Nicotine potentiation of excitatory inputs to ventral tegmental area dopamine neurons

J Neurosci. 2011 May 4;31(18):6710-20. doi: 10.1523/JNEUROSCI.5671-10.2011.


Drug-induced changes in synaptic strength are hypothesized to contribute to appetitive behavior and addiction. Nicotine, the major addictive substance in tobacco, activates nicotinic receptors (nAChRs) to initiate a series of adaptive changes at the cellular and circuit levels in brain, particularly the ventral tegmental area (VTA). Our laboratory previously reported that nicotine facilitates induction of long-term potentiation (LTP) in VTA dopamine (DA) neurons by increasing glutamate release via activation of α7 nAChRs on the glutamate terminals, suggesting a critical presynaptic contribution of nicotine in LTP induction. In the present study, we used an in vitro exposure paradigm to study the effect of nicotine on excitatory synaptic strength. Brief exposure of nicotine to brain slices from drug-naive adult rats followed by a period of recovery resulted in an NMDA receptor (NMDAR)-dependent increase of AMPA receptor/NMDAR ratio in VTA DA neurons, which is consistent with the induction of LTP. These effects are similar to that induced by a single in vivo nicotine injection intraperitoneally. The induction of synaptic potentiation required excitation of DA neurons mediated by somatodendritic α4β2 nAChRs, as well as enhancement of NMDAR function via D(5) dopamine receptors, also on DA neurons. Nicotine-induced increase of presynaptic glutamate release also contributed to the induction of synaptic plasticity, likely through increased activation of NMDAR. These results identified important receptor systems involved in nicotine-induced long-term changes in excitatory synaptic input to VTA DA neurons. The data also revealed remarkable similarity in the mechanisms underlying synaptic plasticity induced by nicotine and cocaine in the VTA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Analysis of Variance
  • Animals
  • Dopamine / metabolism*
  • Electrophysiology
  • Immunohistochemistry
  • Long-Term Potentiation / drug effects*
  • Long-Term Potentiation / physiology
  • Male
  • Neurons / drug effects*
  • Neurons / metabolism
  • Nicotine / pharmacology*
  • Nicotinic Agonists / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, AMPA / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Receptors, Nicotinic / metabolism
  • Synapses / drug effects
  • Synapses / physiology
  • Ventral Tegmental Area / drug effects*
  • Ventral Tegmental Area / physiology


  • Nicotinic Agonists
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Nicotinic
  • Nicotine
  • Dopamine