Relapse induced by cues predicting cocaine depends on rapid, transient synaptic potentiation

Abstract

Cocaine addiction is characterized by long-lasting vulnerability to relapse arising because neutral environmental stimuli become associated with drug use and then act as cues that induce relapse. It is not known how cues elicit cocaine seeking, and why cocaine seeking is more difficult to regulate than seeking a natural reward. We found that cocaine-associated cues initiate cocaine seeking by inducing a rapid, transient increase in dendritic spine size and synaptic strength in the nucleus accumbens. These changes required neural activity in the prefrontal cortex. This is not the case when identical cues were associated with obtaining sucrose, which did not elicit changes in spine size or synaptic strength. The marked cue-induced synaptic changes in the accumbens were correlated with the intensity of cocaine, but not sucrose seeking, and may explain the difficulty addicts experience in managing relapse to cocaine use.

Figure 1. Cue-induced cocaine-seeking rapidly enlarges spine head diameter in NAcore MSNs

(A) Cue-induced reinstatement of cocaine-seeking increased active lever pressing over the 15, 45, or 120 min prior to euthanizing rats for morphological or A/N measurements (F_(7,92)=39.93, P< 0.0001). (B) Time course of active lever pressing during the cue reinstatement session. (C) Sample dendrites from NAcore MSNs in yoked saline (d_h= 0.329 μm) or cocaine-trained rats at T=0 (0.422 μm), T=15 (0.528 μm) min after initiating cue-induced reinstatement. (D) Cumulative distribution of spine head diameter reveals changes in d_h between treatment groups (group: F_(5,1698)= 8769, P< 0.0001; d_h F_(4,1698)= 115.2, P< 0.0001; interaction: F_(20,1698)= 21, P< 0.0001). (E) Cocaine self-administration increased d_h (F_(6,326)= 43.98, P< 0.0001). Spine d_h was elevated at T=15, decreased below pre-reinstatement levels at T=45, and returned to pre-reinstatement levels at T=120. (F) The increase in d_h at 15 min was significantly correlated with active lever pressing. N in panel D is the number of rats, and N shown as the number in bars corresponds to either number of animals (panel A) or the number of neurons quantified (panel E). Five to 12 neurons were measured from each rat. Data are shown as mean ± SEM. *p< 0.05, compared to yoked saline or extinction lever presses, #p< 0.05, compared to T=0 cocaine.

Figure 2. Sucrose trained rats to not show increased spine head diameter during cue-induced reinstatement

(A,B) Sucrose-trained rats show significant cue-induced reinstatement (F_(3,31)= 86.981, P< 0.001). (C) Sucrose reinstatement was not accompanied by a change in d_h. N is the number in bars and corresponds to either number of animals (panel A) or the number of neurons quantified (panel C). Five to 12 neurons were measured from each rat. Data are shown as mean ± SEM. *p< 0.05, compared to yoked saline or extinction lever presses.

Figure 3. Synaptic potentiation initiated by cue-induced cocaine seeking

(A) Sample AMPA and NMDA current traces from each group. (B) AMPA to NMDA ratios (A/N) were significantly elevated in animals withdrawn with extinction training from cocaine self-administration (1.423 ± 0.075) compared to yoked saline animals (1.064 ± 0.050). In addition, the initiation of cue-induced reinstatement further elevated A/N at T=15 (1.780 ± 0.060). Ratios remained elevated at T=45 (1.815 ± 0.122), and returned to pre-reinstatement levels by T=120 (1.538 ± 0.103) (F_(4,101)= 14.45, P< 0.001). (C) The increase in A/N at 15 min was significantly correlated with the number of active lever presses. (D) Cue-induced reinstatement of sucrose seeking did not alter A/N. Two to five neurons were recorded from each animal. Data are shown as mean ± SEM. *p< 0.05 compared to yoked saline animals at T=0 (white bar); #p< 0.01 compared to T=0 (black bar).

Figure 4. Inactivation of the PL prevents cue-induced reinstatement and the increase in d_h and A/N in NAcore

(A) B/M infusions into PL inhibited cue-induced reinstatement (T=15; F_(5,59)= 11.971, P< 0.001; N is shown in bars). (B) Sample dendrites of animals receiving either aCSF or B/M into PL prior to initiating cue-induced reinstatement and sacrificed 15 min later. (C,D) B/M into PL inhibited the mean increase in d_h (t₍₈₂₎= 7.504, P< 0.001; see inset) and shifted the cumulative distribution to the left. (E) B/M into PL inhibited the increase in A/N (t₍₁₇₎= 2.554, P= 0.021). Data are shown as mean ± SEM. *p< 0.05, comparing aCSF to B/M