Activation of D1/5 Dopamine Receptors: A Common Mechanism for Enhancing Extinction of Fear and Reward-Seeking Behaviors

Neuropsychopharmacology. 2016 Jul;41(8):2072-81. doi: 10.1038/npp.2016.5. Epub 2016 Jan 14.


Dopamine is critical for many processes that drive learning and memory, including motivation, prediction error, incentive salience, memory consolidation, and response output. Theories of dopamine's function in these processes have, for the most part, been developed from behavioral approaches that examine learning mechanisms in appetitive tasks. A parallel and growing literature indicates that dopamine signaling is involved in consolidation of memories into stable representations in aversive tasks such as fear conditioning. Relatively little is known about how dopamine may modulate memories that form during extinction, when organisms learn that the relation between previously associated events is severed. We investigated whether fear and reward extinction share common mechanisms that could be enhanced with dopamine D1/5 receptor activation. Pharmacological activation of dopamine D1/5 receptors (with SKF 81297) enhanced extinction of both cued and contextual fear. These effects also occurred in the extinction of cocaine-induced conditioned place preference, suggesting that the observed effects on extinction were not specific to a particular type of procedure (aversive or appetitive). A cAMP/PKA biased D1 agonist (SKF 83959) did not affect fear extinction, whereas a broadly efficacious D1 agonist (SKF 83822) promoted fear extinction. Together, these findings show that dopamine D1/5 receptor activation is a target for the enhancement of fear or reward extinction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / administration & dosage
  • 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / analogs & derivatives
  • Animals
  • Benzazepines / administration & dosage
  • Cocaine / administration & dosage
  • Conditioning, Classical / drug effects
  • Cyclic AMP / metabolism
  • Extinction, Psychological / drug effects
  • Extinction, Psychological / physiology*
  • Fear / drug effects
  • Fear / physiology*
  • Male
  • Mice, Inbred C57BL
  • Receptors, Dopamine D1 / agonists
  • Receptors, Dopamine D1 / physiology*
  • Receptors, Dopamine D5 / agonists
  • Receptors, Dopamine D5 / physiology*
  • Reward*
  • beta-Arrestins / metabolism


  • 3-allyl-6-chloro-7,8-dihydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine
  • Benzazepines
  • Receptors, Dopamine D1
  • beta-Arrestins
  • Receptors, Dopamine D5
  • 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
  • SK&F 81297
  • SK&F 83959
  • Cyclic AMP
  • Cocaine