Subthalamic low-frequency oscillations predict vulnerability to cocaine addiction

Abstract

Identifying vulnerable individuals before they transition to a compulsive pattern of drug seeking and taking is a key challenge in addiction to develop efficient prevention strategies. Oscillatory activity within the subthalamic nucleus (STN) has been associated with compulsive-related disorders. To study compulsive cocaine-seeking behavior, a core component of drug addiction, we have used a rat model in which cocaine seeking despite a foot-shock contingency only emerges in some vulnerable individuals having escalated their cocaine intake. We show that abnormal oscillatory activity within the alpha/theta and low-beta bands during the escalation of cocaine intake phase predicts the subsequent emergence of compulsive-like seeking behavior. In fact, mimicking STN pathological activity in noncompulsive rats during cocaine escalation turns them into compulsive ones. We also find that 30 Hz, but not 130 Hz, STN deep brain stimulation (DBS) reduces pathological cocaine seeking in compulsive individuals. Our results identify an early electrical signature of future compulsive-like cocaine-seeking behavior and further advocates the use of frequency-dependent STN DBS for the treatment of addiction.

Keywords: addiction; compulsive seeking; deep brain stimulation; electrical biomarker; subthalamic nucleus.

Fig. 1.

Escalation of cocaine self-administration promotes compulsive cocaine seeking in a subpopulation of rats. (A) The experimental time course. (B) Punishment contingency reduced the number of seeking cycles completed in all animals. While both groups displayed equivalent levels of cocaine seeking during baseline, “shock-resistant” rats (i.e., “compulsive,” orange dots, n = 17) completed more seeking cycles than “shock-sensitive” rats (white dots, n = 36; Bonferroni post hoc: ^###P < 0.001 resistant versus sensitive, 0.89 ≤ Cohen’s d (effect size) ≤ 2.44) during punished sessions. The dashed line indicates compulsivity threshold below which animals are considered “shock-sensitive” (Materials and Methods). (C) The number of seeking cycles completed during the last sessions of baseline and punishment (arrowheads in B) for the “shock-sensitive” (Left) and the “shock-resistant” (Right) groups (Bonferroni post hoc: ***P < 0.001 baseline versus punishment, 11.89 ≤ Cohen’s dz ≤ 12.78; ^###P < 0.001 resistant versus sensitive, Cohen’s d = 1.44). (D) Punishment contingency reduced the percentage of checking lever presses performed per cycle completed. While both groups did not differ during baseline, “shock-resistant” rats (orange dots) performed more checking lever presses than “shock-sensitive” rats (white dots; Bonferroni post hoc: ^#P < 0.05 resistant versus sensitive, 0.71 ≤ Cohen’s d ≤ 1.5) during punished sessions. (E) Percentages of checking lever presses performed per cycle completed during the last session of baseline and punishment (arrowheads in D) for the “shock-sensitive” (Left) and the “shock-resistant” (Right) groups; Bonferroni post hoc: ***P < 0.001 baseline versus punishment, 4.87 ≤ Cohen’s dz ≤ 18.53; ^##P < 0.01 resistant versus sensitive, Cohen’s d = 1.15). All graphs indicate mean ± SEM. Connected small dots represent individual data points across conditions.

Fig. 2.

Compulsive rats exhibit pathological STN low-frequency oscillations during cocaine escalation: a predictive marker for vulnerability to addiction. (A) Future “shock-sensitive” (white dots, n = 12) and “shock-resistant” (orange dots, n = 5) rats exhibited similar drug intake during cocaine escalation (expressed here as the total number of cocaine injections received during each 6 h session; Bonferroni post hoc: *P < 0.05, 1.28 ≤ Cohen’s dz (effect size) ≤ 17.28). The brown rectangles indicate LFPs recording sessions. (B) “Shock-resistant” rats (orange dots) completed more seeking cycles than “shock-sensitive” rats (white dots; Bonferroni post hoc: ^##P < 0.01 resistant versus sensitive, 0.65 ≤ Cohen’s d ≤ 3.85) during punished sessions. The dashed line indicates compulsivity threshold below which animals are considered “shock-sensitive.” (C) Session-frequency power spectrum showing basal (i.e., before cocaine) LFPs power changes normalized (in %) to session 1 in “shock-resistant” (Left) and “shock-sensitive” (Right) animals. (D–F) Quantifications of LFPs power before and after 6 h of cocaine access. During baseline recordings (Before), “shock-resistant” rats (orange dots) showed a progressive power increase in alpha/theta and beta (D and E); Bonferroni post hoc: ^$P < 0.05, ^$$P < 0.01, ^$$$P < 0.001 versus session 1, 1.27 ≤ Cohen’s dz ≤ 3.86) but not in gamma band (F). No increase was observed in “shock-sensitive” animals (white dots; Bonferroni post hoc: ^##P < 0.01 resistant versus sensitive, 1.31 ≤ Cohen’s d ≤ 1.5). After the 6 h session of cocaine self-administration (After), the increased baseline power in the resistant animals on session 15 in both alpha/theta and beta bands was reduced (Bonferroni post hoc: ***P < 0.001, 1.22 ≤ Cohen’s dz ≤ 1.26) but cocaine self-administration had no effect in the gamma band. The line graphs indicate mean ± SEM.

