The clinical use of methylphenidate (MPH, Ritalin) for treatment of attention-deficit/hyperactivity disorder is widespread, and there is a growing problem of MPH abuse, especially in college-age adults. College students use MPH non-medically, mainly to enhance performance, stay up late to study or to get high. In addition, adults of all ages are using high doses of MPH off-label for energy and cognitive enhancement. The abused dosages of MPH are 2-10 times those recommended for clinical use, however, little is known about the neurobiological effects of chronic exposure to these MPH doses. Our laboratory has recently discovered an unexpected consequence of chronic high-dose MPH treatment in mice. We have found that the behavioral and neurochemical responses to fluoxetine are qualitatively transformed. Fluoxetine is a serotonin (5-HT) transporter inhibitor which normally reduces extracellular nucleus accumbens (NAc) dopamine (DA) levels in control animals and fails to act as a reinforcer. Remarkably, however, we found that following chronic MPH treatment, fluoxetine takes on the characteristics of a psychostimulant drug, exhibiting rewarding effects as well as DA-elevating effects. Given that serotonergic drugs often suppress the reinforcing effects of DA agonists, these and other data suggest the possibility of a fundamental alteration in 5-HT-DA interactions whereby activation of the 5-HT system leads to elevated DA levels in limbic brain areas and activation of reward-related processes. We hypothesize that chronically elevated DA levels causes 5-HT1B receptors in the VTA to become supersensitive and their activation stimulates DA release into the NAc and other DA terminal regions. We hypothesize that this change could specifically increase the reinforcing effects of drugs with strong 5-HT activity such as MDMA, potentially leading to enhanced risk of polydrug abuse in people taking MPH. To explore the impact of chronic MPH treatment in mice on specific interactions between the 5-HT and DA systems, and to explore the neurochemical and behavioral consequences of MPH self-administration in rats, we propose to examine 1) 5-HT alterations in response to i.p. MPH treatment in mice, 2) Sites of 5-HT action, using dual probe microdialysis in mice 3) MPH self-administration in rats 4) 5-HT alterations in response to MPH self-administration.

Public Health Relevance

The prevalence of methylphenidate abuse has been estimated to be 5-26% of college students, and a significant proportion of these users develop problem use and dependence behaviors with other drugs. We have discovered an MPH-induced change in mice wherein 5-HT drugs (or doses) that were neutral or aversive became rewarding and elevated mesolimbic DA levels, and this has led us to postulate that abused drugs with strong 5-HT activity (such as MDMA, fenfluramine, methamphetamine, etc) may elicit greater euphoria/reward and thus have greater abuse/addiction potential in people who have taken MPH at high doses. Additionally, the MPH- induced changes in 5-HT receptors and function may lead to altered psychomotor effects and side effects of primarily 5-HT drugs such as antidepressants, which are commonly prescribed to adults who are exposed to MPH.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Pilotte, Nancy S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Wake Forest University Health Sciences
Schools of Medicine
United States
Zip Code
Calipari, Erin S; Siciliano, Cody A; Zimmer, Benjamin A et al. (2015) Brief intermittent cocaine self-administration and abstinence sensitizes cocaine effects on the dopamine transporter and increases drug seeking. Neuropsychopharmacology 40:728-35
Calipari, Erin S; Ferris, Mark J; Siciliano, Cody A et al. (2014) Intermittent cocaine self-administration produces sensitization of stimulant effects at the dopamine transporter. J Pharmacol Exp Ther 349:192-8
Daigle, Tanya L; Ferris, Mark J; Gainetdinov, Raul R et al. (2014) Selective deletion of GRK2 alters psychostimulant-induced behaviors and dopamine neurotransmission. Neuropsychopharmacology 39:2450-62
Calipari, Erin S; Jones, Sara R (2014) Sensitized nucleus accumbens dopamine terminal responses to methylphenidate and dopamine transporter releasers after intermittent-access self-administration. Neuropharmacology 82:1-10
Siciliano, Cody A; Calipari, Erin S; Ferris, Mark J et al. (2014) Biphasic mechanisms of amphetamine action at the dopamine terminal. J Neurosci 34:5575-82
Siciliano, Cody A; Calipari, Erin S; Jones, Sara R (2014) Amphetamine potency varies with dopamine uptake rate across striatal subregions. J Neurochem 131:348-55
Ferris, Mark J; EspaƱa, Rodrigo A; Locke, Jason L et al. (2014) Dopamine transporters govern diurnal variation in extracellular dopamine tone. Proc Natl Acad Sci U S A 111:E2751-9
Calipari, Erin S; Ferris, Mark J; Jones, Sara R (2014) Extended access of cocaine self-administration results in tolerance to the dopamine-elevating and locomotor-stimulating effects of cocaine. J Neurochem 128:224-32
Espana, Rodrigo A; Jones, Sara R (2013) Presynaptic dopamine modulation by stimulant self-administration. Front Biosci (Schol Ed) 5:261-76
Ferris, Mark J; Calipari, Erin S; Yorgason, Jordan T et al. (2013) Examining the complex regulation and drug-induced plasticity of dopamine release and uptake using voltammetry in brain slices. ACS Chem Neurosci 4:693-703

Showing the most recent 10 out of 16 publications