The mechanisms by which antipsychotics (neuroleptics) produce their therapeutic effects in schizophrenia are largely unknown. Although neuroleptic efficacy is attributed to central dopamine D2 and/or serotonin 5-HT2 receptor antagonism, clinical improvements in schizophrenia are not seen until two or three weeks after daily neuroleptic administration. The mechanisms underlying the neuroleptic response must therefore occur downstream from initial receptor blockade and be a consequence of chronic neurotransmitter receptor blockade. The goal of the present study was to use neuroleptics with varied dopamine vs. serotonergic receptor blocking profiles to elucidate some of these intracellular post receptor mechanisms. Since the final steps of both dopamine and serotonin synthesis require the enzyme aromatic L-amino acid decarboxylase (AADC), the effects of neuroleptics on AADC gene (mRNA) expression were examined in PC12 cells and compared to their effects on the synthetic enzyme tyrosine hydroxylase (TH) and ' c-fos' (an early immediate gene [IEG]) mRNA. The neuroleptics examined did not significantly regulate AADC mRNA in PC12 cells, and only haloperidol upregulated TH and 'c-fos' mRNA. Later studies in rats showed that acute neuroleptic administration increased ' c-fos' mRNA, whereas the immunoreactivity of a related IEG (delta FosB) was increased upon chronic treatment. These studies and a subsequent dose response study demonstrated that upregulation of both 'c-fos' mRNA and delta FosB immunoreactivity was most prominent in dopaminergic projection areas including the striatum and nucleus accumbens. Because it has been suggested that neuroleptic treatment might prevent neurodegeneration in schizophrenia, the effects of neuroleptics on the mRNA expression of neuroprotective target genes of delta FosB were examined both ' in vivo' and 'in vitro'. These genes included brain-derived neurotrophic factor (BDNF), the neuroprotective enzyme superoxide dismutase (SOD), and the low affinity nerve growth factor receptor (p75). While dopamine D2 blockade unfavorably regulated BDNF and p75 mRNA, 5-HT 2 blockade either had no effect on or favorably regulated BDNF, SOD, and p75 mRNA. Thus, although little about the contribution of serotonergic blockade in the neuroleptic response was determined, dopaminergic blockade regulated IEG's and several of their target genes. Future studies will be needed to understand the role of 5-HT2 receptor blockade in the neuroleptic response.
| Identifer | oai:union.ndltd.org:USASK/oai:usask.ca:etd-10212004-002450 |
| Date | 01 January 2000 |
| Creators | Chlan-Fourney, Jennifer |
| Contributors | Li, Xin-Min, Juorio, Augusto V. |
| Publisher | University of Saskatchewan |
| Source Sets | University of Saskatchewan Library |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://library.usask.ca/theses/available/etd-10212004-002450 |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Saskatchewan or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
Page generated in 0.0023 seconds