Dynamics of nuclear receptor target gene regulation

Ligand-regulated nuclear receptors, such as estrogen receptors, glucocorticoid receptor, vitamin D receptor, and peroxisome proliferator-activated receptors, belong to the most widely studied and best understood transcription factors. Therefore, the dynamic nature of transcriptional regulation was observed first with different members of the nuclear receptor superfamily, but is now also extended to other transcription factors, such as nuclear factor κB. Dynamic and in part cyclical processes were observed on the level of translocation into the nucleus, association with genomic binding sites, exchange of co-regulators and chromatin modifiers, occurrence of chromatin marks, and activities of RNA polymerase II resulting in mRNA synthesis. In this review, we summarize recent findings on the dynamic regulation of nuclear receptor target genes in the chromatin context

Effects of Nicotine in the Dopaminergic System of Mice Lacking the Alpha4 Subunit of Neuronal Nicotinic Acetylcholine

The mesostriatal dopaminergic system influences locomotor activity and the reinforcing properties of many drugs of abuse including nicotine. Here we investigate the role of the a4 nicotinic acetylcholine receptor (nAChR) subunit in mediating the effects of nicotine in the mesolimbic dopamine system in mice lacking the a4 subunit. We show that there are two distinct populations of receptors in the substantia nigra and striatum by using autoradiographic labelling with I a-conotoxin MII. These receptors are comprised of the a4, b2 and a6 nAChR subunits and non-a4, b2, and a6 nAChR subunits. Non-a4 subunit-containing nAChRs are located on dopaminergic neurons, are functional and respond to nicotine as demonstrated by patch clamp recordings. In vivo microdialysis performed in awake, freely moving mice reveal that mutant mice have basal striatal dopamine levels which are twice as high as those observed in wild-type mice. Despite the fact that both wild-type and a4 null mutant mice show a similar increase in dopamine release in response to intrastriatal KCl perfusion, a nicotine-elicited increase in dopamine levels is not observed in mutant mice. Locomotor activity experiments show that there is no difference between wild-type and mutant mice in basal activity in both habituated and nonhabituated environments. Interestingly, mutant mice sustain an increase in cocaine-elicited locomotor activity longer than wild-type mice. In addition, mutant mice recover from depressant locomotor activity in response to nicotine at a faster rate. Our results indicate that a4-containing nAChRs exert a tonic control on striatal basal dopamine release, which is mediated by a heterogeneous population of nAChRs