Marsida Kallupi1, Jenni Kononoff2, Philippe A Melas3, Johanna S Qvist4, Giordano de Guglielmo5, Eric R Kandel6, Olivier George7. 1. Department of Psychiatry, University of California, San Diego School of Medicine, San Diego, CA, 92093, USA; Department of Neuroscience, The Scripps Research Institute, 10550 N.Torrey Pines Rd, La Jolla, CA, 92037, USA. Electronic address: mkallupi@health.ucsd.edu. 2. Department of Neuroscience, The Scripps Research Institute, 10550 N.Torrey Pines Rd, La Jolla, CA, 92037, USA. 3. Department of Neuroscience, Columbia University, New York, NY, 10032, USA; Mortimer B. Zuckerman Mind Brain Behavior Institute, Jerome L. Greene Science Center, New York, NY, 10027, USA; Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, 17176, Sweden. 4. Department of Neuroscience, Columbia University, New York, NY, 10032, USA; Mortimer B. Zuckerman Mind Brain Behavior Institute, Jerome L. Greene Science Center, New York, NY, 10027, USA. 5. Department of Psychiatry, University of California, San Diego School of Medicine, San Diego, CA, 92093, USA; Department of Neuroscience, The Scripps Research Institute, 10550 N.Torrey Pines Rd, La Jolla, CA, 92037, USA. 6. Department of Neuroscience, Columbia University, New York, NY, 10032, USA; Mortimer B. Zuckerman Mind Brain Behavior Institute, Jerome L. Greene Science Center, New York, NY, 10027, USA; Kavli Institute for Brain Science, Columbia University, New York, NY, 10032, USA; Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA. 7. Department of Psychiatry, University of California, San Diego School of Medicine, San Diego, CA, 92093, USA; Department of Neuroscience, The Scripps Research Institute, 10550 N.Torrey Pines Rd, La Jolla, CA, 92037, USA. Electronic address: olgeorge@health.ucsd.edu.
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.
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.
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