Abstract
Monitoring gene expression has been intensively used to identify neurobiological and neuroanatomical substrates associated with administration of antipsychotic drugs. Transcription factors of the Nur family (Nurr1, Nur77, and Nor-1) are orphan nuclear receptors that have been recently associated with dopamine neurotransmission. Nurr1 is involved in midbrain dopamine neuron development. Nur77 and Nor-1 are expressed in dopaminoceptive areas such as the striatum, nucleus accumbens, and prefrontal cortex. To better understand the relationship between Nur and antipsychotic drug effects, we conducted a comprehensive evaluation of the effect of various typical and atypical antipsychotic drugs on the modulation of Nur mRNA levels. We show that differential patterns of Nur expression can be obtained with typical and atypical antipsychotic drugs. Modulation of Nur77 and Nor-1 mRNA expression by antipsychotics can be used to calculate an index that is predictive of the typical or atypical profile of antipsychotic drugs. Inductions of Nur by anti-psychotic drugs are correlated with dopamine D2 receptor in the striatum and D2 and D3 receptor subtypes in the nucleus accumbens. The 5-hydroxytryptamine2A/D2 affinity ratio of antipsychotics can also predict these patterns of inductions. In addition to classical gene patterns induced in the striatal complex (striatum, accumbens) and cortex, most antipsychotic drugs tested strongly induced Nur77, Nor-1, and increased Nurr1 mRNA levels in the substantia nigra and ventral tegmental area. These data suggest that typical and atypical antipsychotic drugs might induce in multiple brain regions distinct Nur-dependent transcriptional activities, which may contribute to their pharmacological effects.
Footnotes
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There is no conflict of interest related to the data presented in this work. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.104.080184.
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ABBREVIATIONS: EPS, extrapyramidal symptom; 5-HT, 5-hydroxytryptamine (serotonin); cRNA, complementary RNA; StDL, dorsolateral striatum; StVL, ventrolateral striatum; AcSh, nucleus accumbens shell; AcC, nucleus accumbens core; StDM, dorsomedial striatum; StVM, ventromedial striatum; mPFC, medial prefrontal cortex; CA1, field CA1 of hippocampus; CA3, field CA3 of hippocampus; DG, dentate gyrus; SN, substantia nigra; VTA, ventral tegmental area; AP-1, activator protein-1; RXR, retinoid X receptor.
- Received November 4, 2004.
- Accepted December 17, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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