| 1 | Neuropharmacology 2004 Sep 47: 527-37 |
|---|---|
| PMID | 15380371 |
| Title | The atypical antipsychotic drug clozapine enhances chronic PCP-induced regulation of prefrontal cortex 5-HT2A receptors. |
| Abstract | The ability of antipsychotic drugs to affect 5-HT(2A) receptor function has been widely suggested to contribute to their therapeutic properties. We have cOMPared the ability of the antipsychotic drugs clozapine and haloperidol, alone and in combination with chronic phencyclidine (PCP), to modulate 5-HT(2A) receptor binding and mRNA. Acute (i.p. 45 min) and chronic (21-day) clozapine (osmotic minipump (OMP); 20 mg/kg/day) produced widespread decreases in 5-HT(2A) receptor binding (-60%-80%), measured using [(3)H]ketanserin autoradiography. Conversely, 5-HT(2A) mRNA levels, determined using in-situ hybridisation, were modestly increased by chronic clozapine treatment (+10%-30%). Chronic PCP treatment, at a dose (2.58 mg/kg i.p. intermittently for 28 days) that reproduces many of the neurochemical deficits ofschizophrenia降低5 th (2 a)受体结合e prefrontal cortex (PFC; -16%), consistent with the changes in post-mortem brain tissue fromschizophrenic病人。Combined chronic PCP (i.p.) and clozapine (OMP) treatment down-regulated 5-HT(2A) receptor binding in many areas, similar to the effects of clozapine treatment alone and clozapine further enhanced the effects of PCP in the prefrontal cortex. In contrast 5-HT(2A) mRNA was not altered. Haloperidol treatment alone (1 mg/kg/day;OMP) and in combination with PCP (i.p.), generally produced no changes in 5-HT(2A) receptor protein or mRNA. Hence chronic PCP treatment, as employed here, mimics the decreased 5-HT(2A) receptor binding observed in the PFC ofschizophrenic病人。氯氮平的提高自然response of PCP to down-regulate PFC 5-HT(2A) receptors may contribute to it's improved therapeutic profile against negative symptoms and cognitive deficits. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Neuropharmacology 2004 Sep 47: 527-37 |
| PMID | 15380371 |
| Title | The atypical antipsychotic drug clozapine enhances chronic PCP-induced regulation of prefrontal cortex 5-HT2A receptors. |
| Abstract | The ability of antipsychotic drugs to affect 5-HT(2A) receptor function has been widely suggested to contribute to their therapeutic properties. We have cOMPared the ability of the antipsychotic drugs clozapine and haloperidol, alone and in combination with chronic phencyclidine (PCP), to modulate 5-HT(2A) receptor binding and mRNA. Acute (i.p. 45 min) and chronic (21-day) clozapine (osmotic minipump (OMP); 20 mg/kg/day) produced widespread decreases in 5-HT(2A) receptor binding (-60%-80%), measured using [(3)H]ketanserin autoradiography. Conversely, 5-HT(2A) mRNA levels, determined using in-situ hybridisation, were modestly increased by chronic clozapine treatment (+10%-30%). Chronic PCP treatment, at a dose (2.58 mg/kg i.p. intermittently for 28 days) that reproduces many of the neurochemical deficits ofschizophrenia降低5 th (2 a)受体结合e prefrontal cortex (PFC; -16%), consistent with the changes in post-mortem brain tissue fromschizophrenic病人。Combined chronic PCP (i.p.) and clozapine (OMP) treatment down-regulated 5-HT(2A) receptor binding in many areas, similar to the effects of clozapine treatment alone and clozapine further enhanced the effects of PCP in the prefrontal cortex. In contrast 5-HT(2A) mRNA was not altered. Haloperidol treatment alone (1 mg/kg/day;OMP) and in combination with PCP (i.p.), generally produced no changes in 5-HT(2A) receptor protein or mRNA. Hence chronic PCP treatment, as employed here, mimics the decreased 5-HT(2A) receptor binding observed in the PFC ofschizophrenic病人。氯氮平的提高自然response of PCP to down-regulate PFC 5-HT(2A) receptors may contribute to it's improved therapeutic profile against negative symptoms and cognitive deficits. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Schizophr. Res. 2005 Sep 77: 229-39 |
| PMID | 15946825 |
| Title | Characterization of olfactory bulb glomeruli in schizophrenia. |
