Reversal of dopamine inhibition of dopaminergic neurons of the ventral tegmental area is mediated by protein kinase C

Neuropsychopharmacology. 2012 Jan;37(2):543-56. doi: 10.1038/npp.2011.222. Epub 2011 Oct 5.


Adaptation of putative dopaminergic (pDA) neurons in the ventral tegmental area (VTA) to drugs of abuse may alter information processing related to reward and reinforcement and is an important factor in the development of addiction. We have demonstrated that prolonged increases in the concentration of dopamine (DA) result in a time-dependent decrease in sensitivity of pDA neurons to DA, which we termed DA inhibition reversal (DIR). In this study, we used extracellular recordings to examine factors mediating DIR. A 40 min administration of DA (2.5-10 μM), but not the DA D2 receptor agonist quinpirole (50-200 nM), resulted in inhibition of neuronal firing followed by DIR. In the presence of 100 nM cocaine, inhibition followed by DIR was seen with much lower DA concentrations. Reversal of quinpirole inhibition could be induced by an activator of protein kinase C, but not of protein kinase A. Inhibitors of protein kinase C or phospholipase C blocked the development of DIR. Disruption of intracellular calcium release also prevented DIR. Reduction of extracellular calcium or inhibition of store-operated calcium entry blocked DIR, but the L-type calcium channel blocker nifedipine did not. DIR was age-dependent and not seen in pDA VTA neurons from rat pups younger than 15 days postnatally. Our data indicate that DIR is mediated by protein kinase C, and implicate a conventional protein kinase C. This characterization of DIR gives insight into the regulation of autoinhibition of pDA VTA neurons, and the resulting long-term alteration in information processing related to reward and reinforcement.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Age Factors
  • Animals
  • Calcium Channel Blockers / administration & dosage
  • Calcium Channel Blockers / pharmacology
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic AMP-Dependent Protein Kinases / physiology
  • Dopamine / administration & dosage
  • Dopamine / pharmacology
  • Dopamine / physiology*
  • Dopamine Agonists / administration & dosage
  • Dopamine Agonists / pharmacology
  • Dopaminergic Neurons / physiology*
  • Dose-Response Relationship, Drug
  • Drug Interactions / physiology
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Microinjections
  • Neural Inhibition / drug effects
  • Neural Inhibition / physiology*
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / physiology*
  • Rats
  • Rats, Inbred F344
  • Type C Phospholipases / antagonists & inhibitors
  • Type C Phospholipases / physiology
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / metabolism
  • Ventral Tegmental Area / physiology*


  • Calcium Channel Blockers
  • Dopamine Agonists
  • Cyclic AMP-Dependent Protein Kinases
  • Protein Kinase C
  • Type C Phospholipases
  • Dopamine