Regional specificity in the real-time development of phasic dopamine transmission patterns during acquisition of a cue-cocaine association in rats

Abstract

Drug seeking is significantly regulated by drug-associated cues and associative learning between environmental cues and cocaine reward is mediated by dopamine transmission within the nucleus accumbens (NAc). However, dopamine transmission during early acquisition of a cue-cocaine association has never been assessed because of the technical difficulties associated with resolving cue-evoked and cocaine-evoked dopamine release within the same conditioning trial. Here, we used fast-scan cyclic voltammetry to measure sub-second fluctuations in dopamine concentration within the NAc core and shell during the initial acquisition of a cue-cocaine Pavlovian association. Within the NAc core, cue-evoked dopamine release developed during conditioning. However, within the NAc shell, the predictive cue appeared to cause an unconditioned decrease in dopamine concentration. The pharmacological effects of cocaine also differed between sub-regions, as cocaine increased phasic dopamine release events within the NAc shell but not the core. Thus, real-time measurements not only revealed the initial development of a conditioned neurochemical response but also demonstrated differential phasic dopamine transmission patterns across NAc sub-regions during the acquisition of a cue-cocaine association.

Figure 1

Representative [DA] traces reveal region-specific phasic dopamine communication during the acquisition of a cue-cocaine association. Probe placements (one placement per rat) and individual [DA] traces early or late within the conditioning session. A) Measurements were made in the NAc core (blue; n = 5) or the NAc shell (orange; n = 5). B) [DA] trace from the NAc core during the first conditioning block (trial 7) C) and during the last conditioning block (trial 25). D) [DA] trace from the NAc shell during the first conditioning block (trial 5) E) and during the last conditioning block (trial 28).

Figure 2

Real-time dopamine transmission patterns during early acquisition of a cue-cocaine association. A and C) Mean change in [DA] is represented as change in color during the 90 s sampling window (x-axis) for each conditioning trial (y-axis). The i.v. cocaine infusion (3 s) is represented by the dark grey box and the predictive cue (20 s) is represented by the light grey box. B and D) Quantification of [DA] within the NAc core and shell during cue-cocaine association. Trial numbers are indicated on the figure and dopamine concentrations were binned in 2.5 s intervals. A) Within the NAc core (n = 5), cue-evoked dopamine release is increased across conditioning trials. Cocaine-evoked increases in [DA] were present early in the conditioning session but inconsistent thereafter. B) Within the NAc core (blue; n = 5), [DA] was not altered during the first conditioning block (trials 1 to 10) by either cue presentation or cocaine infusions. However, during the second (trials 11 to 20) and third conditioning blocks (trial 21 to 30), [DA] was significantly increased during cue presentation with dark blue bars indicating a significant increase over the the pre-cue/infusion baseline (i.e. the first four bins) (p < 0.05). C) Within the NAc shell (n = 5), [DA] is lowest during cue presentation and the cue-evoked attenuation in [DA] was present from the onset of the conditioning session. Cocaine robustly increased [DA] at later time points consistent with its known pharmacokinetics. Cocaine-evoked dopamine release continued following multiple drug infusions and [DA] levels were highest toward the end of the session. D) Within the NAc shell (light orange; n = 5), [DA] was significantly decreased (indicated by white bars) during cue presentation during all conditioning blocks. In the final conditioning block (trials 21 to 30) [DA] was significantly increased (dark orange) over the pre-cue/infusion baseline (p < 0.05) (beginning 20 s after drug infusion). B and D) error bars equal standard error from the mean.

Figure 3

Transient probability within the NAc core and shell during early acquisition of a cue-cocaine association. A and B) The presence or absence of dopamine transients during 2.5 s bins across the conditioning trials was used to determine transient probability. A) Within the NAc core, the probability of all dopamine transients is coded in light blue and the probability of transients greater than 100 nM is coded in grey. During the first conditioning block (trials 1 to 10) transient probability was not altered by the predictive cue or cocaine infusion. However, during the middle and last conditioning blocks, the probability of all dopamine transients was significantly increased (dark blue) and the probability of transients over 100 nM was also significantly increased (yellow) during the first bin of cue onset compared to the pre-cue/infusion baseline. B) Within the NAc shell, the probability of all dopamine transients is coded as orange and the probability of transients greater than 100 nM is coded as grey. For all conditioning blocks, neither the predictive cue nor cocaine infusion significantly altered the probability of dopamine transients if transients of all concentration were assessed. However, cocaine significantly increased the probability of transients over 100 nM in the final conditioning block (trials 21 to 30) relative to the pre-cue/infusion baseline (indicated by yellow bars). A and B) Significance level was p < 0.05; error bars equal standard error from the mean.

Figure 4

Discrete cues predictive of sucrose delivery decrease [DA] within the NAc shell during the first session in a Pavlovian conditioning paradigm. A, B, C, and D) Black box indicates onset and duration of the predictive cue and the white box indicates onset and duration of computer controlled intra-oral sucrose delivery by an infusion pump. A) Mean [DA] across all 30 conditioning trials (solid line) and mean plus standard error (dashed line). B) Mean [DA] averaged into 2 s bins for statistical analysis across all 30 trials. C) Mean [DA] across the first 10 conditioning trials (solid line) and mean plus standard error (dashed line). D) Mean [DA] averaged into 2 s bins for statistical analysis across the first 10 trials. B and D) Yellow box indicate significant difference at p < 0.05; error bars indicate standard error from the mean.

Figure 5

Sub-region differences in dopamine transmission patterns. and Pavlovian approach behavior. Mean (solid lines) and mean plus standard error (dashed lines) for 100 ms fluctuations in [DA] from the NAc core (blue) and NAc shell (orange). Change in [DA] from the final conditioning block (trials 21 to 30). For each 90 s collection window, the lowest current value during the 10 s pre-cue/infusion baseline period was the point chosen for background subtraction