Cocaine Disinhibits Dopamine Neurons by Potentiation of GABA Transmission in the Ventral Tegmental Area

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Science  27 Sep 2013:
Vol. 341, Issue 6153, pp. 1521-1525
DOI: 10.1126/science.1237059

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Drugs, Dopamine, and Disinhibition

Drugs often change the neuronal circuitry in the brain and thereby cause a long-lasting change in behavior. Using a wide range of in vivo and in vitro techniques in mice, Bocklisch et al. (p. 1521) observed that cocaine profoundly altered dopamine neuron function and that drug-evoked synaptic plasticity in a specific set of neurons represents a crucial step in circuit remodeling.


Drug-evoked synaptic plasticity in the mesolimbic system reshapes circuit function and drives drug-adaptive behavior. Much research has focused on excitatory transmission in the ventral tegmental area (VTA) and the nucleus accumbens (NAc). How drug-evoked synaptic plasticity of inhibitory transmission affects circuit adaptations remains unknown. We found that medium spiny neurons expressing dopamine (DA) receptor type 1 (D1R-MSNs) of the NAc project to the VTA, strongly preferring the GABA neurons of the VTA. Repeated in vivo exposure to cocaine evoked synaptic potentiation at this synapse, occluding homosynaptic inhibitory long-term potentiation. The activity of the VTA GABA neurons was thus reduced and DA neurons were disinhibited. Cocaine-evoked potentiation of GABA release from D1R-MSNs affected drug-adaptive behavior, which identifies these neurons as a promising target for novel addiction treatments.

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