Enhanced inhibition of synaptic transmission by dopamine in the nucleus accumbens during behavioral sensitization to cocaine

Abstract

Neural adaptations in the nucleus accumbens (NAc), a key component of the mesolimbic dopamine (DA) system, are thought to mediate several of the long-term behavioral sequelas of chronic in vivo exposure to drugs of abuse. Here, we examine whether the modulation of excitatory synaptic transmission by DA in the NAc shell is modified after chronic cocaine exposure that induced behavioral sensitization. The DA-induced inhibition of AMPA receptor-mediated synaptic responses was enhanced in cocaine-treated mice, an effect that was caused by activation of D1-like receptors. DA did not enhance NMDA receptor-mediated synaptic responses in saline- and cocaine-treated mice or in the dorsal striatum of control mice. We hypothesize that the enhanced inhibitory effects of DA on synaptic transmission in the NAc are one of a number of adaptations that contribute to a decrease in excitatory drive to NAc after exposure to drugs of abuse.

Fig. 1.

Repeated cocaine administration induces behavioral sensitization. Mean ± SEM acute locomotor activity in response to saline and cocaine injections is shown. Locomotor activity was monitored for 15 min immediately after each injection.

Fig. 2.

Chronic cocaine treatment enhances inhibitory actions of DA on AMPAR EPSCs. A, Summary graph of the effects of DA (75 μm) in saline (n = 12 cells, 8 mice) and cocaine-treated (n = 12 cells, 9 mice) mice.B, Sample experiments from saline (top) and cocaine-treated (bottom) mice displaying the effect of 20 μm DA. Sample traces were collected at the times indicated on the graph. Calibration: top, 50 msec, 100 pA; bottom, 50 msec, 200 pA.C, Summary graph of the effects of DA (20 μm) in saline (n = 9 cells, 7 mice) and cocaine-treated (n = 10 cells, 5 mice) mice. D, Magnitude of inhibition of AMPAR EPSCs by DA in saline and cocaine-treated mice (*p < 0.05).

Fig. 3.

The DA-induced depression of excitatory synaptic transmission in cocaine-treated mice is mediated by D1-like receptors.A, Summary graph showing effects of DA (20 μm) on field EPSPs in saline (n = 11 slices, 8 mice) and cocaine-treated (n = 28 slices, 20 mice) mice. Sample traces were collected at the times indicated on the graph. Calibration: 4 msec, 0.1 mV. B, Summary of experiments in which DA (20 μm) was applied to slices from cocaine-treated mice first in the absence and then in the presence of SCH-23390 (10 μm; n = 6 slices, 6 mice). fEPSP amplitudes were renormalized when SCH-23390 was applied to minimize possible effects of experimental drift.

Fig. 4.

DA does not potentiate NMDAR EPSCs in either the NAc or dorsal striatum. A1, Example of an experiment in which DA (75 μm) was applied while simultaneously monitoring AMPAR EPSCs and NMDAR EPSCs at +40 mV. Note that application of d-APV (50 μm) had minimal effect on the measurement of the AMPAR EPSC but eliminated the NMDAR EPSC.A2, Top traces show the dual-component EPSC, the AMPAR EPSC obtained after application of d-APV, and the NMDAR EPSC obtained by subtraction of the two traces.Bottom traces show the dual-component EPSC before and after application of DA. Arrows show time points at which measurements were made. Calibration: 50 msec, 100 pA.B, Summary graph of the effects of DA (75 μm) on NMDAR EPSCs and AMPAR EPSCs in saline (n = 8 cells, 5 mice) and cocaine-treated (n = 15 cells, 9 mice) mice. C, Summary graph of the effects of DA (100 μm) on NMDAR EPSCs and AMPAR EPSCs recorded in slices from control mice using perforated-patch recording techniques (n = 5 cells, 4 mice). D, Summary graph of the effects of DA (30–75 μm) on NMDAR EPSCs and AMPAR EPSCs in dorsal striatum slices from control mice (n = 4 cells, 4 mice). E, Mean AMPAR/NMDAR ratio during baseline and at the end of DA application for experiments shown inB–D. In all cases, DA did not affect the AMPAR/NMDAR ratios.