Accelerated development of cocaine-associated dopamine transients and cocaine use vulnerability following traumatic stress

Abstract

Post-traumatic stress disorder and cocaine use disorder are highly co-morbid psychiatric conditions. The onset of post-traumatic stress disorder generally occurs prior to the development of cocaine use disorder, and thus it appears that the development of post-traumatic stress disorder drives cocaine use vulnerability. We recently characterized a rat model of post-traumatic stress disorder with segregation of rats as susceptible and resilient based on anxiety-like behavior in the elevated plus maze and context avoidance. We paired this model with in vivo fast scan cyclic voltammetry in freely moving rats to test for differences in dopamine signaling in the nucleus accumbens core at baseline, in response to a single dose of cocaine, and in response to cocaine-paired cues. Further, we examined differences in the acquisition of cocaine self-administration across groups. Results indicate that susceptibility to traumatic stress is associated with alterations in phasic dopamine signaling architecture that increase the rate at which dopamine signals entrain to cocaine-associated cues and increase the magnitude of persistent cue-evoked dopamine signals following training. These changes in phasic dopamine signaling correspond with increases in the rate at which susceptible rats develop excessive cocaine-taking behavior. Together, our studies demonstrate that susceptibility to traumatic stress is associated with a cocaine use-vulnerable phenotype and suggests that differences in phasic dopamine signaling architecture may contribute to the process by which this vulnerability occurs.

Fig. 1

Predator odor exposure stress produces two distinct populations. a Schematic of the stress and segregation procedure timeline. b Schematic of the segregation algorithm. c Distribution of butyric acid- and TMT-exposed rats that met susceptible criteria. Chi-square analysis showed a significant effect of TMT exposure on group distribution (chi = 95.72, p < 0.001). Note that butyric acid-exposed rats meeting susceptible criteria were nevertheless classified as controls. d Time spent in the open arms of the elevated plus maze (EPM). One-way ANOVA revealed a significant effect of group (F_(2,57) = 9.142, p < 0.001). e Avoidance of the odor paired context chamber. One-way ANOVA revealed a significant effect of group (F_(2,57) = 9.121, p < 0.001). f Change in time spent in the unpaired chamber. One-way ANOVA revealed no significant effects. Chi square: ^###p < 0.001. Bonferroni post hoc: ***p < 0.001

Fig. 2

Fast scan cyclic voltammetry experimental procedures. Schematic of the experimental design used for the FSCV experiments. Rats underwent surgery and then recovered for 6–10 days. Following recovery, rats underwent the stress and segregation protocol for control (butyric acid exposure) or stress (TMT exposure) conditions as previously described [18]. Three consecutive days of FSCV testing were carried out to examine the: (1) pharmacological effects of cocaine—Pharmacological Effect Test; (2) development of cue-evoked DA transients across cue-cocaine pairings—Cue-cocaine Association Test; and (3) the magnitude of persistent of cue-evoked DA transients associated with cocaine—Cue-evoked Dopamine Test

Fig. 3

Susceptible rats express changes in phasic DA signaling architecture before and after cocaine. a Color plots and current versus time plots for control, resilient, and susceptible rats at baseline and after cocaine delivery. DA transients are identified with pound signs, and example cyclic voltammograms for individual transients are shown above each current versus time plot. b Average DA transient frequency across the 6-min baseline recording session. One-way ANOVA revealed a significant effect of group (F_(2,22) = 52.74, p < 0.001). c Intertransient interval histogram measured across the 6-min baseline recording session. Between subjects two-way ANOVA with group as a between-subjects measure and intertransient interval as the repeated measure revealed a significant effect of group (F_(2,715) = 25.91, p < 0.001), interval (F_(35,715) = 41.03, p < 0.001), and group × interval interaction (F_(70,715) = 5.910, p < 0.001). Shaded regions indicate s.e.m. d Average DA transient magnitude measured across the 6-min baseline recording session. One-way ANOVA revealed no effect of group. e DA transient magnitude histogram normalized for frequency and measured across the 6-min baseline recording session. Between subjects two-way ANOVA with group as a between-subjects measure and DA magnitude as the repeated measure revealed a significant effect of magnitude (F_(35,720) = 27.14, p < 0.001), but no effect of group or interaction. Shaded regions indicate s.e.m. f Average DA transient frequency during baseline recording and after cocaine delivery. Two-way ANOVA with group as a between-subjects measure and time as the repeated measure revealed a significant effect of group (F_(2,205) = 106.7, p < 0.001) and time (F_(10,205) = 5.461, p < 0.001), but no interaction. g Change in DA transient frequency calculated as a percent of baseline across baseline and after cocaine delivery. Two-way ANOVA with group as a between-subjects measure and time as the repeated measure revealed a significant effect of time (F_(10,170) = 5.095, p < 0.001), but no effect of group or interaction. h Average DA transient frequency during baseline recording and after delivery of cocaine. Two-way ANOVA with group as a between-subjects measure and time as the repeated measure revealed a significant effect of time (F_(10,190) = 6.028, p < 0.001), but no effect of group or interaction. i Change in DA transient magnitude calculated as a percent of baseline across baseline and after delivery of cocaine. Two-way ANOVA with group as a between–subjects measure and time as the repeated measure revealed a significant effect of group (F_(2,19) = 4.959, p < 0.05), and time (F_(10,190) = 6.585, p < 0.001), but no interaction. Control n = 8, Resilient n = 10, Susceptible n = 5. Bonferroni post hoc: *p < 0.05; ***p < 0.001. COC = 1.5 mg/kg IV cocaine. Data are shown as mean (±s.e.m.)

