Psychopharmacology (2006) 186: 235–245 DOI 10.1007/s00213-006-0371-x ORIGINAL INVESTIGATION Jennifer L. Perry . Andrew D. Morgan . Justin J. Anker . Nancy K. Dess . Marilyn E. Carroll Escalation of i.v. cocaine self-administration and reinstatement of cocaine-seeking behavior in rats bred for high and low saccharin intake Received: 30 December 2005 / Accepted: 2 March 2006 / Published online: 5 April 2006 # Springer-Verlag 2006 Abstract Rationale: Rats selectively bred for high saccharin (HiS) intake consume more alcohol, acquire intravenous (i.v.) cocaine self-administration more rapidly, and show more dysregulated patterns of cocaine self- administration than their low saccharin-consuming (LoS) counterparts. Objectives: The purpose of the present study was to determine whether HiS and LoS rats also differ in the escalation, maintenance, extinction, and reinstatement of i.v. cocaine self-administration. Materials and methods: Two experiments were con- ducted in separate groups of rats. In the first experiment, HiS and LoS female rats were allowed to self-administer cocaine [0.4 mg/kg; fixed ratio (FR) 1] under short (ShA, 2 h per day) or long (LgA, 12 h per day) access conditions for 21 days. Session lengths were subsequently equated (2 h), and FR1-maintained cocaine self-administration was examined. In the second experiment, additional groups of HiS and LoS female rats were given access to cocaine (0.4 mg/kg; FR 1) self-administration during 2-h sessions for 10 days. Subsequently, saline was substituted for cocaine, and responding was extinguished. After a 14- day extinction period, saline- and cocaine-[5, 10, and 15 mg/kg, intraperitoneal (i.p.)] induced reinstatement of drug-seeking behavior was measured. Results: HiS LgA rats escalated their cocaine intake more rapidly than LoS rats, and during the 2 h sessions after escalation cocaine self-administration was significantly higher in HiS LgA rats, compared to LoS LgA rats. HiS rats responded on the cocaine-paired lever more than LoS rats during mainte- nance, extinction, and cocaine-(15 mg/kg) induced reinstatement. Conclusions: These results suggest that HiS and LoS rats have distinct drug-seeking and drug- taking profiles. The HiS and LoS rats differ along a wide range of behavioral dimensions and represent an im- portant model to study the interactions of excessive intake of dietary substances and vulnerability to drug abuse. Keywords Cocaine . Escalation . Extinction . Genetic . Intravenous . Maintenance . Reinstatement . Selective breeding . Self-administration Introduction Individual differences in the effects of drugs of abuse and/ or vulnerability to self-administer these drugs are well- established in humans and animals (Crabbe 2002; Nestler 2000). In animal models, differences in behavioral reac- tivity have been used as one factor that is related to vulnerability to drug abuse. For example, rats that show high novelty-induced locomotor activity (high responders, HR) acquired intravenous (i.v.) amphetamine (Piazza et al. 1989, 1990) and cocaine (Mantsch et al. 2001; Piazza et al. 1998) self-administration faster than those that show low novelty-induced locomotor activity (low responders, LR). Female HR rats also show greater reinstatement of drug- seeking behavior than female LR rats (Larson and Carroll 2005); however, there were no HR/LR differences in reinstatement of drug-seeking behavior in males (Sutton et al. 2000). The elevated response to novelty and corre- sponding drug self-administration in HR rats has been suggested, in part, to be analogous to high sensation- seeking behaviors in humans (Dellu et al. 1996). While elevated novelty-seeking behavior in rats is generally predictive of increased vulnerability to acquire drug self-administration and reinstate drug-seeking behav- ior after a period of abstinence, it does not consistently predict self-administration performance during steady-state or maintenance phases of drug self-administration (e.g., Carroll and Campbell 2000; Kosten et al. 1997). In contrast to novelty-induced locomotor activity, stress-induced self- grooming behavior has been associated with drug self- J. L. Perry (*) . A. D. Morgan . J. J. Anker . M. E. Carroll Department of Psychiatry, University of Minnesota Medical School, MMC 392, Minneapolis, MN 55455, USA e-mail: perry050@umn.edu Tel.: +1-612-6247813 Fax: +1-612-6248935 N. K. Dess Department of Psychology, Occidental College, 1600 Campus Road, Los Angeles, CA 90041, USA