Treatment of schizophrenia (SZ) patients with monoaminergic antagonist drugs (typical or atypical neuroleptics) has an antipsychotic effect, but negative symptoms and cognition are not significantly improved. Hence, there is an urgent need to find new molecular targets for the development of pharmacological agents active on cognitive deficits and negative symptoms. In this regard, nicotine receptor agonists are some of the most promising treatment options currently under investigation (Freedman et al, 2008). Postmortem examination of the brain of SZ patients reveals: a) a decrease of high and low affinity nicotinic acetylcholine receptor (nAChR) subtypes in telencephalic GABAergic neurons, which is possibly alleviated by nicotine abuse, and b) a neuropathology of cortical, hippocampal and striatal GABAergic neurons that includes decreased expression of GAD67, the 67 kDa isoform of the glutamic acid decarboxylase enzyme that synthesizes GABA, and decreased expression of other GABAergic proteins including reelin and the NR2A subunit of the NMDA receptor (Guidotti et al, 2005; Lewis et al, 2005; Lisman et al, 2008; Woo et al, 2004; 2008). Evidence suggests that this GABAergic neuropathology of SZ brain is accompanied by the overexpression of DNA-methyltransferases 1 and 3a (DNMT1 and DNMT3a) in GABAergic neurons (Costa et al, 2007; Ruzicka et al, 2007; Veldic et al, 2005; 2007; Zhubi et al, 2009). DNMTs are the enzymes that catalyze the methylation of the cytosine carbon atom in position 5' of CpG dinucleotides of several gene promoters. To model this neuropathology in mice, we will use offspring of mothers subjected to restraint stress during pregnancy. These mice are characterized by increased levels of DNMT1 and 3a and decreased GAD67. Our preliminary experiments in normal mice (Satta et al, 2008) suggest that nicotine, acting at central nAChRs (1422, 17) present in GABAergic neurons, reduces the expression of DNMT1 and elicits GAD67 promoter demethylation, thereby upregulating the expression of GAD67. Hence, the use of synthetic nAChR ligands to selectively downregulate DNMT in GABAergic neurons may be an innovative attempt to control the downregulation of GAD67 and other genes operative in selected populations of telencephalic GABAergic neurons of SZ patients, while leaving the function of DNMT in cells that do not express nAChRs intact. To be investigated is whether selective 1422 nAChR agonists (A-85380, ABT-594), partial agonists (AMOP-H-OH), or 17 nAChR agonists (PN -282987), partial agonists (GTS-21) or positive allosteric modulators (galantamine) are better suited to downregulate DNMT and upregulate GAD67 expression in telencephalic GABAergic neurons. Thus, the proposed research is aimed at studying the action of nAChR ligands on the epigenetic regulation of GABAergic neurons to better understand the pathogenesis and pharmacological treatment of sensory/cognitive components of SZ, bipolar disorder and other diseases with psychiatric or cholinergic components.
Currently available drug treatments may improve psychotic symptoms but have little effect on cognitive deficits and depression-like symptoms. Postmortem brain of psychotic patients reveals a pathology indicating loss of inhibition due to a complex interaction between genetic coding and epigenetic factors (environmental influences on genes). Nicotine may improve cognitive and mood symptoms because of its epigenetic effects on the inhibitory systems of the brain, and this may be why many patients smoke obsessively. The goal of this research is to identify other drugs that have an epigenetic effect on nicotinic receptors and inhibition in the brain, but that do not have the adverse health consequences associated with tobacco smoking.
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