Appetitive to aversive counter-conditioning as intervention to reduce reinstatement of reward-seeking behavior: the role of the serotonin transporter

Addict Biol. 2019 May;24(3):344-354. doi: 10.1111/adb.12596. Epub 2018 Jan 2.


Counter-conditioning can be a valid strategy to reduce reinstatement of reward-seeking behavior. However, this has not been tested in laboratory animals with extended cocaine-taking backgrounds nor is it well understood, which individual differences may contribute to its effects. Here, we set out to investigate the influence of serotonin transporter (5-HTT) genotype on the effectiveness of counter-conditioning after extended access to cocaine self-administration. To this end, 5-HTT+/+ and 5-HTT-/- rats underwent a touch screen-based approach to test if reward-induced reinstatement of responding to a previously counter-conditioned cue is reduced, compared with a non-counter-conditioned cue, in a within-subject manner. We observed an overall extinction deficit of cocaine-seeking behavior in 5-HTT-/- rats and a resistance to punishment during the counter-conditioning session. Furthermore, we observed a significant decrease in reinstatement to cocaine and sucrose associated cues after counter-conditioning but only in 5-HTT+/+ rats. In short, we conclude that the paradigm we used was able to produce effects of counter-conditioning of sucrose seeking behavior in line with what is described in literature, and we demonstrate that it can be effective even after long-term exposure to cocaine, in a genotype-dependent manner.

Keywords: cocaine; counter-conditioning; reinstatement; serotonin transporter; touch-screen.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Cocaine / pharmacology*
  • Conditioning, Psychological / drug effects*
  • Cues
  • Dopamine Uptake Inhibitors / pharmacology*
  • Extinction, Psychological
  • Rats, Inbred Strains
  • Reinforcement, Psychology
  • Reward*
  • Self Administration
  • Serotonin Plasma Membrane Transport Proteins / genetics*
  • Serotonin Plasma Membrane Transport Proteins / physiology


  • Dopamine Uptake Inhibitors
  • Serotonin Plasma Membrane Transport Proteins
  • Cocaine