not significantly affect the D4 receptors in the frontal cortex. The density of D2 receptors, determined by [3H]spiperone binding to striatum, was increased by long-term treatment with haloperidol, but it was not significantly changed by that with clozapine.

show abstract

Characterization of [3H]clozapine binding sites in rat brain

Cited by 11 publications

References 27 publications

Effect of clozapine on interval timing and working memory for time in the peak-interval procedure with gaps

Effect of clozapine on interval timing and working memory for time in the peak-interval procedure with gaps

mRNA Distribution and Heterologous Expression of Orphan Cytochrome P450 20A1

Long-term treatment with haloperidol or clozapine does not affect dopamine D4 receptors in rat frontal cortex

Contact Info

Product

Resources

About