title: Serotonin depletion exacerbates changes in striatal gene expression following quinolinic acid injection.
abstract: Controversy exists as to whether serotonin (5-HT) plays a neuroprotective role during brain injury. We sought to determine if prior 5-HT depletion alters gene expression patterns normally associated with NMDA receptor-mediated excitotoxicity of the rodent striatum. Adult male Sprague-Dawley rats were treated systemically with saline or p-chlorophenylalanine (pCPA, 350 mg/kg) to block 5-HT synthesis. After 3 days, these rats received unilateral injection (1 microliter) of quinolinic acid (QA, 40 micrograms in 0.1 M phosphate buffered saline, pH 7.4) or saline vehicle directly into the anterior striatum. All rats were sacrificed 6 or 48 h later. Striatal tissues containing the saline or QA injection site were subjected to Northern analysis of preprotachykinin (PPT), preproenkephalin (PPE), and zif/268 mRNAs, as well as HPLC-EC detection of monoamines. At the time of the intrastriatal injection, 5-HT levels were depleted greater than 95% by pCPA as compared to saline controls. At 48 h post-QA injection, PPT and PPE mRNAs were markedly reduced within the striatal lesion site of saline/QA and pCPA/QA groups with respect to their contralateral uninjected control sides. In the pCPA/QA group, striatal PPE and PPT mRNA levels were further reduced as compared to the saline/QA group with PPE mRNA reductions reaching statistical significance at 95% (ANOVA with Scheffe F-test). Exacerbation of the excitotoxic lesion in the 5-HT depleted rat was further exemplified by a larger increase in zif/268 mRNA measured at 6 h post-intrastriatal injection in the pCPA/QA group as compared to saline/QA animals (P < 0.05 by ANOVA with Scheffe F-test). These results suggest that 5-HT depletion may adversely affect neuronal survival following intrastriatal QA exposure and lend support to the hypothesis that increasing 5-HT levels during NMDA receptor-mediated excitotoxicity may spare neurons destined to degenerate.
authors.affiliation: Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Cummings
authors.forename: P D
authors.initials: PD
authors.lastname: Walker
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004745:Enkephalins / Q000235:genetics; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D010134:Fenclonine / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D008845:Microinjections; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D011498:Protein Precursors / Q000235:genetics; D017378:Quinolinic Acid / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists*; D012701:Serotonin / Q000096:biosynthesis / Q000378:metabolism*; D018490:Serotonin Agents / Q000494:pharmacology; D015320:Tachykinins / Q000235:genetics
chemical_list: D004745:Enkephalins; D018690:Excitatory Amino Acid Agonists; D011498:Protein Precursors; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D018490:Serotonin Agents; D015320:Tachykinins; C044206:preprotachykinin; D012701:Serotonin; C033660:preproenkephalin; D017378:Quinolinic Acid; D010134:Fenclonine