Dual control of dopamine synthesis and release by presynaptic and postsynaptic dopamine D2 receptors.

  • Anzalone A
  • Lizardi-Ortiz J
  • Ramos M
 et al. 
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Dysfunctions of dopaminergic homeostasis leading to either low or high dopamine (DA) levels are causally linked to Parkinson's disease, schizophrenia, and addiction. Major sites of DA synthesis are the mesencephalic neurons originating in the substantia nigra and ventral tegmental area; these structures send major projections to the dorsal striatum (DSt) and nucleus accumbens (NAcc), respectively. DA finely tunes its own synthesis and release by activating DA D2 receptors (D2R). To date, this critical D2R-dependent function was thought to be solely due to activation of D2Rs on dopaminergic neurons (D2 autoreceptors); instead, using site-specific D2R knock-out mice, we uncover that D2 heteroreceptors located on non-DAergic medium spiny neurons participate in the control of DA levels. This D2 heteroreceptor-mediated mechanism is more efficient in the DSt than in NAcc, indicating that D2R signaling differentially regulates mesolimbic- versus nigrostriatal-mediated functions. This study reveals previously unappreciated control of DA signaling, shedding new light on region-specific regulation of DA-mediated effects.

Author-supplied keywords

  • *Dopamine/me [Metabolism]
  • *Neurons/cy [Cytology]
  • *Neurons/ph [Physiology]
  • *Presynaptic Terminals/me [Metabolism]
  • *Receptors, Dopamine D2/me [Metabolism]
  • *Synapses/me [Metabolism]
  • 3,4-Dihydroxyphenylacetic Acid/me [Metabolism]
  • Analysis of Variance
  • Animals
  • Biophysics
  • Chromatography, High Pressure Liquid/mt [Methods]
  • Dopamine Agents/pd [Pharmacology]
  • Dose-Response Relationship, Drug
  • Electric Stimulation/mt [Methods]
  • Electrochemical Techniques
  • Excitatory Postsynaptic Potentials/de [Drug Effect
  • Excitatory Postsynaptic Potentials/ge [Genetics]
  • Homovanillic Acid/me [Metabolism]
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Motor Activity/ge [Genetics]
  • Mutation/ge [Genetics]
  • Neurons/de [Drug Effects]
  • Patch-Clamp Techniques
  • Phosphorylation/de [Drug Effects]
  • Phosphorylation/ge [Genetics]
  • Presynaptic Terminals/de [Drug Effects]
  • Quinpirole/pd [Pharmacology]
  • RNA, Messenger/me [Metabolism]
  • Reaction Time/ge [Genetics]
  • Receptors, Dopamine D2/ge [Genetics]
  • Substantia Nigra/cy [Cytology]
  • Substantia Nigra/de [Drug Effects]
  • Synapses/de [Drug Effects]
  • Tyrosine 3-Monooxygenase/me [Metabolism]
  • Ventral Tegmental Area/cy [Cytology]
  • Ventral Tegmental Area/de [Drug Effects]

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  • Andrea Anzalone

  • Jose E Lizardi-Ortiz

  • Maria Ramos

  • Claudia De Mei

  • F Woodward Hopf

  • Ciro Iaccarino

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