Individual differences in cocaine- and amphetamine-induced activation of male Sprague-Dawley rats: contribution of the dopamine transporter.
Previously we found that outbred male Sprague-Dawley rats can be classified as either low or high cocaine responders (LCRs or HCRs, respectively), based on their open-field locomotor response to acute cocaine (COC; 10 mg/kg, i.p.). Here, we extended this analysis to amphetamine (AMPH; 0.5, 1, and 5 mg/kg, i.p.) and found that the individual differences in behavioral activation were not as pronounced as with COC. This was confirmed with observational analysis of behaviors. Differences in drug-induced activation could involve differential dopamine transporter (DAT) function/trafficking. To address this possibility, we measured [3H]DA uptake into dorsal striatal synaptosomes prepared from rats injected 30 min earlier with saline, COC, or AMPH to determine DAT activity, and radioligand binding to determine the total number of DATs. Striatal [3H]DA uptake in COC-treated HCRs was significantly higher than in LCRs. Furthermore, regardless of LCR/HCR classification, uptake in individual COC-treated rats was significantly correlated with their locomotor behavior in the 30 min after drug administration. In contrast, AMPH-treated rats did not differ in uptake, nor were uptake and locomotor activity correlated. DAT number did not differ between LCRs or HCRs, or between AMPH-treated rats. In addition, when individual differences in COC-induced behavior were no longer detected in LCRs and HCRs 1 week after initial classification, uptake was also similar. Together, these results suggest that a difference in expression of functional DATs on the cell surface contributes to the individual differences observed in COC-induced, but not AMPH-induced, behavioral activation of rats.
Neuroscience Program, Department of Pharmacology, University of Colorado Health Sciences Center, Denver, CO, USA.
Sophia K
SK
Briegleb
Joshua M
JM
Gulley
Brian R
BR
Hoover
Nancy R
NR
Zahniser
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal; D003042:Cocaine / Q000494:pharmacology*; D004298:Dopamine / Q000493:pharmacokinetics; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005106:Exploratory Behavior / Q000187:drug effects; D019416:Head Movements / Q000187:drug effects; D007206:Individuality; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013239:Stereotyped Behavior / Q000187:drug effects; D013574:Synaptosomes / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics
D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493216:Slc6a3 protein, rat; D014316:Tritium; D000661:Amphetamine; D003042:Cocaine; D004298:Dopamine