Increased gabaergic input to ventral tegmental area dopaminergic neurons associated with decreased cocaine reinforcement in mu-opioid receptor knockout mice

Neuroscience. 2005;130(2):359-67. doi: 10.1016/j.neuroscience.2004.10.002.


There is general agreement that dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens and prefrontal cortex play a key role in drug reinforcement. The activity of these neurons is strongly modulated by the inhibitory and excitatory input they receive. Activation of mu-opioid receptors, located on GABAergic neurons in the VTA, causes hyperpolarization of these GABAergic neurons, thereby causing a disinhibition of VTA dopaminergic neurons. This effect of mu-opioid receptors upon GABA neurotransmission is a likely mechanism for mu-opioid receptor modulation of drug reinforcement. We studied mu-opioid receptor signaling in relation to cocaine reinforcement in wild-type and mu-opioid receptor knockout mice using a cocaine self-administration paradigm and in vitro electrophysiology. Cocaine self-administration was reduced in mu-opioid receptor knockout mice, suggesting a critical role of mu-opioid receptors in cocaine reinforcement. The frequency of spontaneous inhibitory post-synaptic currents onto dopaminergic neurons in the ventral tegmental area was increased in mu-opioid receptor knockout mice compared with wild-type controls, while the frequency of spontaneous excitatory post-synaptic currents was unaltered. The reduced cocaine self-administration and increased GABAergic input to VTA dopaminergic neurons in mu-opioid receptor knockout mice supports the notion that suppression of GABAergic input onto dopaminergic neurons in the VTA contributes to mu-opioid receptor modulation of cocaine reinforcement.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Afferent Pathways / drug effects
  • Afferent Pathways / metabolism
  • Afferent Pathways / physiopathology
  • Animals
  • Cocaine / pharmacology*
  • Cocaine-Related Disorders / metabolism
  • Cocaine-Related Disorders / physiopathology
  • Disease Models, Animal
  • Dopamine / metabolism
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Mice
  • Mice, Knockout
  • Neural Inhibition / drug effects
  • Neural Inhibition / physiology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Receptors, Opioid, mu / genetics*
  • Reinforcement, Psychology*
  • Self Administration
  • Synapses / drug effects
  • Synapses / metabolism
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology
  • Up-Regulation / drug effects
  • Up-Regulation / physiology
  • Ventral Tegmental Area / drug effects*
  • Ventral Tegmental Area / metabolism
  • Ventral Tegmental Area / physiopathology
  • gamma-Aminobutyric Acid / metabolism*


  • Receptors, Opioid, mu
  • gamma-Aminobutyric Acid
  • Cocaine
  • Dopamine