Low and high cocaine locomotor responding male Sprague-Dawley rats differ in rapid cocaine-induced regulation of striatal dopamine transporter function.
Adult outbred Sprague-Dawley rats can be classified as either low or high cocaine responders (LCRs or HCRs, respectively). Importantly, LCRs and HCRs are distinguished by their differential responsiveness to acute cocaine-induced (but not baseline) locomotor activity, inhibition of the dopamine transporter (DAT) and resulting extracellular DA (HCR > LCR), as well as by repeated cocaine-induced locomotor sensitization and measures of cocaine's rewarding and reinforcing effects (LCR > HCR). Curiously, 30 min after acute cocaine HCRs exhibit greater DAT-mediated [(3)H]DA uptake into striatal synaptosomes than LCRs. To investigate this finding further, we measured locomotor activity, striatal [(3)H]DA uptake kinetics and DAT cell surface expression in LCRs and HCRs over an extended period (25-180 min) after a single relatively low-dose of cocaine (10 mg/kg, i.p.). HCRs exhibited the "predicted" locomotor response: a marked initial activation that returned to baseline by 120 min post-injection. While LCRs exhibited a >50% lower maximal locomotor response, this increase was sustained, lasting approximately 33% longer than in HCRs. At 25 min post-cocaine, maximal velocity (V(max)) of [(3)H]DA uptake was significantly higher by 25% in HCRs than LCRs, with no difference in affinity (K(m)). Despite the DAT V(max) difference, however, DAT surface expression did not differ between LCRs and HCRs. There was a similar trend (HCR > LCR) for DAT V(max) at 40 min, but not at 150 or 180 min. These findings suggest that, compared to LCRs, HCRs have an enhanced ability to rapidly up-regulate DAT function in response to acute cocaine, which may contribute to their more "normal" cocaine-induced locomotor activation.
Mandt
Bruce H
BH
University of Colorado Denver, Department of Pharmacology, Aurora, CO 80217, USA. Bruce.Mandt@ucdenver.edu
Zahniser
Nancy R
NR
D000818:Animals; D019921:Biotinylation / Q000379:methods; D003042:Cocaine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D007700:Kinetics; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014316:Tritium / Q000378:metabolism
D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D014316:Tritium; D003042:Cocaine; D004298:Dopamine