D2 dopamine receptor regulation of learning, sleep and plasticity

Eur Neuropsychopharmacol. 2015 Apr;25(4):493-504. doi: 10.1016/j.euroneuro.2015.01.011. Epub 2015 Jan 24.


Dopamine and sleep have been independently linked with hippocampus-dependent learning. Since D2 dopaminergic transmission is required for the occurrence of rapid-eye-movement (REM) sleep, it is possible that dopamine affects learning by way of changes in post-acquisition REM sleep. To investigate this hypothesis, we first assessed whether D2 dopaminergic modulation in mice affects novel object preference, a hippocampus-dependent task. Animals trained in the dark period, when sleep is reduced, did not improve significantly in performance when tested 24h after training. In contrast, animals trained in the sleep-rich light period showed significant learning after 24h. When injected with the D2 inverse agonist haloperidol immediately after the exploration of novel objects, animals trained in the light period showed reduced novelty preference upon retesting 24h later. Next we investigated whether haloperidol affected the protein levels of plasticity factors shown to be up-regulated in an experience-dependent manner during REM sleep. Haloperidol decreased post-exploration hippocampal protein levels at 3h, 6h and 12h for phosphorylated Ca(2+)/calmodulin-dependent protein kinase II, at 6h for Zif-268; and at 12h for the brain-derived neurotrophic factor. Electrophysiological and kinematic recordings showed a significant decrease in the amount of REM sleep following haloperidol injection, while slow-wave sleep remained unaltered. Importantly, REM sleep decrease across animals was strongly correlated with deficits in novelty preference (Rho=0.56, p=0.012). Altogether, the results suggest that the dopaminergic regulation of REM sleep affects learning by modulating post-training levels of calcium-dependent plasticity factors.

Keywords: BDNF; CaMKII; Haloperidol; Object recognition; REM sleep; Zif-268.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomechanical Phenomena
  • Brain-Derived Neurotrophic Factor / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Dark Adaptation / drug effects
  • Dark Adaptation / physiology
  • Dopamine D2 Receptor Antagonists / pharmacology
  • Early Growth Response Protein 1 / metabolism
  • Electric Stimulation
  • Exploratory Behavior / drug effects
  • Exploratory Behavior / physiology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Haloperidol / pharmacology
  • Hippocampus / drug effects
  • Learning / drug effects
  • Learning / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Multivariate Analysis
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology*
  • Receptors, Dopamine D2 / metabolism*
  • Sleep / drug effects
  • Sleep / physiology*
  • Time Factors


  • Brain-Derived Neurotrophic Factor
  • Dopamine D2 Receptor Antagonists
  • Early Growth Response Protein 1
  • Egr1 protein, mouse
  • Receptors, Dopamine D2
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Haloperidol