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1.
Figure 2

Figure 2. From: The Presynaptic Component of the Serotonergic System is Required for Clozapine's Efficacy.

Kinase profiling reveals activity of clozapine only at checkpoint kinase 2 (ChK2). (a) Shown are results from a kinase profile performed with a Caliper microfluidics-based screening platform (part no. 760373) that comprises 20 different purified kinases. Clozapine (10 μM) was tested against all the kinases shown above and data are presented as % inhibition of kinase activity. (b) Dose-response studies with clozapine and the nonspecific kinase inhibitor staurosporine at Chk2. Data represent mean±error of N=3 separate determinations. EC50 values determined using GraphPad Prizm.

Prem N Yadav, et al. Neuropsychopharmacology. 2011 February;36(3):638-651.
2.
Figure 1

Figure 1. From: The Presynaptic Component of the Serotonergic System is Required for Clozapine's Efficacy.

Mining the druggable genome identifies molecular targets for clozapine action. (a) Results from hierarchical clustering analysis of affinities of approved typical and atypical antipsychotic drugs at molecular targets implicated in antipsychotic drug action (Gray and Roth, 2007; Roth et al, 2004). See Supplementary Table 2 for complete data set. Arrow indicates location of node specifying clozapine and olanzapine. (b) Summary results from an interrogation of clozapine, olanzapine, and haloperidol at >300 distinct molecular targets (see Supplementary Table 2 for complete data set).

Prem N Yadav, et al. Neuropsychopharmacology. 2011 February;36(3):638-651.
3.
Figure 4

Figure 4. From: The Presynaptic Component of the Serotonergic System is Required for Clozapine's Efficacy.

5-HT2A receptor is not essential for clozapine's antipsychotic drug actions. (a) Pretreatment (30 min) with clozapine (0.5 mg/kg) significantly blocked PCP (7.0 mg/kg)-induced stereotypy in pet1+/+ mice, but had no significant effect on pet1−/− mice (N=8 per group). However, haloperidol (0.1 mg/kg) significantly attenuated PCP-induced stereotypy in both group of mice. Data are expressed as mean total stereotypy counts in 60 min after PCP administration (±SEM). *p<0.01, two-way ANOVA followed by Bonferroni post test for multiple comparisons. NS, not significant. (b) Clozapine normalizes the PCP induced PPI deficit in 5-HT2A KO mice. Effect of clozapine on PCP (7.0 mg/kg)-induced disruption of prepulse inhibition (PPI) was measured. Clozapine pretreatment (30 min) completely normalized disruption of PPI by PCP in both WT and KO mice (N=8 per group). *p<0.01, two-way ANOVA followed by Bonferroni post test for multiple comparisons.

Prem N Yadav, et al. Neuropsychopharmacology. 2011 February;36(3):638-651.
4.
Figure 6

Figure 6. From: The Presynaptic Component of the Serotonergic System is Required for Clozapine's Efficacy.

Upregulation and supersensitization of postsynaptic 5-HT1A receptors in pet1−/−. (a) Comparison of 5-HT1A expression (Bmax estimates) in cortex, midbrain, and hippocampus. Bmax values were obtained by [3H]-WAY100635 saturation binding, and data are presented as mean±SEM (N=5 to 6 per genotype). *p<0.05, unpaired t-test. (b, c) 5-CT-induced changes in whole-cell current in CA1 pyramidal neurons. (a) Representative chart recordings of current elicited by bath application of 5-CT. All cells were recorded in voltage clamp mode with cells held at −60 mV; length of line above each chart depicts the amount of time the drug was in chamber. (b) Graphical presentation of whole-cell current index are presented from 12 cells per group derived from 6 mice per genotype. (*p<0.05, unpaired t-test.)

Prem N Yadav, et al. Neuropsychopharmacology. 2011 February;36(3):638-651.
5.
Figure 7

Figure 7. From: The Presynaptic Component of the Serotonergic System is Required for Clozapine's Efficacy.

