Role of Dopamine 2 Receptor in Impaired Drug-Cue Extinction in Adolescent Rats

Cereb Cortex. 2016 Jun;26(6):2895-904. doi: 10.1093/cercor/bhw051. Epub 2016 Mar 5.


Adolescent drug users display resistance to treatment such as cue exposure therapy (CET), as well as increased liability to relapse. The basis of CET is extinction learning, which involves dopamine signaling in the medial prefrontal cortex (mPFC). This system undergoes dramatic alterations during adolescence. Therefore, we investigated extinction of a cocaine-associated cue in adolescent and adult rats. While cocaine self-administration and lever-alone extinction were not different between the two ages, we observed that cue extinction reduced cue-induced reinstatement in adult but not adolescent rats. Infusion of the selective dopamine 2 receptor (D2R)-like agonist quinpirole into the infralimbic cortex (IL) of the mPFC prior to cue extinction significantly reduced cue-induced reinstatement in adolescents. This effect was replicated by acute systemic treatment with the atypical antipsychotic aripiprazole (Abilify), a partial D2R-like agonist. These data suggest that adolescents may be more susceptible to relapse due to a deficit in cue extinction learning, and highlight the significance of D2R signaling in the IL for cue extinction during adolescence. These findings inspire new tactics for improving adolescent CET, with aripiprazole representing an exciting potential pharmacological adjunct for behavioral therapy.

Keywords: adolescence; aripiprazole; dopamine; extinction; infralimbic cortex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipsychotic Agents / pharmacology
  • Aripiprazole / pharmacology
  • Cocaine / administration & dosage
  • Cocaine-Related Disorders / drug therapy
  • Cocaine-Related Disorders / metabolism*
  • Cues
  • Disease Models, Animal
  • Dopamine Agonists / pharmacology
  • Dopamine Uptake Inhibitors / administration & dosage
  • Extinction, Psychological / drug effects
  • Extinction, Psychological / physiology*
  • Learning / drug effects
  • Learning / physiology
  • Male
  • Motivation / drug effects
  • Motivation / physiology
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / growth & development*
  • Prefrontal Cortex / metabolism*
  • Quinpirole / pharmacology
  • Random Allocation
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D2 / agonists
  • Receptors, Dopamine D2 / metabolism*
  • Self Administration


  • Antipsychotic Agents
  • DRD2 protein, rat
  • Dopamine Agonists
  • Dopamine Uptake Inhibitors
  • Receptors, Dopamine D2
  • Quinpirole
  • Aripiprazole
  • Cocaine