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Repeated cocaine exposure in vivo facilitates LTP induction in midbrain dopamine neurons

Abstract

Drugs of abuse are known to cause persistent modification of neural circuits, leading to addictive behaviours1,2,3,4,5. Changes in synaptic plasticity in dopamine neurons of the ventral tegmental area (VTA) may contribute to circuit modification induced by many drugs of abuse, including cocaine6,7,8,9,10,11,12,13. Here we report that, following repeated exposure to cocaine in vivo, excitatory synapses to rat VTA dopamine neurons become highly susceptible to the induction of long-term potentiation (LTP) by correlated pre- and postsynaptic activity. This facilitated LTP induction is caused by cocaine-induced reduction of GABAA (γ-aminobutyric acid) receptor-mediated inhibition of these dopamine neurons. In midbrain slices from rats treated with saline or a single dose of cocaine, LTP could not be induced in VTA dopamine neurons unless GABA-mediated inhibition was reduced by bicuculline or picrotoxin. However, LTP became readily inducible in slices from rats treated repeatedly with cocaine; this LTP induction was prevented by enhancing GABA-mediated inhibition using diazepam. Furthermore, repeated cocaine exposure reduced the amplitude of GABA-mediated synaptic currents and increased the probability of spike initiation in VTA dopamine neurons. This cocaine-induced enhancement of synaptic plasticity in the VTA may be important for the formation of drug-associated memory.

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Figure 1: Repeated cocaine exposure facilitates LTP induction in VTA dopamine neurons.
Figure 2: The effect of blocking GABA-mediated inhibition on LTP induction in dopamine neurons.
Figure 3: Effects of cocaine exposure on GABA-mediated inhibition of VTA neurons.
Figure 4: A critical level of GABA-mediated inhibition regulates LTP induction in dopamine neurons.
Figure 5: Comparison of LTP induced by two different protocols and cocaine-induced changes in the AMPA-to-NMDA receptor ratio.

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Acknowledgements

This work was supported by grants from the US National Institutes of Health.

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Correspondence to Qing-song Liu or Mu-ming Poo.

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Supplementary information

Supplementary Figures

This file contains Supplementary Figures S1–S5 and accompanying legends, which show cocaine-induced locomotor sensitization, the idenfication of dopamine neurons, the effect of bicuculline on EPSPs or EPSCs at different membrane potentials and the effect of biccculline and diazepam on IPSCs in VTA dopamine neurons. (DOC 474 kb)

Supplementary Tables

This file contains Supplementary Tables S1 and S2, which show that repeated cocaine exposure has no signifincant effect on passive membrane properties of VTA dopamine neurons, but increases the probability of spike initiation. (DOC 41 kb)

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Liu, Qs., Pu, L. & Poo, Mm. Repeated cocaine exposure in vivo facilitates LTP induction in midbrain dopamine neurons. Nature 437, 1027–1031 (2005). https://doi.org/10.1038/nature04050

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