Deep brain stimulation of the nucleus accumbens shell attenuates cocaine withdrawal but increases cocaine self-administration, cocaine-induced locomotor activity, and GluR1/GluA1 in the central nucleus of the amygdala in male cocaine-dependent rats - PubMed (original) (raw)
Deep brain stimulation of the nucleus accumbens shell attenuates cocaine withdrawal but increases cocaine self-administration, cocaine-induced locomotor activity, and GluR1/GluA1 in the central nucleus of the amygdala in male cocaine-dependent rats
Marsida Kallupi et al. Brain Stimul. 2022 Jan-Feb.
Abstract
Background: Cocaine addiction is a major public health problem. Despite decades of intense research, no effective treatments are available. Both preclinical and clinical studies strongly suggest that deep brain stimulation of the nucleus accumbens (NAcc) is a viable target for the treatment of cocaine use disorder (CUD).
Objective: Although previous studies have shown that DBS of the NAcc decreases cocaine seeking and reinstatement, the effects of DBS on cocaine intake in cocaine-dependent animals have not yet been investigated.
Methods: Rats were made cocaine dependent by allowing them to self-administer cocaine in extended access conditions (6 h/day, 0.5 mg/kg/infusion). The effects of monophasic bilateral high-frequency DBS (60 μs pulse width and 130 Hz frequency) stimulation with a constant current of 150 μA of the NAcc shell on cocaine intake was then evaluated. Furthermore, cocaine-induced locomotor activity, irritability-like behavior during cocaine abstinence, and the levels of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits 1 and 2 (GluR1/GluA1 and GluR2/GluA2) after DBS were investigated.
Results: Contrary to our expectations, DBS of the NAcc shell induced a slight increase in cocaine self-administration, and increased cocaine-induced locomotion after extended access of cocaine self-administration. In addition, DBS decreased irritability-like behavior 18 h into cocaine withdrawal. Finally, DBS increased both cytosolic and synaptosomal levels of GluR1, but not GluR2, in the central nucleus of the amygdala but not in other brain regions.
Conclusions: These preclinical results with cocaine-dependent animals support the use of high-frequency DBS of the NAcc shell as a therapeutic approach for the treatment of the negative emotional state that emerges during cocaine abstinence, but also demonstrate that DBS does not decrease cocaine intake in active, long-term cocaine users. These data, together with the existing evidence that DBS of the NAcc shell reduces the reinstatement of cocaine seeking in abstinent animals, suggest that NAcc shell DBS may be beneficial for the treatment of the negative emotional states and craving during abstinence, although it may worsen cocaine use if individuals continue drug use.
Keywords: Amygdala; Cocaine addiction; Glutamate; High-frequency stimulation; Neuromodulation; Withdrawal.
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Figures
Figure 1.. Experimental design and electrode placements.
(A) Timeline of the experiment. (B) Schematic illustration of electrode placements in the NAcc shell (black dots) and a representative image of the placement. The gray dots represent misplaced electrodes.
Figure 2.. Training and escalation of cocaine self-administration.
(A) Rats were first trained to self-administer cocaine (0.5 mg/kg/infusion) during 1-h sessions (n = 13). (B) The escalation of cocaine self-administration after seventeen 6-h sessions. *p < 0.05, **p < 0.01, ****p < 0.0001, significantly different from day 1. (C) The first hour (i.e., the loading phase) of the 6-h self-administration session demonstrated significant escalation of cocaine intake during 17 sessions compared with day 1. ***p < 0.001. (D) The rats were divided into Sham and DBS groups according to equal baseline intake during the 6 h-session for the subsequent studies. n = 6-7. Note that the rats were not stimulated for the group assignment.
Figure 3.. Deep brain stimulation of the NAcc shell increases cocaine self-administration.
(A) Deep brain stimulation started 30 min before the self-administration session and remained on for a total of 2 h. An increase in cocaine intake during the first 90 min of the session was observed only in the first session of DBS (ON1). *p < 0.05. (B) Deep brain stimulation increased average cocaine intake (i.e., the average of both ON1 and ON2) during the first 90 min when DBS was on. *p < 0.05. (C) Deep brain stimulation increased cocaine intake during the entire 6-h session only in the first session of DBS. *p < 0.05. (D) Deep brain stimulation increased average cocaine intake (i.e., the average of ON1 and ON2) during the entire 6-h session. ***p < 0.001. (E) Sham treatment had no effect on cocaine intake during the first 90 min of the 6-h session. (F) Sham treatment had no effect on average cocaine intake (i.e., the average of both ON1 and ON2) during the first 90 min of the self-administration session. (G) Sham treatment had no effect on cocaine intake during the entire 6-h session. (H) Sham treatment had no effect on average cocaine intake (i.e., the average of ON1 and ON2) during the entire 6-h session. n = 6-7.
Figure 4.. Deep brain stimulation of the NAcc shell increases the psychostimulant effect of cocaine but decreases irritability-like behavior.
(A) Rats were exposed to DBS or Sham treatment immediately before placing them in the open field. After 30 min of habituation, the rats were challenged with an acute injection of cocaine (10 mg/kg, i.p.). The DBS group exhibited an increase in cocaine-induced locomotor activity. *p < 0.05. n = 6-7. (B) Irritability-like behavior during cocaine withdrawal was decreased by DBS immediately before testing. *p < 0.05. n = 6-7.
Figure 5.. Deep brain stimulation increases GluR1/GluA1 levels in the central nucleus of the amygdala (CeA) in both synaptosomal and cytosolic fractions.
(A) In the synaptosomal fractions of eight brain regions, DBS increased the levels of GluR1 in the CeA (p = 0.033, Bonferroni post hoc test). (B) No changes in GluR2/GluA2 were observed in any of the studied brain regions. (C) In the cytosolic fractions, DBS increased the levels of GluR1 in the CeA (p = 0.007, Bonferroni post hoc test). (D) No significant changes in GluR2 were observed, although a trend was found in the CeA (p = 0.094, Bonferroni post hoc test). NAcc, nucleus accumbens; DSTR, dorsal striatum; vPFC, ventral prefrontal cortex; dPFC, dorsal prefrontal cortex; CeA, central nucleus of the amygdala; INS, insular cortex; VTA, ventral tegmental area. The data are expressed as mean ± SEM. Representative Western blots are shown below the figures. The approximate molecular weights of the observed band sizes were ~100 kDa for GluR1 and GluR2, ~38 kDa for synaptophysin (Syn), and ~42 kDa for β-actin (Actin). n = 5–7/group. *p < 0.05, **p < 0.01.
References
- SAMHSA A, Results from the 2018 National Survey on Drug Use and Health: Summary of national findings. Annual Report, 2019.
- Muller UJ, et al. , Nucleus Accumbens Deep Brain Stimulation for Alcohol Addiction - Safety and Clinical Long-term Results of a Pilot Trial. Pharmacopsychiatry, 2016. 49(4): p. 170–3. -PubMed
- Voges J, et al. , Deep brain stimulation surgery for alcohol addiction. World Neurosurg, 2013. 80(3–4): p. S28 e21–31. -PubMed
- Kuhn J, et al. , Successful deep brain stimulation of the nucleus accumbens in severe alcohol dependence is associated with changed performance monitoring. Addict Biol, 2011. 16(4): p. 620–3. -PubMed