Temporally dependent changes in cocaine-induced synaptic plasticity in the nucleus accumbens shell are reversed by D1-like dopamine receptor stimulation - PubMed (original) (raw)

Temporally dependent changes in cocaine-induced synaptic plasticity in the nucleus accumbens shell are reversed by D1-like dopamine receptor stimulation

Pavel I Ortinski et al. Neuropsychopharmacology. 2012 Jun.

Abstract

Dopaminergic and glutamatergic inputs to the nucleus accumbens shell have a central role in reward processing. Non-contingent cocaine administration generates a number of long-term AMPA receptor-dependent changes in synaptic efficacy. However, the synaptic consequences of cocaine self-administration and the potential role of dopamine in these processes remain unclear. Here, we examined the influence of D1 dopamine receptor (D1DR) activation on excitatory synaptic plasticity in the accumbens shell of adult rats following cocaine self-administration. Our results indicated that during the first 2 days following cocaine exposure both pre- and post-synaptic mechanisms contribute to a net decrease in AMPA receptor-mediated signaling. This is reflected by decreased frequency of miniature EPSCs (mEPSCs) attributable to enhanced cannabinoid receptor activity, decreased mEPSC amplitude, and increased paired-pulse ratio of evoked EPSCs. In contrast, the only changes observed in the shell 3-4 weeks following cocaine self-administration were increased mEPSCs amplitudes and AMPA/NMDA ratios. We further found that although these cocaine-induced neuroadaptations during early and late abstinence have different synaptic expression mechanisms, they were normalized by stimulation of D1DRs. Thus, pre-exposure to the D1DR agonist, SKF38393, during the initial period of abstinence increased excitatory synaptic strength, but reduced excitatory signaling after weeks of abstinence. Taken together, these results indicate that the direction of changes in excitatory transmission induced by cocaine self-administration switches over the first few weeks of abstinence. Moreover, D1DRs gate the stability of these cocaine-induced changes at glutamatergic synapses in the accumbens shell by utilizing multiple temporally distinct mechanisms, which has implications for the treatment of cocaine craving and addiction.

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Figures

Figure 1

Figure 1

D1DR stimulation increases the mEPSC amplitude and frequency in cocaine-experienced animals at 1–2 days of abstinence. (a) Left, a schematic of a coronal brain section illustrating the two subdivisions of the nucleus accumbens. Shaded box indicates the area of the shell used for all recordings. Middle, an infrared differential interference contrast image of an MSN in the nucleus accumbens shell (open arrow) with the recording electrode (closed arrow) impaling the cell. Right, a confocal microscope image of an accumbens shell MSN filled with Alexa 568. Scale bars, 25 μm. (b) Left, mEPSC traces from cells in cocaine-experienced and yoked saline animals with and without SKF38393 (10 μM) pre-treatment. Right, same traces normalized to the peak amplitude illustrate differences in mEPSC decay. (c) Cumulative probability distributions indicate reduced mEPSC amplitudes in cells from cocaine-experienced rats relative to yoked saline controls, under basal conditions (ie, without SKF38393 pre-treatment; p<0.05, K–S test). SKF38393 pre-treatment results in a rightward shift of the distribution for cells from the cocaine-experienced, but not yoked saline control group. The inset shows mean mEPSC amplitudes for all groups (_n_=12–17 cells/5–6 animals). **t(28)=2.98, p<0.01 vs yoked controls; #t(32)=2.66, p<0.05 vs cocaine no SKF; Student's _t_-test. (d) Representative traces illustrate effects of SKF38393 pre-treatment on mEPSC frequency. (e) Cumulative probability distributions of mEPSC inter-event intervals show reduced frequency of mEPSCs under basal conditions in cocaine-experienced animals relative to yoked saline controls (p<0.01, K–S test). The mEPSCs frequency deficit is absent following SKF38393 pre-treatment. Inset shows the effect of SKF38393 on mEPSC frequency in all recorded cells (black horizontal lines indicate the mean). Mean (±SEM) frequencies are as follows: yoke 7.8±0.9 Hz; cocaine 4.4±0.7 Hz; yoke SKF 8.7±1.6 Hz; cocaine SKF 10±1.4 Hz. Notice that three cells from the yoke SKF group had very frequent events contributing to the leftward shift of the cumulative probability distribution. **t(30)=2.98, p<0.01 vs yoked controls; ##t(32)=3.64, p<0.01 vs cocaine no SKF; Student's _t_-test.

