Currently, and globally, we are facing the worst epidemic of psychoactive drug abuse resulting in hundreds of thousands of lives annually. Besides alcohol and opioid use and misuse, there has been an increase in illicit abuse of psychostimulants. Epigenetics is a relatively novel area of research that studies heritable alterations in gene expression. Long-term administration of psychoactive drugs may lead to transcriptional changes in brain regions related to drug-seeking behaviors and rewards that can be passed down transgenerationally. Epigenetic biomarkers such as DNA methylation and histone modifications contribute to disease diagnoses. This review aims to look at the epigenetic modifications brought forth by psychoactive drug abuse.

The majority of animal studies on methylphenidate (MP) use intraperitoneal (IP) injections, subcutaneous (SC) injections, or the oral gavage route of administration. While all these methods allow for delivery of MP, it is the oral route that is clinically relevant. IP injections commonly deliver an immediate and maximum dose of MP due to their quick absorption. This quick-localized effect can give timely results but will only display a small window of the psychostimulant’s effects on the animal model. On the opposite side of the spectrum, a SC injection does not accurately represent the pathophysiology of an oral exposure because the metabolic rate of the drug would be much slower. The oral-gavage method, while providing an oral route, possesses some adverse effects such as potential animal injury and can be stressful to the animal compared to voluntary drinking. It is thus important to allow the animal to have free consumption of MP, and drinking it to more accurately mirror human treatment. The use of a two-bottle drinking method allows for this. Rodents typically have a faster metabolism than humans, which means this needs to be considered when administering MP orally while reaching target pharmacokinetic levels in plasma. With this oral two-bottle approach, the pathophysiological effects of MP on development, behavior, neurochemistry and brain function can be studied. The present review summarizes these effects of oral MP which have important implications in medicine.

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