Methylphenidate (MPH, Ritalin) is a stimulant commonly prescribed for the treatment of attention- deficit/hyperactivity disorder. Intravenous (i.v.) MPH administration has become increasingly prevalent in recent years, and is an alarming trend given the lack of research on its behavioral and neurobiological consequences (DeSantis et al, 2008;Gautschi &Zellweger, 2006;Shaw et al., 2008;Teter et al., 2006). The subjective effects of MPH are indistinguishable from both cocaine (COC) and amphetamine (AMPH) when administered via the same route (Rosen et al., 1985;Silverman and Ho, 1980;Rush and Baker, 2001). MPH is an AMPH analog that inhibits the dopamine (DA) and norepinephrine transporters, and although MPH is not a substrate for the transporter, it has been shown to release DA at high concentrations (Heal et al, 2009). Thus, MPH possesses DAT interactions that are similar, in part, with other psychostimulants such as COC and AMPH. The studies that have examined the effects of experimenter-delivered MPH on DA neurobiology are inconsistent, and different paradigms can cause different, sometimes opposite, effects. The proposed studies will investigate escalation of MPH intake, a paradigm that models the transition from recreational use to an addictive state. The underlying neurochemical alterations that accompany increases in intake of MPH will be identified in addition to long-term alterations DAT/psychostimulant interactions. This research will then assess the behavioral relevance of these neurochemical alterations by examining the rewarding and reinforcing effects of MPH, COC, and AMPH. Finally, using transgenic DAT over-expressing mice, a hypothesized mechanism for MPH SA-induced increases in psychostimulant neurochemical potency, reinforcing efficacy, and reward will be tested.

Public Health Relevance

The research proposed in this NRSA addresses a major concern for public health, the neurobiological consequences of methylphenidate (MPH) abuse. Many children are prescribed MPH for the treatment of ADHD (Biederman &Faraone, 2006;Kollins et al, 2010), and in addition, 4.8 million people reported abusing the easily attainable psychostimulant in 2008 (SAMHSA, 2008). There are distressingly, numerous reports and case studies documenting intravenous administration of MPH (Gautschi &Zellweger, 2006;Levine et al., 1986;Parran &Jasinski, 1991;Shaw et al., 2008;Teter et al., 2006). The current models of MPH administration do not mimic human use of the compound and thus, little is known about the behavioral and neurobiological consequences of MPH abuse. By studying long access MPH self-administration, a paradigm that models the switch from abuse to addiction in humans, we will be able to determine relevant alterations that occur after extended use of the drug. In addition, by determining the effects of MPH self-administration on the rewarding and reinforcing effects of other psychostimulants, we will be able to identify the patterns that may be most dangerous in producing psychostimulant abuse in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31DA031533-02
Application #
8446692
Study Section
Special Emphasis Panel (ZRG1-F02A-J (20))
Program Officer
Babecki, Beth
Project Start
2012-07-01
Project End
2013-12-29
Budget Start
2013-07-01
Budget End
2013-12-29
Support Year
2
Fiscal Year
2013
Total Cost
$21,055
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Physiology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Salvatore, Michael F; Calipari, Erin S; Jones, Sara R (2016) Regulation of Tyrosine Hydroxylase Expression and Phosphorylation in Dopamine Transporter-Deficient Mice. ACS Chem Neurosci 7:941-51
Siciliano, Cody A; Calipari, Erin S; Yorgason, Jordan T et al. (2016) Increased presynaptic regulation of dopamine neurotransmission in the nucleus accumbens core following chronic ethanol self-administration in female macaques. Psychopharmacology (Berl) 233:1435-43
Siciliano, Cody A; Calipari, Erin S; Yorgason, Jordan T et al. (2016) Chronic ethanol self-administration in macaques shifts dopamine feedback inhibition to predominantly D2 receptors in nucleus accumbens core. Drug Alcohol Depend 158:159-63
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
Siciliano, Cody A; Calipari, Erin S; Cuzon Carlson, Verginia C et al. (2015) Voluntary ethanol intake predicts κ-opioid receptor supersensitivity and regionally distinct dopaminergic adaptations in macaques. J Neurosci 35:5959-68
Sun, H; Calipari, E S; Beveridge, T J R et al. (2015) The brain gene expression profile of dopamine D2/D3 receptors and associated signaling proteins following amphetamine self-administration. Neuroscience 307:253-61
Siciliano, Cody A; Calipari, Erin S; Ferris, Mark J et al. (2015) Adaptations of presynaptic dopamine terminals induced by psychostimulant self-administration. ACS Chem Neurosci 6:27-36
Ferris, Mark J; Calipari, Erin S; Rose, Jamie H et al. (2015) A Single Amphetamine Infusion Reverses Deficits in Dopamine Nerve-Terminal Function Caused by a History of Cocaine Self-Administration. Neuropsychopharmacology 40:1826-36
Calipari, Erin S; Ferris, Mark J; Siciliano, Cody A et al. (2015) Differential influence of dopamine transport rate on the potencies of cocaine, amphetamine, and methylphenidate. ACS Chem Neurosci 6:155-62
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

Showing the most recent 10 out of 26 publications