Figure 2

Figure 2

D1DR stimulation decreases the mEPSC amplitude and does not affect frequency in cocaine-experienced animals at 3–4 weeks of abstinence. (a) Left, mEPSC traces from cells in cocaine-experienced and yoked saline animals with and without SKF38393 (10 μM) pre-treatment. Right, same traces normalized to the peak amplitude for comparison of mEPSC decay. (b) Cumulative probability distributions indicate increased basal mEPSC amplitudes in cells from cocaine-experienced rats relative to yoked saline controls (p<0.01, K–S test). SKF38393 pre-treatment only affects the amplitude distribution in the cocaine-experienced group, shifting it toward smaller mEPSC amplitudes. The inset shows mean mEPSC amplitudes for all groups (_n_=13–20 cells/5–7 animals). *t(35)=2.35, p<0.05 vs yoked controls; #t(33)=2.31, p<0.05 vs cocaine no SKF; Student's _t_-test. (c) Representative traces illustrate the effects of SKF38393 pre-treatment on mEPSC frequency. (d) Cumulative probability distributions of mEPSC inter-event intervals and scatterplots of mEPSC frequencies (inset). Mean (±SEM) frequencies are as follows: yoke 5.1±0.7 Hz; cocaine 6.1±0.9 Hz; yoke SKF 7.2±1.3 Hz; cocaine SKF 6.5±0.8 Hz. There were no differences between any of the groups in either the cumulative inter-event interval distributions or the mean mEPSC frequencies.

Figure 3

Figure 3

Effects of SKF38393 pre-treatment on PPR in early and late abstinence from cocaine self-administration. (a) Sample paired eEPSC comparing the effects of cocaine exposure and SKF38393 incubation on PPRs in early abstinence from cocaine self-administration. Inter-stimulus interval is 100 ms. Stimulus artifacts are omitted. (b) Same as in (a) but in late abstinence. (c) Mean PPRs measured at inter-stimulus intervals (ISIs) of 20–500 ms at 1–2 days of abstinence from cocaine self-administration. There is a significant main effect of treatment (repeated-measures ANOVA, F(3,44)=3.353, _p_=0.027). Post hocs on the main effect of treatment revealed a significant effect of yoke vs cocaine and cocaine vs cocaine SKF groups (*Tukey's HSD post hoc). In all, 11–15 cells from 4 to 5 animals were recorded in each group. (d) Mean paired pulse ratios at 3–4 weeks of abstinence. Differences between groups are not significant (repeated-measures ANOVA, F(3,39)=1.647, _p_=0.194). 10–12 cells from 4 to 5 animals were recorded in each group.

Figure 4

Figure 4

Pre-synaptic effects of cocaine self-administration and D1 agonist pre-treatment in early abstinence involve modulation of CB1 receptor signaling. (a) Bar histograms illustrate an enhanced effect of AM251 on mEPSC frequency in neurons from cocaine-experienced animals at 1–2 days of abstinence from cocaine self-administration. This effect is suppressed following incubation with SKF38393. (b) Same as (a), but at 3–4 weeks of abstinence. In all, 8–11 cells from 4 to 5 animals were recorded in each group. **t(18)=4.33, p<0.01 vs not treated yoke; ##t(17)=4.24, p<0.01 vs not treated cocaine; Student's _t_-tests.

Figure 5

Figure 5

SKF38393 pre-exposure reverses the cocaine-associated changes in AMPA/NMDA ratio. (a, c) Representative average current traces show AMPA (thin traces) and compound, AMPA+NMDA (thick traces) receptor-mediated eEPSCs from yoked saline and cocaine-experienced groups with and without SKF38393 pre-treatment in early (a) and late (c) abstinence. Each trace is an average of 50 individual eEPSCs. For display purposes, AMPA receptor-mediated currents are shown as outward-going. Arrows indicate time-points for measurement of the NMDA component (see Subjects and methods). (b, d) Mean AMPA/NMDA ratios in early (b) and late (d) abstinence from cocaine self-administration. In all, 11–15 cells from 4 to 5 animals were recorded in each of the groups. *t(21)=2.61, p<0.05 vs yoke; #t(24)=2.71, p<0.05 vs not treated cocaine; Student's _t_-test.

Figure 6

Figure 6

In vivo microinjection of SKF38393 rescues mEPSC amplitude and frequency deficits. (a) Sample mEPSC traces from NAc shell MSNs of yoked saline and cocaine animals following an injection of saline (0.5 μl) into the NAc shell of the left hemisphere and SKF38393 (1 μg/0.5 μl) into the NAc shell of the right hemisphere. Microinjections and recordings were performed 24 h following the last self-administration session (see Subjects and methods for details). (b) Decreased mEPSC amplitudes in saline-treated hemispheres are restored to control levels in the SKF38393-treated hemispheres. **t(19)=2.91, p<0.01; #t(20)=2.65, p<0.05, Student's _t_-tests; C, SKF38393 microinjection rescues the reduction in mEPSC frequency. **t(19)=4.31, p<0.001; #t(20)=2.67, p<0.05; Student's _t_-tests; _n_=10–11 cells from four animals.

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