| Abstract | Olfactory deficits, observed inschizophrenia, may be associated with a disruption of synaptic transmission in the olfactory system. Using immunohistochemistry and optical densitometry, we assessed the integrity of the synaptic connection between olfactory receptor neurons and olfactory bulb target neurons inschizophreniaby cOMParing the level of eight proteins, expressed in the olfactory bulb glomeruli, amongschizophreniaand control subjects. Inschizophrenia, no change was observed in the levels ofOMP, GAP43 and NCAM, proteins expressed by olfactory receptor neurons, suggesting an intact innervation of the olfactory bulb by these neurons. This was supported by the absence of change in calbindin level, which has been shown to decrease after the destruction of the olfactory epithelium. The level of synaptophysin, a pre-synaptic protein, was also unchanged. These findings suggested that axons of olfactory receptor neurons establish synapses with their olfactory bulb targets inschizophrenia. The absence of change in the level of poorly phosphorylated neurofilament of moderate and high molecular weight (NFM/HP) suggested no lack of dendritic innervation despite a previously seen reduction of glomerular MAP2 level inschizophreniasubjects. This and above findings were consistent with the absence of change in the level of beta-tubulin III, a protein expressed by neurons of both olfactory epithelium and bulb. Finally, we noted no significant decrease in trkB level, a neurotrophin receptor involved in the olfactory epithelium maintenance. This study showed no evidence of major structural alteration of the synapse between the olfactory epithelium and bulb inschizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Schizophr. Res. 2013 Nov 150: 366-72 |
| PMID | 24035561 |
| Title | Proteoglycan abnormalities in olfactory epithelium tissue from subjects diagnosed with schizophrenia. |
| Abstract | Emerging evidence points to proteoglycan abnormalities in the pathophysiology ofschizophrenia(SZ). In particular, markedly abnormal expression of chondroitin sulfate proteoglycans (CSPGs), key cOMPonents of the extracellular matrix, was observed in the medial temporal lobe. CSPG functions, including regulation of neuronal differentiation and migration, are highly relevant to the pathophysiology of SZ. CSPGs may exert similar functions in the olfactory epithelium (OE), a continuously regenerating neural tissue that shows cell and molecular abnormalities in SZ. We tested the hypothesis that CSPG expression in OE may be altered in SZ. CSPG-positive cells in postmortem OE from non-psychiatric control (n=9) and SZ (n=10) subjects were counted using cOMPuter-assisted light microscopy. 'Cytoplasmic' CSPG (c-CSPG) labeling was detected in sustentacular cells and some olfactory receptor neurons (c-CSPG+ORNs), while 'pericellular' CSPG (p-CSPG) labeling was found in basal cells and some ORNs (p-CSPG+ORNs). Dual labeling for CSPG and markers for mature and immature ORNs suggests that c-CSPG+ORNs correspond to mature ORNs, and p-CSPG+ORNs to immature ORNs. Previous studies in the same cohort demonstrated that densities of mature ORNs were unaltered (Arnold et al., 2001). In the present study, numerical densities of c-CSPG+ORNs were significantly decreased in SZ (p<0.025; 99.32% decrease), suggesting a reduction of CSPG expression in mature ORNs. Previous studies showed a striking increase in the ratios of immature neurons with respect to basal cells. In this study, we find that the ratio of p-CSPG+ORNs/CSPG+basal cells was significantly increased (p=0.03) in SZ, while numerical density changes of p-CSPG+ORNs (110.71% increase) or CSPG+basal cells (53.71% decrease), did not reach statistical significance. Together, these results indicate that CSPG abnormalities are present in the OE of SZ and specifically point to a reduction of CSPG expression in mature ORNs in SZ. Given the role CSPGs play in OE cell differentiation and axon guidance, we suggest that altered CSPG expression may contribute to ORN lineage dysregulation, and olfactory identification abnormalities, observed in SZ. |
| SCZ Keywords | schizophrenia, schizophrenic |