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Neuroscience ; 130(2): 359-67, 2005.
Article in English | MEDLINE | ID: mdl-15664692

ABSTRACT

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.


Subject(s)
Cocaine/pharmacology , Neurons/metabolism , Receptors, Opioid, mu/genetics , Reinforcement, Psychology , Ventral Tegmental Area/drug effects , gamma-Aminobutyric Acid/metabolism , Afferent Pathways/drug effects , Afferent Pathways/metabolism , Afferent Pathways/physiopathology , Animals , 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 , Self Administration , Synapses/drug effects , Synapses/metabolism , Synaptic Transmission/drug effects , Synaptic Transmission/physiology , Up-Regulation/drug effects , Up-Regulation/physiology , Ventral Tegmental Area/metabolism , Ventral Tegmental Area/physiopathology
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