Journal
NEUROPSYCHOPHARMACOLOGY
Volume 36, Issue 7, Pages 1366-1374Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/npp.2011.21
Keywords
schizophrenia; varenicline; DNA methyltransferase-1; GAD(67); A-85380; PNU-282987
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Funding
- NIMH NIH HHS [R01 MH093348, R01 MH070855] Funding Source: Medline
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Nicotine improves cognitive performance and attention in both experimental animals and in human subjects, including patients affected by neuropsychiatric disorders. However, the specific molecular mechanisms underlying nicotine-induced behavioral changes remain unclear. We have recently shown in mice that repeated injections of nicotine, which achieve plasma concentrations comparable to those reported in high cigarette smokers, result in an epigenetically induced increase of glutamic acid decarboxylase 67 (GAD(67)) expression. Here we explored the impact of synthetic alpha(4)beta(2) and alpha(7) nAChR agonists on GABAergic epigenetic parameters. Varenicline (VAR), a high-affinity partial agonist at alpha(4)beta(2) and a lower affinity full agonist at alpha(7) neuronal nAChR, injected in doses of 1-5 mg/kg/s.c. twice daily for 5 days, elicited a 30-40% decrease of cortical DNA methyltransferase (DNMT)1 mRNA and an increased expression of GAD(67) mRNA and protein. This upregulation of GAD(67) was abolished by the nAChR antagonist mecamylamine. Furthermore, the level of MeCP2 binding to GAD(67) promoters was significantly reduced following VAR administration. This effect was abolished when VAR was administered with mecamylamine. Similar effects on cortical DNMT1 and GAD(67) expression were obtained after administration of A-85380, an agonist that binds to alpha(4)beta(2) but has negligible affinity for alpha(3)beta(4) or alpha(7) subtypes containing nAChR. In contrast, PNU-282987, an agonist of the homomeric alpha(7) nAChR, failed to decrease cortical DNMT1 mRNA or to induce GAD(67) expression. The present study suggests that the alpha(4)beta(2) nAChR agonists may be better suited to control the epigenetic alterations of GABAergic neurons in schizophrenia than the alpha(7) nAChR agonists. Neuropsychopharmacology (2011) 36, 1366-1374; doi:10.1038/npp.2011.21; published online 2 March 2011
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