INTRODUCTIONSubstance dependence is one of the most established physiological states following chronic exposure to an addictive drug. It is characterized by a cluster of physio-behavioral and cognitive phenomena which include the persistent desire or unsuccessful efforts to cut down substance abuse, unrestrained drug taking despite harmful consequences, higher priority given to drug use than to other social, recreational activities and obligations, tolerance to the drug's euphorigenic effects and a physical withdrawal state (International Classification of Diseases (ICD)-10).Measuring the dependence liability of a certain substance is a challenging task as some components of dependence cannot be gauged objectively in the laboratory. Pro-addictive behaviors such as tolerance and withdrawal can be well studied in animal subjects and they have provided us with important information on the effects of drugs on health and longterm consequences of substance use. However, it is diffi cult to measure the cognitive aspect of dependence (such as drug craving, loss of control and persistent drug use), although this is slowly being addressed by recent neuroimaging techniques Repeated administration of addictive drugs causes cellular and molecular changes believed to be the mechanism of pro-addictive behaviors. Neuroadaptations also take place with repeated administration of amphetamine, methylphenidate and atomoxetine, drugs for Attention Defi cit Hyperactivity Disorders (ADHD), and it is speculated that these changes may serve as markers to demonstrate the dependence liability of these therapies. In this review, we enumerate the neuroadaptive changes in molecules associated with neuronal signaling and plasticity, as well as neuronal morphology wrought by repeated administration of ADHD medications. We provide the current perspective on the dependence liability of these therapies, and also suggest of some factors that need to be considered in future investigations, so that what is drawn from animal studies would be better consolidated with those known clinically. (Maganti, 2004). On the other hand, a number of studies have emerged and those investigations center on the molecular and cellular changes in the brain associated with chronic