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Comparative Study
.2007 Jul 25;27(30):7921-8.
doi: 10.1523/JNEUROSCI.1859-07.2007.

Cocaine experience controls bidirectional synaptic plasticity in the nucleus accumbens

Affiliations
Comparative Study

Cocaine experience controls bidirectional synaptic plasticity in the nucleus accumbens

Saïd Kourrich et al. J Neurosci..

Abstract

Plasticity of glutamatergic synapses is a fundamental mechanism through which experience changes neural function to impact future behavior. In animal models of addiction, glutamatergic signaling in the nucleus accumbens (NAc) exerts powerful control over drug-seeking behavior. However, little is known about whether, how or when experience with drugs may trigger synaptic plasticity in this key nucleus. Using whole-cell synaptic physiology in NAc brain slices, we demonstrate that a progression of bidirectional changes in glutamatergic synaptic strength occurs after repeated in vivo exposure to cocaine. During a protracted drug-free period, NAc neurons from cocaine-experienced mice develop a robust potentiation of AMPAR-mediated synaptic transmission. However, a single re-exposure to cocaine during extended withdrawal becomes a potent stimulus for synaptic depression, abruptly reversing the initial potentiation. These enduring modifications in AMPAR-mediated responses and plasticity may provide a neural substrate for disrupted processing of drug-related stimuli in drug-experienced individuals.

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Figures

Figure 1.
Figure 1.
Repeated cocaine administration increases NAc excitatory synaptic strength.A, Experimental timeline.B, Sample EPSCs from saline- (sal) and cocaine-treated (coc) animals. Calibration: 100 ms, 20 pA.C, AMPAR/NMDAR ratio values from neurons in saline- (open circles;n = 8 cells, 5 mice) and cocaine-treated mice (filled circles;n = 7 cells, 6 mice). Hash marks indicate mean values.D, Left, Examples of evoked AMPA-mediated EPSCs at membrane potentials from −80 mV to + 40 mV. Calibration: 50 pA, 20 ms. Right,I–V relationship for AMPAR EPSCs in saline- and cocaine-treated mice (n = 8 cells, 5 mice in each group). The lines represent the linear regression (r = 0.99 for each group). Error bars represent SEM.
Figure 2.
Figure 2.
Repeated cocaine administration increases the amplitude and frequency of AMPAR mEPSCs without changing the paired-pulse ratio.A, Sample traces of mEPSCs from neurons in saline- (sal) and cocaine-treated (coc) groups. Calibration: 100 ms, 20 pA.B, Cumulative probability for mEPSC amplitude (left) and mEPSC interevent interval (right) obtained in saline- (gray line;n = 12 cells, 6 mice) and cocaine-treated mice (black line;n = 7 cells, 4 mice).C, Mean values for mEPSC amplitude and frequency. *p < 0.05.D, Mean paired-pulse ratio values in saline- (n = 10 cells, 6 mice) and cocaine-treated (n = 9 cells, 4 mice) mice are shown for different interstimulus intervals (two-way ANOVA,F(1,68) = 1.907,p > 0.05). Error bars represent SEM.
Figure 3.
Figure 3.
Repeated cocaine administration does not affect synaptic NMDAR function.A, Top, Samples of mEPSCs recorded at −65 mV in zero Mg2+ solution in the absence (top) and presence (bottom) ofd-APV (50 μm) in a cocaine-treated mouse. Calibration: 100 ms, 20 pA. Bottom, Sample averaged traces of mEPSCs obtained in each condition plus the subtracted trace that yielded an average NMDAR mEPSC. Calibration: 10 ms, 2 pA. Bottom right, Mean NMDAR mEPSC amplitude values for individual neurons [n = 5 cells, 4 mice for saline (sal);n = 12 cells, 6 mice for cocaine (coc)]. Hash marks indicate group means.B, Left, Sample traces of NMDAR EPSCs from saline- and cocaine-treated mice (in gray) are shown with a superimposed double exponential curve (in black). Calibration: 500 ms, 20 pA. Right, Weighted decay time constant (τw) values of evoked NMDAR EPSCs from saline- (n = 8 cells, 5 mice) and cocaine-treated (n = 7 cells, 6 mice) mice. Hash marks indicate group means. Error bars represent SEM.
Figure 4.
Figure 4.
Cocaine-induced NAc synaptic potentiation is absent during early withdrawal and does not develop after a single cocaine exposure.A, Timeline for experiments inB.B, Left, Mean AMPAR/NMDAR ratio from naive mice (n = 16 cells, 5 mice), saline-treated mice (sal;n = 18 cells, 5 mice), and cocaine-treated mice (coc;n = 21 cells, 6 mice; ANOVA,F(2,53) = 4.843,p = 0.012; Student–Newman–Keulspost hoc test, *p < 0.05). Right,I–V relationship for AMPAR EPSCs in naive, saline-treated, and cocaine-treated mice. The lines represent the linear regression (r = 0.99 for each group).C, Timeline for experiments inD.D, Left, Mean AMPAR/NMDAR ratio from saline- and cocaine-treated mice (15 mg/kg early withdrawal,n = 6 cells, 4 mice in each group; 40 mg/kg early withdrawal,n = 11 cells, 6 mice for saline andn = 7 cells, 4 mice for cocaine; 40 mg/kg extended withdrawal,n = 11 cells, 5 mice for saline andn = 12 cells, 5 mice for cocaine). Error bars represent SEM.
Figure 5.
Figure 5.
Cocaine exposure history determines whether NAc excitatory synapses exhibit potentiation or depression.A, Experimental timeline.B, Left, Sample EPSCs from naive and cocaine-treated mice. Calibration: 100 ms, 20 pA. Right, Mean AMPAR/NMDAR ratio in naive (n = 6 cells, 3 mice), coc-nochal (coc treatment with no challenge;n = 8 cells, 5 mice), coc-sal (coc treatment with sal challenge;n = 11 cells, 6 mice), and coc-coc (coc treatment with coc challenge;n = 13 cells, 6 mice) groups.#Significantly different from each bar labeled with an asterisk (ANOVA,F(3,29) = 8.167,p = 0.0004; Student–Newman–Keulspost hoc test,p < 0.05).C,I–V relationship for AMPAR EPSCs in coc-nochal/coc-sal and coc-coc mice. Data from coc-nochal and coc-sal have been pooled because there is no significant difference between groups. The lines represent the linear regression (r = 0.99 for each group).D, Summary graph indicating percentage decrease of AMPAR/NMDAR ratio in cocaine-challenged mice relative to saline-challenged controls. Animals that had no previous drug experience (repeated saline;n = 13 cells, 6 mice for saline challenge, andn = 7 cells, 5 mice for cocaine challenge) showed no significant depression. Drug-experienced animals (coc-coc vs coc-sal; normalized to coc-sal) exhibited significant depression. Error bars represent SEM.
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References

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