A modeling study suggesting a possible pharmacological target to mitigate the effects of ethanol on reward-related dopaminergic signaling

J Neurophysiol. 2008 May;99(5):2703-7. doi: 10.1152/jn.00024.2008. Epub 2008 Mar 19.


Midbrain dopaminergic neurons are involved in several critical brain functions controlling goal-directed behaviors, reinforcing/reward processes, and motivation. Their dysfunctions alter dopamine release and contribute to a vast range of neural disorders, from Parkinson's disease to schizophrenia and addictive behaviors. These neurons have thus been a natural target of pharmacological treatments trying to ameliorate the consequences of several neuropathologies. From this point of view, a clear experimental link has been recently established between the increase in the pacemaker frequency of dopaminergic neurons in vitro after acute ethanol application and a particular ionic current (I(h)). The functional consequences in vivo, however, are not clear and they are very difficult to explore experimentally. Here we use a realistic computational model of dopaminergic neurons in vivo to suggest that ethanol, through its effects on I(h), modifies the temporal structure of the spiking activity. The model predicts that the dopamine level may increase much more during bursting than during pacemaking activity, especially in those brain regions with a slow dopamine clearance rate. The results suggest that a selective pharmacological remedy could thus be devised against the rewarding effects of ethanol that are postulated to mediate alcohol abuse and addiction, targeting the specific HCN genes expressed in dopaminergic neurons.

Publication types

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

MeSH terms

  • Animals
  • Central Nervous System Depressants / antagonists & inhibitors*
  • Central Nervous System Depressants / pharmacology*
  • Computer Simulation
  • Cyclic Nucleotide-Gated Cation Channels / physiology
  • Dendrites / physiology
  • Dopamine / physiology*
  • Electrophysiology
  • Ethanol / antagonists & inhibitors*
  • Ethanol / pharmacology*
  • Evoked Potentials / drug effects
  • Evoked Potentials / physiology
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Models, Neurological*
  • Potassium Channels / physiology
  • Rats
  • Reward*
  • Signal Transduction / drug effects*


  • Central Nervous System Depressants
  • Cyclic Nucleotide-Gated Cation Channels
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Potassium Channels
  • Ethanol
  • Dopamine