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Long-term depression in the nucleus accumbens: a neural correlate of behavioral sensitization to cocaine

Abstract

A compelling model of experience-dependent plasticity is the long-lasting sensitization to the locomotor stimulatory effects of drugs of abuse. Adaptations in the nucleus accumbens (NAc), a component of the mesolimbic dopamine system, are thought to contribute to this behavioral change. Here we examine excitatory synaptic transmission in NAc slices prepared from animals displaying sensitization 10–14 days after repeated in vivo cocaine exposure. The ratio of AMPA (α-amino-3-hydroxy-5-methyl-4- isoxazole propionic acid) receptor- to NMDA (N-methyl-d-aspartate) receptor-mediated excitatory postsynaptic currents (EPSCs) was decreased at synapses made by prefrontal cortical afferents onto medium spiny neurons in the shell of the NAc. The amplitude of miniature EPSCs at these synapses also was decreased, as was the magnitude of long-term depression. These data suggest that chronic in vivo administration of cocaine elicits a long-lasting depression of excitatory synaptic transmission in the NAc, a change that may contribute to behavioral sensitization and addiction.

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Figure 1: Behavioral sensitization induced by repeated cocaine administration.
Figure 2: Repeated cocaine administration induces a decrease in the AMPAR/NMDAR ratio of synaptic currents in the shell but not in the core of NAc.
Figure 3: Repeated cocaine had no significant effect on paired-pulse facilitation in either shell or core.
Figure 4: Repeated cocaine administration had no effect on the amplitude or frequency of shell AMPAR mEPSCs.
Figure 5: Repeated cocaine administration did not affect NMDAR mEPSC amplitude or response to NMDA in shell neurons.
Figure 6: Repeated cocaine treatment decreased the amplitude of AMPAR quantal EPSCs in cortical synapses onto NAc shell neurons.
Figure 7: Repeated cocaine treatment decreased the magnitude of LTD in shell neurons.

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Acknowledgements

This work was supported by grants from NIDA (R.M., M.T.) and the State of California for medical research on alcohol and substance abuse through the University of California, San Francisco (A.B.). We thank T. Robinson, S. Nicola and G. Hjelmstad for comments on the paper and D. Saal for help with some experiments.

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Correspondence to Robert C. Malenka.

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Thomas, M., Beurrier, C., Bonci, A. et al. Long-term depression in the nucleus accumbens: a neural correlate of behavioral sensitization to cocaine. Nat Neurosci 4, 1217–1223 (2001). https://doi.org/10.1038/nn757

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