The potential role of dopamine D₃ receptor neurotransmission in cognition

Eur Neuropsychopharmacol. 2013 Aug;23(8):799-813. doi: 10.1016/j.euroneuro.2013.05.006. Epub 2013 Jun 20.


Currently available treatments have limited pro-cognitive effects for neuropsychiatric disorders, such as schizophrenia, Parkinson's disease and Alzheimer's disease. The primary objective of this work is to review the literature on the role of dopamine D₃ receptors in cognition, and propose dopamine D₃ receptor antagonists as possible cognitive enhancers for neuropsychiatric disorders. A literature search was performed to identify animal and human studies on D₃ receptors and cognition using PubMed, MEDLINE and EMBASE. The search terms included "dopamine D₃ receptor" and "cognition". The literature search identified 164 articles. The results revealed: (1) D₃ receptors are associated with cognitive functioning in both healthy individuals and those with neuropsychiatric disorders; (2) D₃ receptor blockade appears to enhance while D₃ receptor agonism seems to impair cognitive function, including memory, attention, learning, processing speed, social recognition and executive function independent of age; and (3) D₃ receptor antagonists may exert their pro-cognitive effect by enhancing the release of acetylcholine in the prefrontal cortex, disinhibiting the activity of dopamine neurons projecting to the nucleus accumbens or prefrontal cortex, or activating CREB signaling in the hippocampus. These findings suggest that D₃ receptor blockade may enhance cognitive performance in healthy individuals and treat cognitive dysfunction in individuals with a neuropsychiatric disorder. Clinical trials are needed to confirm these effects.

Keywords: Cognition; Dopamine D3 receptor; Dopamine D3 receptor antagonist.

Publication types

  • Review

MeSH terms

  • Animals
  • Cognition Disorders / drug therapy
  • Cognition Disorders / etiology
  • Cognition Disorders / metabolism
  • Cognition* / drug effects
  • Dopamine Antagonists / pharmacology
  • Dopamine Antagonists / therapeutic use
  • Humans
  • Mental Disorders / physiopathology
  • Molecular Targeted Therapy
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / metabolism*
  • Neurons / drug effects
  • Neurons / metabolism*
  • Performance-Enhancing Substances / pharmacology
  • Performance-Enhancing Substances / therapeutic use
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism*
  • Receptors, Dopamine D3 / antagonists & inhibitors
  • Receptors, Dopamine D3 / metabolism*
  • Synaptic Transmission* / drug effects


  • DRD3 protein, human
  • Dopamine Antagonists
  • Nerve Tissue Proteins
  • Performance-Enhancing Substances
  • Receptors, Dopamine D3