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Opioids block long-term potentiation of inhibitory synapses

Abstract

Excitatory brain synapses are strengthened or weakened in response to specific patterns of synaptic activation, and these changes in synaptic strength are thought to underlie persistent pathologies such as drug addiction, as well as learning1. In contrast, there are few examples of synaptic plasticity of inhibitory GABA (γ-aminobutyric acid)-releasing synapses. Here we report long-term potentiation of GABAA-mediated synaptic transmission (LTPGABA) onto dopamine neurons of the rat brain ventral tegmental area, a region required for the development of drug addiction. This novel form of LTP is heterosynaptic, requiring postsynaptic NMDA (N-methyl-d-aspartate) receptor activation at glutamate synapses, but resulting from increased GABA release at neighbouring inhibitory nerve terminals. NMDA receptor activation produces nitric oxide, a retrograde signal released from the postsynaptic dopamine neuron. Nitric oxide initiates LTPGABA by activating guanylate cyclase in GABA-releasing nerve terminals. Exposure to morphine both in vitro and in vivo prevents LTPGABA. Whereas brief treatment with morphine in vitro blocks LTPGABA by inhibiting presynaptic glutamate release, in vivo exposure to morphine persistently interrupts signalling from nitric oxide to guanylate cyclase. These neuroadaptations to opioid drugs might contribute to early stages of addiction, and may potentially be exploited therapeutically using drugs targeting GABAA receptors.

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Figure 1: GABAergic synapses on dopamine neurons are potentiated after HFS.
Figure 2: Chelating postsynaptic Ca 2+ or blocking NMDARs prevents LTP GABA , whereas GABA A receptor activation is not required.
Figure 3: LTP GABA requires NO–cGMP signalling.
Figure 4: Opioids block LTP GABA both in vitro and in vivo by distinct mechanisms.

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Acknowledgements

This work was supported by NIH grants to J.A.K. and E.C.P. We are grateful to B. Connors and C. Aizenman for discussions and to J. Downing-Park for technical assistance.

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Correspondence to Julie A. Kauer.

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Nugent, F., Penick, E. & Kauer, J. Opioids block long-term potentiation of inhibitory synapses. Nature 446, 1086–1090 (2007). https://doi.org/10.1038/nature05726

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