Reducing the desire for cocaine with subthalamic nucleus deep brain stimulation

Abstract

Deep brain stimulation (DBS) is a reversible technique that is currently used for the treatment of Parkinson disease and may be suitable for the treatment of psychiatric disorders. Whether DBS inactivates the target structure is still a matter of debate. Here, from findings obtained in rats, we propose DBS of the subthalamic nucleus (STN) as a possible treatment for cocaine addiction to be further tested in human studies. We show that STN DBS reversibly reduces the motivation to work for an i.v. injection of cocaine, and it increases motivation to work for sucrose pellets. These opposite effects may result from STN DBS effect on the positive affective properties of these rewards. Indeed, we further show that STN DBS reduces the preference for a place previously associated with the rewarding properties of cocaine, and it increases the preference for a place associated with food. Because these findings are consistent with those observed after STN lesions [Baunez C, Dias C, Cador M, Amalric M (2005) Nat Neurosci 8:484-489], they suggest that STN DBS mimics an inactivation of the STN on motivational processes. Furthermore, given that one of the major challenges for cocaine addiction is to find a treatment that reduces the craving for the drug without diminishing the motivation for naturally rewarding activities, our findings validate STN as a good target and DBS as the appropriate technique for a promising therapeutic strategy in the treatment of cocaine addiction.

Fig. 1.

Histology and consummatory behavior under STN DBS. (A) Photograph of the track of a stimulating electrode implanted at the level of the STN (outlined with dashed lines according to the atlas) (16).The brain slice was stained with cresyl violet, allowing delimitation of the STN because of the density of neurons and their orientation in this structure. (B) Effect of STN DBS on food intake over 24-h periods under various conditions: OFF stimulation with no connection (white bar), OFF stimulation with connection to the stimulation system (gray bar), ON stimulation (black bar), and OFF stimulation with connection to the stimulation system (gray bar). Error bars illustrate standard errors (SEM). (C) Effect of STN DBS on performance under a FR1 schedule of reinforcement for food (Upper Graphs) and for cocaine (Lower Graphs). Results are illustrated in terms of mean number of rewards obtained in nonstimulated control animals (OFF, white bar) and STN DBS animals (ON, black bar) during each session and the mean number of perseverative lever presses (i.e., lever presses during the inactivation period of the lever (before reward collection in the magazine for food experiment and during injection time and 20-s timeout period in the cocaine experiment). Asterisk indicates significantly different from OFF condition.

Fig. 2.

Effects of STN DBS on willingness of the animals to produce an effort to obtain food or cocaine. Behavioral performances on the progressive ratio task illustrated as the mean number of rewards obtained (Upper) and the mean breaking point (i.e., last ratio reached) (Lower) for food reward (A) and for i.v. cocaine (B) in rats ON (black bars; n = 14 and 9 for A and B respectively) and OFF STN DBS (white bars; n = 8 and 9 for A and B respectively). Error bars illustrate standard errors (SEM). *P < 0.05 (ANOVA group effect), significant difference between groups STN DBS OFF and STN DBS ON.

Fig. 3.

STN DBS reversibility on its behavioral effects in the progressive ratio task for i.v. cocaine. Performance is illustrated as the mean number of injections obtained (A) and the mean ratio reached (B) during 10 sessions under the initial conditions of stimulation (Left) (OFF n = 7 (white bar), ON n = 9 (black bar) and after reversal of the stimulation conditions (former ON group was turned OFF, n = 9 (right white bar), and former OFF group was turned ON, n = 7 (Right, black bar). Error bars illustrate standard errors (SEM). *P < 0.05 (ANOVA group effect), significant difference between groups STN DBS OFF and STN DBS ON. #, P < 0.05; ##, P < 0.01; paired t test between the initial condition and its reversal.

Fig. 4.

Effects of STN DBS on conditioned place preference for food and for cocaine. The bars represent the score of preference for food [A; STN DBS OFF (white bar) n = 7 and STN DBS ON (black bar) n = 9] and for cocaine (10 mg/kg; i.p.) [B; STN DBS OFF (white bar) n = 7 and STN DBS ON (black bar) n = 7]. Error bars illustrate standard errors (SEM). *P < 0.05; **P < 0.01 (Mann–Whitney test), significant difference between groups STN DBS OFF and STN DBS ON. #, P < 0.05, sign test: score of preference significantly different from zero.