Journal
BIOCHEMICAL PHARMACOLOGY
Volume 86, Issue 2, Pages 309-316Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2013.04.013
Keywords
Addiction; Attention deficit/hyperactivity disorder; Cocaine; Dopamine transporter function; Methylphenidate; Spontaneously hypertensive rat
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Funding
- National Institute of Health [R01 DA011716]
- Kentucky Opportunity Fellowship
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Attention deficit/hyperactivity disorder (ADHD) is attributed to dysfunction of the prefrontal cortex. Methylphenidate, an inhibitor of dopamine and norepinephrine transporters (DAT and NET, respectively), is a standard treatment for ADHD. The Spontaneously Hypertensive Rat (SHR) is a well-established animal model of ADHD. Our previous results showed that methylphenidate treatment in adolescent SHR enhanced cocaine self-administration during adulthood, and alterations in DAT function in prefrontal cortex play a role in this response. Importantly, prefrontal cortex subregions, orbitofrontal cortex (OFC) and medial prefrontal cortex (mPFC), have been shown to have distinct roles in ADHD and cocaine self-administration. In the current study, SHR, Wistar Kyoto (WKY) and Wistar (WIS) rats received a therapeutically relevant dose of methylphenidate (1.5 mg/kg, p.o.) or vehicle during adolescence and then OFC and mPFC DAT function and cellular expression were assessed during adulthood. In both OFC and mPFC, no strain differences in V-max or K-m for dopamine uptake into synaptosomes were found between vehicle-treated SHR, WKY and WIS. Methylphenidate increased DAT V-max in SHR mPFC and decreased DAT V-max in WKY OFC. Also, methylphenidate decreased DAT K-m in WIS OFC. Further, methylphenidate did not alter DAT cellular localization, indicating that methylphenidate treatment during adolescence regulated DAT function in SHR mPFC in a trafficking-independent manner. Thus, the increase in mPFC DAT function was an SHR-specific long term consequence of methylphenidate treatment during adolescence, which may be responsible for the treatment-induced alterations in behavior including the observed increases in cocaine self-administration. (C) 2013 Elsevier Inc. All rights reserved.
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