title: Rescue of dopamine transporter function in hypoinsulinemic rats by a D2 receptor-ERK-dependent mechanism.
abstract: The dopamine (DA) transporter (DAT) is a major target for abused drugs and a key regulator of extracellular DA. A rapidly growing literature implicates insulin as an important regulator of DAT function. We showed previously that amphetamine (AMPH)-evoked DA release is markedly impaired in rats depleted of insulin with the diabetogenic agent streptozotocin (STZ). Similarly, functional magnetic resonance imaging experiments revealed that the blood oxygenation level-dependent signal following acute AMPH administration in STZ-treated rats is reduced. Here, we report that these deficits are restored by repeated, systemic administration of AMPH (1.78 mg/kg, every other day for 8 d). AMPH stimulates DA D(2) receptors indirectly by increasing extracellular DA. Supporting a role for D(2) receptors in mediating this "rescue," the effect was completely blocked by pre-treatment of STZ-treated rats with the D(2) receptor antagonist raclopride before systemic AMPH. D(2) receptors regulate DAT cell surface expression through ERK1/2 signaling. In ex vivo striatal preparations, repeated AMPH injections increased immunoreactivity of phosphorylated ERK1/2 (p-ERK1/2) in STZ-treated but not control rats. These data suggest that repeated exposure to AMPH can rescue, by activating D(2) receptors and p-ERK signaling, deficits in DAT function that result from hypoinsulinemia. Our data confirm the idea that disorders influencing insulin levels and/or signaling, such as diabetes and anorexia, can degrade DAT function and that insulin-independent pathways are present that may be exploited as potential therapeutic targets to restore normal DAT function.
authors.affiliation: Department of Physiology and Pharmacology, The University of Texas Health Science Center, San Antonio, TX 78229, USA.
authors.forename: W Anthony
authors.initials: WA
authors.lastname: Owens
authors.forename: Jason M
authors.initials: JM
authors.lastname: Williams
authors.forename: Christine
authors.initials: C
authors.lastname: Saunders
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: Avison
authors.forename: Aurelio
authors.initials: A
authors.lastname: Galli
authors.forename: Lynette C
authors.initials: LC
authors.lastname: Daws
mesh_terms: D000661:Amphetamine / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000098:blood supply / Q000187:drug effects; D001931:Brain Mapping; D003342:Corpus Striatum / Q000098:blood supply / Q000187:drug effects*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000473:pathology*; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000627:therapeutic use; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007091:Image Processing, Computer-Assisted; D007328:Insulin / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008279:Magnetic Resonance Imaging; D008297:Male; D010100:Oxygen / Q000097:blood; D020891:Raclopride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D017448:Receptors, Dopamine D2; D020891:Raclopride; D000661:Amphetamine; D010100:Oxygen; D004298:Dopamine