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Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons

Abstract

How do drugs of abuse modify neural circuitry and thereby lead to addictive behaviour? As for many forms of experience-dependent plasticity, modifications in glutamatergic synaptic transmission have been suggested to be particularly important1,2,3,4. Evidence of such changes in response to in vivo administration of drugs of abuse is lacking, however. Here we show that a single in vivo exposure to cocaine induces long-term potentiation of AMPA (α-amino-3-hydroxy-5-methyl-isoxazole propionic acid)-receptor-mediated currents at excitatory synapses onto dopamine cells in the ventral tegmental area. Potentiation is still observed 5 but not 10 days after cocaine exposure and is blocked when an NMDA (N-methyl-d-aspartate) receptor antagonist is administered with cocaine. Furthermore, long-term potentiation at these synapses is occluded and long-term depression is enhanced by in vivo cocaine exposure. These results show that a prominent form of synaptic plasticity can be elicited by a single in vivo exposure to cocaine and therefore may be involved in the early stages of the development of drug addiction.

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Figure 1: A single exposure to cocaine induced an increase in the AMPAR/NMDAR ratio of glutamatergic synaptic currents in VTA dopamine cells.
Figure 2: Cocaine exposure had no effect on paired-pulse modulation but increased mEPSC frequency and mEPSC amplitude.
Figure 3: Cocaine exposure caused a larger response to AMPA but not NMDA and did not change the total amount of AMPAR subunits.
Figure 4: Cocaine-induced increase in AMPAR/NMDAR ratio in the VTA lasted for 5 but not 10 days after injection and did not occur in the hippocampus or in GABA neurons in the VTA.
Figure 5: Cocaine-induced potentiation was blocked by the NMDAR antagonist MK-801, occluded LTP and enhanced LTD.

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Acknowledgements

We thank S. Nicola and H. Fields for comments on this manuscript, members of the Bonci and Malenka labs for discussions, and J. Kim for help with injections. This work was supported by funds provided by the State of California for medical research on alcohol and substance abuse through the University of California, San Francisco (A.B. and J.L.W) and by grants from the NIH (R.C.M.).

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Correspondence to Antonello Bonci.

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Ungless, M., Whistler, J., Malenka, R. et al. Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons. Nature 411, 583–587 (2001). https://doi.org/10.1038/35079077

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