Deficits in dopamine clearance and locomotion in hypoinsulinemic rats unmask novel modulation of dopamine transporters by amphetamine.
Insulin affects brain reward pathways and there is converging evidence that this occurs through insulin regulation of the dopamine (DA) transporter (DAT). In rats made hypoinsulinemic by fasting, synaptosomal DA uptake is reduced. Interestingly, [3H]DA uptake is increased in hypoinsulinemic rats with a history of amphetamine self-administration. The possibility that amphetamine and insulin act in concert to regulate DAT activity prompted this study. Here we show that [3H]DA uptake, measured in vitro and clearance of exogenously applied DA in vivo, is significantly reduced in rats made hypoinsulinemic by a single injection of streptozotocin. Strikingly, amphetamine (1.78 mg/kg, given every other day for 8 days) restored DA clearance in streptozotocin-treated rats but was without effect on DA clearance in saline-treated rats. Basal locomotor activity of streptozotocin-treated rats was lower compared to control rats; however, in streptozotocin-treated rats, hyperlocomotion induced by amphetamine increased over successive amphetamine injections. In saline-treated rats the locomotor stimulant effect of amphetamine remained stable across the four amphetamine injections. These results provide exciting new evidence that actions of amphetamine on DA neurotransmission are insulin-dependent and further suggest that exposure to amphetamine may cause long-lasting changes in DAT function.
Department of Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, USA.
W Anthony
WA
Owens
Rajkumar J
RJ
Sevak
Ruggero
R
Galici
Xiaoying
X
Chang
Martin A
MA
Javors
Aurelio
A
Galli
Charles P
CP
France
Lynette C
LC
Daws
D000661:Amphetamine / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000503:physiopathology*; D004298:Dopamine / Q000378:metabolism* / Q000493:pharmacokinetics; D015259:Dopamine Agents / Q000008:administration & dosage / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins; D004334:Drug Administration Schedule; D007328:Insulin / Q000097:blood*; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects*; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D007328:Insulin; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493216:Slc6a3 protein, rat; D000661:Amphetamine; D004298:Dopamine