Perturbation of epigenetic mechanisms, which is likely associated with an overexpression of DNA-methyltransferase 1 (DNMT1)in telencephalic GABAergic neurons of schizophrenia (SZ) patients, participates in the pathophysiology of cognitive disorders.

We hypothesize that tobacco abuse, which is very frequent in SZ patients, may be an attempt to self-medicate cognitive dysfunction by reducing DNMT1 overexpression.

In mice treated with nicotine (4.5mg/kg/sc twice a day for 5 days) and decapitated 2,4,8,12 or 24 hrs after the last dose of nicotine, we counted the number of DNMT1 mRNA- and protein-positive neurons in various brain areas using a two-dimensional counting method.

Mice receiving nicotine exhibited a 30-40% decrease in the number of DNMT1 mRNA- and protein- positive neurons in layers I and II of cingulate, piriform, somatosensory cortices and caudate-putamen. A single dose of nicotine causes only marginal changes in DNMT1 mRNA expression.

The high affinity nicotinic receptor antagonist mecamylamine (2mg/kg/sc twice a day for 5 days)given along with nicotine attenuates the nicotine-induced decrease of DNMT1 mRNA-positive neurons in various brain areas.

We also found that cortical layer I and hippocampal GABAergic neurons include high levels of α4 and α7 nicotinic acetylcholine receptor (nAChR)subunits which can then mediate the action of nicotine on GABAergic interneurons. The observation that repeated injections of nicotine decrease the DNMT1 mRNA and protein expression in telencephalic layer I and II cortical GABAergic neurons suggests that in these neurons, nAChR may have an impact on the epigenetic modulation of chromatin remodeling.