Cocaine but not natural reward self-administration nor passive cocaine infusion produces persistent LTP in the VTA

Neuron. 2008 Jul 31;59(2):288-97. doi: 10.1016/j.neuron.2008.05.024.


Persistent drug-seeking behavior is hypothesized to co-opt the brain's natural reward-motivational system. Although ventral tegmental area (VTA) dopamine (DA) neurons represent a crucial component of this system, the synaptic adaptations underlying natural rewards and drug-related motivation have not been fully elucidated. Here, we show that self-administration of cocaine, but not passive cocaine infusions, produced a persistent potentiation of VTA excitatory synapses, which was still present after 3 months abstinence. Further, enhanced synaptic function in VTA was evident even after 3 weeks of extinction training. Food or sucrose self-administration induced only a transient potentiation of VTA glutamatergic signaling. Our data show that synaptic function in VTA DA neurons is readily but reversibly enhanced by natural reward-seeking behavior, while voluntary cocaine self-administration induced a persistent synaptic enhancement that is resistant to behavioral extinction. Such persistent synaptic potentiation in VTA DA neurons may represent a fundamental cellular phenomenon driving pathological drug-seeking behavior.

Publication types

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

MeSH terms

  • Animals
  • Cocaine / administration & dosage*
  • Conditioning, Operant / drug effects
  • Conditioning, Operant / physiology
  • Infusions, Parenteral
  • Long-Term Potentiation / drug effects*
  • Long-Term Potentiation / physiology
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Reward*
  • Self Administration
  • Ventral Tegmental Area / drug effects*
  • Ventral Tegmental Area / physiology


  • Cocaine