title: Rats classified as low or high cocaine locomotor responders: a unique model involving striatal dopamine transporters that predicts cocaine addiction-like behaviors.
abstract: Individual differences are a hallmark of drug addiction. Here, we describe a rat model based on differential initial responsiveness to low dose cocaine. Despite similar brain cocaine levels, individual outbred Sprague-Dawley rats exhibit markedly different magnitudes of acute cocaine-induced locomotor activity and, thereby, can be classified as low or high cocaine responders (LCRs or HCRs). LCRs and HCRs differ in drug-induced, but not novelty-associated, hyperactivity. LCRs have higher basal numbers of striatal dopamine transporters (DATs) than HCRs and exhibit marginal cocaine inhibition of in vivo DAT activity and cocaine-induced increases in extracellular DA. Importantly, lower initial cocaine response predicts greater locomotor sensitization, conditioned place preference and greater motivation to self-administer cocaine following low dose acquisition. Further, outbred Long-Evans rats classified as LCRs, versus HCRs, are more sensitive to cocaine's discriminative stimulus effects. Overall, results to date with the LCR/HCR model underscore the contribution of striatal DATs to individual differences in initial cocaine responsiveness and the value of assessing the influence of initial drug response on subsequent expression of addiction-like behaviors.
authors.affiliation: Department of Pharmacology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States. Electronic address: dorothy.yamamoto@ucdenver.edu.
authors.forename: Dorothy J
authors.initials: DJ
authors.lastname: Yamamoto
authors.forename: Anna M
authors.initials: AM
authors.lastname: Nelson
authors.forename: Bruce H
authors.initials: BH
authors.lastname: Mandt
authors.forename: Gaynor A
authors.initials: GA
authors.lastname: Larson
authors.forename: Jacki M
authors.initials: JM
authors.lastname: Rorabaugh
authors.forename: Christopher M C
authors.initials: CM
authors.lastname: Ng
authors.forename: Kelsey M
authors.initials: KM
authors.lastname: Barcomb
authors.forename: Toni L
authors.initials: TL
authors.lastname: Richards
authors.forename: Richard M
authors.initials: RM
authors.lastname: Allen
authors.forename: Nancy R
authors.initials: NR
authors.lastname: Zahniser
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects*; D051381:Rats
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D003042:Cocaine
keywords: Cocaine conditioned place preference; Cocaine self-administration; Cocaine sensitization; Dopamine clearance; Dopamine transporter; Dopamine uptake; Drug discrimination; Individual differences to cocaine; Locomotor activity; NMDAR phosphorylation