Selective decreases in amphetamine self-administration and regulation of dopamine transporter function in diabetic rats.
The dopamine transporter (DAT) regulates extracellular dopamine DA levels and is an important site of action for amphetamine and cocaine. Amphetamine and cocaine increase extracellular levels of DA by acting on the DAT; thus, variations in DAT binding sites or activity might influence the action of some drugs of abuse. It was hypothesized that streptozotocin-induced diabetes decreases amphetamine self-administration and that this behavioral change is accompanied by changes in DAT function. Separate groups of male rats responded to receive either amphetamine (0.03 mg/kg/infusion), cocaine (0.25 mg/kg/infusion), or food before and for 7 days after receiving streptozotocin. Rats were sacrificed and [(3)H]DA uptake and [(3)H]WIN 35,428 binding were measured in the striatum. In a second study, rats could self-administer one of several different doses of amphetamine (0.01-0.178 mg/kg/infusion) before and after receiving streptozotocin. In streptozotocin-treated rats, a marked decrease in staining for insulin in pancreatic sections was paralleled by a more than doubling in blood glucose levels. Streptozotocin significantly decreased the number of amphetamine infusions without changing the number of cocaine infusions or food pellets received. Streptozotocin increased DA uptake (V(max)) 1.6- or 2.4-fold in rats that responded for food or amphetamine and increased 3-fold the K(m) for DA only in rats that responded for food; however, [(3)H]WIN 35,428 binding was not changed in any rat. In the second study, streptozotocin only decreased amphetamine self-administration thereby supporting the view that streptozotocin does not simply decrease the potency of amphetamine. These results demonstrate a selective decrease in amphetamine self-administration in diabetic rats that was associated with increased DAT function in the striatum. Collectively, these studies suggest that insulin pathways in the brain may play an important role in regulating DAT activity and amphetamine action.
Galici
Ruggero
R
Department of Pharmacology, The University of Texas Health Science Center, San Antonio, Tex 78229, USA.
Galli
Aurelio
A
Jones
David J
DJ
Sanchez
Teresa A
TA
Saunders
Christine
C
Frazer
Alan
A
Gould
Georgianna G
GG
Lin
Richard Z
RZ
France
Charles P
CP
D000661:Amphetamine / Q000008:administration & dosage*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003042:Cocaine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004298:Dopamine / Q000493:pharmacokinetics*; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004435:Eating / Q000502:physiology; D007328:Insulin / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000032:analysis*; D017072:Neostriatum / Q000378:metabolism*; D009419:Nerve Tissue Proteins; D020799:Pancrelipase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012646:Self Administration; D013311:Streptozocin / Q000494:pharmacology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D001786:Blood Glucose; D050483:Dopamine Plasma Membrane Transport Proteins; D007328:Insulin; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493216:Slc6a3 protein, rat; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D020799:Pancrelipase; D013311:Streptozocin; D000661:Amphetamine; D003042:Cocaine; D004298:Dopamine