Fig. 3.

STN 8 Hz DBS switched “shock-sensitive” rats into “shock resistant” ones. (A) The experimental time course. “Shock-sensitive” rats characterized during the initial punishment protocol (Baseline 1 and Punishment 1) were resubjected to a second escalation protocol (escalation 2) before being retested in the punishment protocol (Baseline 2 and Punishment 2). (B) Punishment delivery suppressed cocaine seeking in “shock-sensitive” animals (Bonferroni post hoc: ***P < 0.001, versus baseline 5; 4.73 ≤ Cohen’s dz (effect size) ≤ 20). No stimulation was applied at that stage, but data are illustrated for the various groups to be stimulated at either 0 (white dots), 8 (red dots) or 70 Hz (blue dots). (C) STN DBS at 8 Hz (red dots, n = 5) or 70 Hz (blue dots, n = 3) had no effect on cocaine intake during escalation 2, compared to OFF control group (white dots, n = 5; Bonferroni post hoc: **P < 0.01, 2.41 ≤ Cohen’s dz ≤ 20). (D) Punishment contingency during punishment 2 reduced the number of seeking cycles completed in all groups, but 8 Hz stimulated rats completed more seeking cycles than control and 70 Hz stimulated rats (Bonferroni post hoc: ^#P < 0.05, 8 Hz versus 0 Hz; ^$P < 0.05, ^$$P < 0.01, 8 Hz versus 70 Hz, 1.78 ≤ Cohen’s d ≤ 3.93) during punishment 2 and reached the criterion to be considered “shock-resistant.” (E) Compulsivity score before (Punishment 1) and after cocaine escalation 2 (Punishment 2; Bonferroni post hoc: **P < 0.001, before versus after, Cohen’s dz = 2.9; ^###P < 0.001, 8 Hz versus 0 and 70 Hz, 2.27 ≤ Cohen’s dz ≤ 2.9). The dashed lines indicate compulsivity threshold below which animals are considered “shock-sensitive.” All graphs indicate mean ± SEM. The connected small dots represent individual data points across conditions.

Fig. 4.

STN DBS at 30 Hz reduces compulsive-like cocaine seeking. (A) The experimental time course: Following five OFF (no DBS) punished sessions, animals were subjected to 5 ON (DBS at 130 or 30 Hz) punished sessions. After five additional OFF sessions, animals were stimulated with the alternate frequency during five ON punished sessions, followed by five OFF sessions. (B) STN DBS at 130 Hz (yellow rectangle) acutely increased the number of seeking cycles completed by “shock-resistant” rats during the two first sessions of STN DBS (orange dots; n = 12) but had no effect in “shock-sensitive” animals (white dots; n = 14; Bonferroni post hoc: *P < 0.05 versus Pre-130 Hz, 1.6 ≤ Cohen’s dz (effect size) ≤ 18.29; ^#P < 0.05, ^##P < 0.01, ^###P < 0.001, resistant versus sensitive, 1.16 ≤ Cohen’s d ≤ 1.87). The dashed line indicates compulsivity threshold below which animals are considered shock sensitive. (C) Averaged (five-session block) number of cycles completed by “shock-sensitive” (Left) and “shock-resistant” (Right) rats during punishment sessions before (Pre 130 Hz, pale gray), during (130 Hz, yellow), and after (Post 130 Hz, dark gray) 130 Hz STN DBS. (D) STN DBS at 30 Hz (green rectangle) decreased the number of seeking cycles completed by “shock-resistant” rats (orange dots; n = 12) but had no effect in “shock-sensitive” animals (white dots; n = 14; Bonferroni post hoc: ***P < 0.001, 2.02 ≤ Cohen’s dz ≤ 18.66; ^$P < 0.05, ^$$P < 0.01 versus last session of 30 Hz DBS, 1.27 ≤ Cohen’s dz ≤ 2.65; ^#P < 0.05, ^##P < 0.01, ^###P < 0.001, resistant versus sensitive, 1.27 ≤ Cohen’s d ≤ 3.24). The dashed line indicates compulsivity threshold below which animals are considered “shock-sensitive.” (E) Five-session block averaging the number of cycles completed by “shock-sensitive” (Left) and “-resistant” (Right) rats before (pale gray), during (green), and after (dark gray) 30 Hz STN DBS (Bonferroni post hoc: **P < 0.01; 6.45 ≤ Cohen’s dz ≤ 20). All graphs indicate mean ± SEM. The connected small dots represent individual data points across conditions.