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bioRxiv · 10.1101/438507

Deep brain stimulation of the nucleus accumbens shell does not decrease cocaine self-administration in cocaine-dependent rats but increases GluR1/GluA1 in the central nucleus of the amygdala

Kononoff, J.·Melas, P. A.·Qvist, J. S.·de Guglielmo, G.·Kallupi, M.·Kandel, E. R.·George, O.
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Abstract

BackgroundCocaine addiction is a major public health problem. Despite decades of intense research, no effective treatments are available. Both preclinical and clinical studies of drug addiction strongly suggest that the nucleus accumbens (NAcc) is a viable target for deep brain stimulation (DBS).\n\nObjectiveAlthough 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.\n\nMethodsRats were made cocaine-dependent by allowing them to self-administer cocaine in long-access sessions (6 h, 0.5 mg/kg/infusion). The effects of high-frequency DBS of the NAcc shell on cocaine intake was then studied. Furthermore, cocaine-induced locomotor activity, irritability-like behavior during cocaine abstinence and the levels of the -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits 1 and 2 (GluR1/GluA1 and GluR2/GluA2) after DBS were investigated.\n\nResultsContrary to our expectations, DBS of the NAcc shell induced a slight increase in both cocaine self-administration and cocaine-induced locomotor activity. In addition, 18 h into cocaine withdrawal, we found that DBS decreased irritability-like behavior. We also found that DBS-induced a robust increase in both cytosolic and synaptosomal levels of GluR1, but not GluR2, specifically in the central nucleus of the amygdala but not in other brain regions.\n\nConclusionsThese preclinical results with cocaine-dependent animals do not support high-frequency DBS of the NAcc shell as a therapeutic approach for the treatment of cocaine addiction in active cocaine users. However, the decrease in irritability-like behavior during cocaine abstinence, together with previous findings showing that DBS of the NAcc shell reduces the reinstatement of cocaine seeking in abstinent animals, warrants future investigations of DBS as a treatment for negative emotional states and craving during abstinence.\n\nHighlightsO_LIHigh-frequency DBS of the NAcc shell for the treatment of cocaine addiction is proposed\nC_LIO_LIDBS of the NAcc shell does not decrease cocaine intake in cocaine-dependent rats\nC_LIO_LIDBS increases the level of GluR1 specifically in the central nucleus of the amygdala\nC_LI

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Kononoff, J., Melas, P. A., Qvist, J. S., de Guglielmo, G., Kallupi, M., Kandel, E. R., George, O.. 2018-10-08. Deep brain stimulation of the nucleus accumbens shell does not decrease cocaine self-administration in cocaine-dependent rats but increases GluR1/GluA1 in the central nucleus of the amygdala. https://doi.org/10.1101/438507

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