Serotonin neurons are silent in pet1−/− mice. (a, b) MDMA-induced locomotor response is abolished in pet1−/− mice. pet1−/− and pet1+/+ littermate controls were injected with 5 mg/kg (a) or 10 mg/kg (b) MDMA after a 30-min acclimatization and then locomotor activity was measured for the next 90 min. *p<0.05, two-way ANOVA followed by Bonferroni correction for multiple comparisons. (c, d) 5-CT-induced changes in membrane potential recorded from the ventromedial subfield of the dorsal raphe. (c) Representative chart recording (in current clamp mode) of a neuron from pet1+/+ mice showing the hyperpolarization induced by 5-CT (100 nM) bath application. (d) The graph summarizes the findings from all of the recorded cells identified as 5-HT containing in the pet1+/+ mice or as 5-HT precursor neurons by β-galactosidase staining in the slices from pet1−/− mice (N=24 per genotype, *p<0.001, unpaired t-test).

Prem N Yadav, et al. Neuropsychopharmacology. 2011 February;36(3):638-651.
6.
Figure 3

Figure 3. From: The Presynaptic Component of the Serotonergic System is Required for Clozapine's Efficacy.

The presynaptic component of serotonin neuronal system is required for clozapine's therapeutic actions in vivo. (a) Effect of clozapine (C, 0.5 mg/kg or 1.0 mg/kg) on PCP (7.0 mg/kg)-induced disruption of prepulse inhibition (PPI) was measured. In pet1+/+ mice, clozapine pretreatment completely normalized disruption of PPI by PCP at all prepulse levels, whereas it had no effect on pet1−/− mice (N=16/group). (b) Effect of olanzapine (O, 0.5 mg/kg) on PCP (7.0 mg/kg)-induced disruption of PPI was measured. Similar to clozapine, olanzapine also did not exhibit any significant effect on PCP-induced PPI deficit in pet1−/− mice. (c, d) Pretreatment (30 min) with clozapine (0.5 mg/kg) significantly blocked PCP (7.0 mg/kg)-induced hyperactivity in pet1+/+ mice, but had no significant effect on pet1−/− mice (N=14 per group). Data are expressed as mean total horizontal distance traveled in 5-min bins over 60 min after PCP administration (±SEM). (e, f) Haloperidol (Hal, 0.1 mg/kg) significantly attenuated PCP-induced hyperactivity in both genotypes (N=12 per group). Data are expressed as mean total horizontal distance traveled over 60 min in 5-min bins after PCP administration (±SEM). *p<0.05, two-way ANOVA followed by Bonferroni post tests for multiple comparisons.

Prem N Yadav, et al. Neuropsychopharmacology. 2011 February;36(3):638-651.
7.
Figure 5

Figure 5. From: The Presynaptic Component of the Serotonergic System is Required for Clozapine's Efficacy.

Postsynaptic supersensitivity of 5-HT2A receptors following deletion of pet1. (a) Immunoblot of WGA immunoprecipitates from cortex membrane lysate of two representative pet-1−/− and pet1+/+ littermate pairs. The same blots were stripped and probed for transferrin receptor as loading controls. (b) Densitometry of immunoblots of WGA IP from five pairs of WT and pet1−/− mice. (c) Bmax estimates were obtained by performing [3H]-ketanserin saturation binding on DLFC membrane homogenates. Data are presented as mean±SEM (N=5 per group). (d) 5-HT2A receptor (green, top and bottom panels) and MAP2 (red) immunochemistry in coronal sections of a pet1−/− and pet+/+ littermate pair. Middle panel is overlay of 5-HT2A (green), MAP2 (red), and Hoechst (blue) immunostaining to compare the distribution of 5-HT2A receptors between dendrites and cell bodies. (e) Estimates of 5-HT2A receptor abundance by immunofluorescence in layer V and in peripheral layers. 12 regions of interest (ROIs), 200 by 200 pixels, were randomly selected for both layer V and the peripheral layers. The mean intensity was then measured for each ROI and these were averaged for each brain section (N=3 per genotype). (f) 5-HT2A-mediated signaling is potentiated in pet1−/− mice. Representative immunoblot of DOI (5.0 mg/kg, i.p. 15 min)-induced pERK1/2 and total ERK1/2 (as loading control) in microdissected cortical lysates. (g) Densitometry of DOI-induced pERK1/2 immunoblots; data are expressed as % vehicle (veh), N=5 to 6 per group, *p<0.05, one-way ANOVA followed by Neuman–Keuls post hoc analysis for multiple comparisons. (h) DOI (0.5–5.0 mg/kg)-induced head twitches were counted as measure of hallucinogenic activity; data are expressed as mean±SEM (N=6–8 per group, *p<0.05, **p<0.01; unpaired t-test).

Prem N Yadav, et al. Neuropsychopharmacology. 2011 February;36(3):638-651.

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