Methylphenidate and Reward: Functional Role of Neurotransmitters in Relapse Process and Drug-Seeking Behavior

Methylphenidate (MPH) is a stimulant medication used to treat attention-deficit hyperactivity disorder (ADHD) and narcolepsy. However, there is evidence that repeated use of MPH can cause brain damage and long-term effects such as impaired cognitive function, changes in brain’s reward circuit, and addiction. One of the biggest threats to someone treated with MPH, especially among children and adolescents, is the craving that can arise following one of many factors or triggering situations and may be displayed as multiple forms of violence and aggression due to drug-seeking behavior in adulthood. The Ventral Striatum and Orbitofrontal Cortex are known as two important regions involved in dopaminergic signaling, reward network, and appetitive conditioning. MPH increases extracellular levels of dopamine and noradrenaline in striatum and NAc primarily by inhibiting the reuptake of these catecholamines by their respective transporters. Self-administration of MPH enhances reward-seeking behaviors and also increases motivation to administer amphetamine. Release of dopamine following MPH injection by activating common signal transduction pathways may modify learning-related molecular changes. Although the dopaminergic system plays an important role in rewarding and MPH-induced relapse, other neurotransmitter systems such as serotonin, adenosine, endocannabinoids, orexins, galanin, glutamate, GABA, acetylcholine, and histamine are involved in modulating the rewarding effects. In this chapter, we discuss our recent research from the MPH conditioned place preference (CPP) test in rodents and monkeys showing its long-lasting rewarding drug effects. Moreover, we present possible reward pathways, changes in neurotransmitters signaling intensity, intracellular signaling, and ultimately, mechanism and regions involved in drug reward and relapse. The inference from the literature mentioned in this review is that regions involved in central representations of predictive reward are a subset of those that really participate in associative learning.