Effects of D1 receptor knockout on fear and reward learning

Neurobiol Learn Mem. 2016 Sep;133:265-273. doi: 10.1016/j.nlm.2016.07.010. Epub 2016 Jul 14.


Dopamine signaling is involved in a variety of neurobiological processes that contribute to learning and memory. D1-like dopamine receptors (including D1 and D5 receptors) are thought to be involved in memory and reward processes, but pharmacological approaches have been limited in their ability to distinguish between D1 and D5 receptors. Here, we examine the effects of a specific knockout of D1 receptors in associative learning tasks involving aversive (shock) or appetitive (cocaine) unconditioned stimuli. We find that D1 knockout mice show similar levels of cued and contextual fear conditioning to WT controls following conditioning protocols involving one, two, or four shocks. D1 knockout mice show increased generalization of fear conditioning and extinction across contexts, revealed as increased freezing to a novel context following conditioning and decreased freezing to an extinguished cue during a contextual renewal test. Further, D1 knockout mice show mild enhancements in extinction following an injection of SKF81297, a D1/D5 receptor agonist, suggesting a role for D5 receptors in extinction enhancements induced by nonspecific pharmacological agonists. Finally, although D1 knockout mice show decreased locomotion induced by cocaine, they are able to form a cocaine-induced conditioned place preference. We discuss these findings in terms of the role of dopamine D1 receptors in general learning and memory processes.

Keywords: Cocaine; D1 receptor; D5 receptor; Dopamine; Extinction; Fear; Learning.

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology*
  • Benzazepines / administration & dosage
  • Benzazepines / pharmacology
  • Cocaine / administration & dosage
  • Cocaine / pharmacology
  • Conditioning, Classical / physiology*
  • Dopamine Agonists / administration & dosage
  • Dopamine Agonists / pharmacology
  • Dopamine Uptake Inhibitors / administration & dosage
  • Dopamine Uptake Inhibitors / pharmacology
  • Extinction, Psychological / physiology*
  • Fear / physiology*
  • Female
  • Generalization, Psychological / physiology*
  • Male
  • Mice
  • Mice, Knockout
  • Receptors, Dopamine D1 / agonists
  • Receptors, Dopamine D1 / physiology*
  • Receptors, Dopamine D5 / agonists
  • Receptors, Dopamine D5 / physiology*
  • Reward*


  • Benzazepines
  • Dopamine Agonists
  • Dopamine Uptake Inhibitors
  • Drd1 protein, mouse
  • Drd5 protein, mouse
  • Receptors, Dopamine D1
  • Receptors, Dopamine D5
  • SK&F 81297
  • Cocaine