Lymnaea stagnalis provides an excellent model system for studying memory because these snails have a well-described set of neurons, a single one of which controls expression of long-term memory of operantly-conditioned respiratory behavior. We have shown that several different manipulations, including pre-training exposure to serotonin (5-HT) or methamphetamine (Meth), submersion of snails after training to prevent memory interference, and exposure to effluent from predatory crayfish (CE), enhances memory persistence. Changes in DNA methylation underlie formation of strong memories in mammals and 5-HT-enhanced long-term facilitation in Aplysia. Here we determined the impact of the DNMT inhibitor, 5-aza-2′ deoxycytidine (5-AZA, 87 µM), on enhanced memory persistence by all four manipulations. We found that 5-HT (100 µM) enhanced memory persistence, which was blocked by 5-AZA pretreatment. Snails pre-exposed to 3.3 µM Meth 4 hr prior to training demonstrated memory 72 hr later, which was not present in controls. This memory-enhancing effect was blocked by pretreatment with 87 µM 5-AZA. Similarly, submersion to prevent interference learning as well as training in CE produced memory that was not present in controls, and these effects were blocked by pretreatment with 87 µM 5-AZA. In contrast, 5-AZA injection did not alter expression of normal (non-enhanced) memory, suggesting that these four stimuli enhance memory persistence by increasing DNA methyltransferase (DNMT) activity, which, in turn, increases expression of memory enhancing genes and/or inhibits memory suppressor genes. These studies lay important groundwork for delineating gene methylation changes that are common to persistent memory produced by different stimuli.