title: Adolescence methylphenidate treatment in a rodent model of attention deficit/hyperactivity disorder: dopamine transporter function and cellular distribution in adulthood.
abstract: 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 (1.5mg/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 Vmax or Km for dopamine uptake into synaptosomes were found between vehicle-treated SHR, WKY and WIS. Methylphenidate increased DAT Vmax in SHR mPFC and decreased DAT Vmax in WKY OFC. Also, methylphenidate decreased DAT Km 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.
authors.affiliation: Department of Pharmaceutical Sciences, 789 South Limestone, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Sucharita S
authors.initials: SS
authors.lastname: Somkuwar
authors.forename: Mahesh
authors.initials: M
authors.lastname: Darna
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Kantak
authors.forename: Linda P
authors.initials: LP
authors.lastname: Dwoskin
mesh_terms: D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy*; D000697:Central Nervous System Stimulants / Q000627:therapeutic use*; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000502:physiology*; D008297:Male; D008774:Methylphenidate / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
chemical_list: D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D008774:Methylphenidate