Fig. 4

Cue-evoked dopamine signals develop more rapidly and persist in susceptible rats. a Example color plots and current versus time plots for control, resilient, and susceptible rats for each trial block. Dashed vertical lines indicate cue and cocaine delivery onset. Horizontal green bars indicate the duration of the cue delivery. Horizontal blue bars indicate the duration of IV cocaine delivery. b Cue-evoked DA transient traces averaged for each trial block for control, resilient, and susceptible rats. c Average DA transient magnitude across trial blocks. Two-way ANOVA with group as the between-subjects measure and trial block as the repeated measure revealed a significant effect of group (F_(2,20) = 12.15, p < 0.001), trial block (F_(5,100) = 10.25, p < 0.001), and a group × trial block interaction (F_(10,100) = 3.137, p < 0.01). d Regression lines used to calculate rate of change for control, resilient, and susceptible rats. Translucent lines depict individual rats and opaque lines represent the average regression line for each group. e Average rate of change in cue-evoked DA transients across the first through fourth trial blocks (trials 1–20) of the cue-cocaine association test day. One-way ANOVA revealed a significant effect of group (F_(2,20) = 12.13, p < 0.001). f Example color plots and current versus time plots for control, resilient, and susceptible rats for the cue-evoked DA test. Dashed vertical lines indicate cue and cocaine delivery onset. Horizontal green bars indicate the duration of the cue delivery. g Persistent cue-evoked DA transient traces averaged across group for control, resilient, and susceptible rats. h Average magnitude of persistent cue-evoked DA signals. One-way ANOVA revealed a significant effect of group (F_(2,20) = 0.022, p < 0.001). Control n = 8, Resilient n = 10, Susceptible n = 5. Bonferroni post hoc: *p < 0.05, **p < 0.01, ***p < 0.001. Data are shown as mean (±s.e.m.)

Fig. 5

Susceptible rats display an increased propensity to self-administer cocaine. a Experimental timeline for cocaine self-administration acquisition experiments. b Number of lever presses made across the 16-day test period. Two-way ANOVA with group as the between-subjects measure and day as the repeated measure revealed a significant effect of group (F_(2,375) = 7.671, p < 0.01), day (F_(15,375) = 7.671, p < 0.001), and a group × day interaction (F_(30,375) = 1.555, p < 0.001). c Cumulative cocaine self-administered across the 16-day test period. Two-way ANOVA with group as the between-subjects measure and day as the repeated measure revealed a significant effect of group (F_(2,375) = 5.92, p < 0.01), day (F_(15,375) = 38.33, p < 0.001), and group × day interaction (F_(30,375) = 5.696, p < 0.01). d Percent of animals that met acquisition criteria across testing days. Log-rank Mantel–Cox (chi square = 11.79, p = 0.003). e Amount of cocaine self-administered without reaching acquisition criteria. One-way ANOVA revealed a significant effect of group (F_(2,25) = 4.63, p < 0.05). f Cumulative cocaine self-administered by rats that met acquisition criteria. Two-way ANOVA with group as the between-subjects measure and day as the repeated measure revealed a significant effect of day (F_(15,210) = 33.69, p < 0.001), and group × day interaction (F_(30,210) = 1.57, p < 0.05). b–e Control n = 11, Resilient n = 11, Susceptible n = 6. f Control n = 6, Resilient n = 5, Susceptible n = 6. Bonferroni post hoc: *p < 0.05, **p < 0.01 ***p < 0.001 susceptible versus control and resilient. Log rank (Mantel–Cox) ^##p < 0.01. Data are shown as mean (±s.e.m.)