Selective α4β2 Nicotinic Acetylcholine Receptor Agonists Target Epigenetic Mechanisms in Cortical GABAergic Neurons
| Autor: | Rosalba Satta, Ekrem Maloku, Adrian Zhubi, Bashkim Kadriu, Alessandro Guidotti, Erbo Dong, Fabio Pibiri |
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| Rok vydání: | 2011 |
| Předmět: |
DNA (Cytosine-5-)-Methyltransferase 1
Epigenomics Male Agonist Nicotine medicine.medical_specialty Methyl-CpG-Binding Protein 2 medicine.drug_class Conditioning Classical Nicotinic Antagonists Mecamylamine Receptors Nicotinic Biology Pharmacology Partial agonist Mice Quinoxalines Internal medicine medicine Animals DNA (Cytosine-5-)-Methyltransferases Nicotinic Agonists RNA Messenger Freezing Reaction Cataleptic Promoter Regions Genetic gamma-Aminobutyric Acid Acetylcholine receptor Cerebral Cortex Neurons Analysis of Variance Behavior Animal Glutamate Decarboxylase Fear Benzazepines Psychiatry and Mental health Nicotinic acetylcholine receptor Nicotinic agonist Endocrinology Gene Expression Regulation Exploratory Behavior Azetidines GABAergic Original Article Cues Varenicline medicine.drug |
| Zdroj: | Neuropsychopharmacology. 36:1366-1374 |
| ISSN: | 1740-634X 0893-133X |
| Popis: | 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 α(4)β(2) and α(7) nAChR agonists on GABAergic epigenetic parameters. Varenicline (VAR), a high-affinity partial agonist at α(4)β(2) and a lower affinity full agonist at α(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 MeCP(2) 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 α(4)β(2) but has negligible affinity for α(3)β(4) or α(7) subtypes containing nAChR. In contrast, PNU-282987, an agonist of the homomeric α(7) nAChR, failed to decrease cortical DNMT1 mRNA or to induce GAD(67) expression. The present study suggests that the α(4)β(2) nAChR agonists may be better suited to control the epigenetic alterations of GABAergic neurons in schizophrenia than the α(7) nAChR agonists. |
| Databáze: | OpenAIRE |
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