Rat strain differences in nicotine self-administration using an unlimited access paradigm

Brain Res. 2002 Mar 15;930(1-2):12-20. doi: 10.1016/s0006-8993(01)03375-3.


An effective animal model for elucidating the neurobiological basis of human smoking should simulate important aspects of this behavior. Therefore, a 23 h unlimited access nicotine self-administration model was used to compare inbred Lewis rats, which have a propensity to self-administer drugs of abuse, to inbred Fisher 344 rats and to the outbred Holtzman strain. Using this unlimited access model, 88.8% of Lewis vs. 57.1% of Holtzman rats achieved maintenance self-administration at a fixed ratio 1 (FR 1) at 0.03 mg/kg IV nicotine (P<0.05). In contrast, Fisher rats did not acquire self-administration under these conditions. Of the Lewis and Holtzman rats that achieved maintenance self-administration on an FR 1 schedule, a greater percentage of Lewis rats acquired nicotine self-administration at FR 2 (P<0.05) and progressed to FR 4 (P<0.05). Using naïve cohorts in a progressive dose reduction study, 83.3% of Lewis rats achieved maintenance at 0.0075 mg/kg nicotine as compared to 31.8% of Holtzman rats (P<0.05). Furthermore, only Lewis rats showed differences in active vs. inactive bar presses during maintenance at sequential dose reductions (P<0.001). Thus, in this unlimited access model, inbred Lewis rats will more reliably acquire nicotine self-administration than outbred Holtzman rats. Moreover, Lewis rats showed a significantly higher likelihood of continuing to self-administer nicotine in face of both increasing work requirements and decreasing drug reinforcement. Therefore, it is likely that Lewis rats would be genetically susceptible to nicotine addiction.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cholinergic Agents / pharmacology*
  • Conditioning, Operant / drug effects
  • Dose-Response Relationship, Drug
  • Male
  • Nicotine / pharmacology*
  • Rats
  • Rats, Inbred F344
  • Rats, Inbred Lew
  • Reinforcement Schedule
  • Self Administration
  • Species Specificity


  • Cholinergic Agents
  • Nicotine