Reduced ethanol consumption by alcohol-preferring (P) rats following pharmacological silencing and deep brain stimulation of the nucleus accumbens shell

Object There is increasing interest in deep brain stimulation (DBS) for the treatment of addiction. Initial testing must be conducted in animals, and the alcohol-preferring (P) rat meets the criteria for an animal model of alcoholism. This study is composed of 2 experiments designed to examine the effects of 1) pharmacological inactivation and 2) DBS of the nucleus accumbens shell (AcbSh) on the consumption of alcohol by P rats. Methods In the first experiment, the effects of reversible inactivation of the AcbSh were investigated by administering intracranial injections of γ–aminobutyric acid (GABA) agonists. Bilateral microinjections of drug were administered to the AcbSh in P rats (8–10 rats/group), after which the animals were placed in operant chambers containing 2 levers—one used to administer water and the other to administer 15% EtOH—to examine the acquisition and maintenance of oral EtOH self-administration. In the second experiment, a DBS electrode was placed in each P rat's left AcbSh. The animals then received 100 or 200 μA (3–4 rats/group) of DBS to examine the effect on daily consumption of oral EtOH in a free-access paradigm. Results In the first experiment, pharmacological silencing of the AcbSh with GABA agonists did not decrease the acquisition of EtOH drinking behavior but did reduce EtOH consumption by 55% in chronically drinking rats. Similarly, in the second experiment, 200 μA of DBS consistently reduced EtOH intake by 47% in chronically drinking rats. The amount of EtOH consumption returned to baseline levels following termination of therapy in both experiments. Conclusions Pharmacological silencing and DBS of the AcbSh reduced EtOH intake after chronic EtOH use had been established in rodents. The AcbSh is a neuroanatomical substrate for the reinforcing effects of alcohol and may be a target for surgical intervention in cases of alcoholism.

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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

Brain Stimulation ◽

10.1016/j.brs.2021.11.003 ◽

2021 ◽

Author(s):

Marsida Kallupi ◽

Jenni Kononoff ◽

Philippe A. Melas ◽

Johanna S. Qvist ◽

Giordano de Guglielmo ◽

...

Keyword(s):

Deep Brain Stimulation ◽

Locomotor Activity ◽

Nucleus Accumbens ◽

Brain Stimulation ◽

Central Nucleus ◽

Nucleus Accumbens Shell ◽

Self Administration ◽

Cocaine Withdrawal ◽

Deep Brain ◽

Stimulation Of

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Intermittent bilateral deep brain stimulation of the nucleus accumbens shell reduces intravenous methamphetamine intake and seeking in Wistar rats

Journal of Neurosurgery ◽

10.3171/2016.4.jns152524 ◽

2017 ◽

Vol 126 (4) ◽

pp. 1339-1350 ◽

Cited By ~ 8

Author(s):

Vinita Batra ◽

Thanh Lam N. Tran ◽

Jessica Caputo ◽

Glenn F. Guerin ◽

Nicholas E. Goeders ◽

...

Keyword(s):

Deep Brain Stimulation ◽

Nucleus Accumbens ◽

Drug Use ◽

Brain Stimulation ◽

Nucleus Accumbens Shell ◽

Self Administration ◽

Sham Treatment ◽

Days Of Therapy ◽

Seeking Behavior ◽

Deep Brain

OBJECTIVE There is increasing interest in neuromodulation for addiction. Methamphetamine abuse is a global health epidemic with no proven treatment. The objective of this study was to examine the effects of intermittent nucleus accumbens shell (AcbSh) deep brain stimulation (DBS) on operant methamphetamine intake and on methamphetamine seeking when stimulation is delivered in an environment different from that of drug use. METHODS Eighteen rats were implanted with intravenous (IV) catheters and bilateral AcbSh electrodes and subsequently underwent daily sessions in 2-lever (active/methamphetamine and inactive/no reward) operant chambers to establish IV methamphetamine self-administration. After stable responding was achieved, 3 hours of DBS or sham treatment was administered (sham: 0 µA, n = 8; active: 200 µA, n = 10) in a separate nondrug environment prior to the daily operant sessions for 5 consecutive days. Immediately following each DBS/sham treatment, rats were placed in the operant chambers to examine the effects of remote stimulation on methamphetamine intake. After the 5 days of therapy were finished, rats reestablished a posttreatment baseline, followed by extinction training, abstinence, and 1 day of relapse testing to assess methamphetamine-seeking behavior. RESULTS There was a decrease in total methamphetamine intake in rats receiving active DBS versus sham on Days 1 (42%) and 2 (44%). Methamphetamine administration returned to baseline levels following the cessation of DBS therapy. Compared with baseline drug responding, methamphetamine seeking was reduced (57%) in the DBS group but not in the sham group. CONCLUSIONS It is feasible to deliver noncontinuous DBS outside of the drug use environment with a resultant decrease in IV methamphetamine intake and seeking. The AcbSh is a neuroanatomical substrate for psychostimulant reinforcement and may be a target for intermittent neuromodulatory therapies that could be administered during brief periods of sobriety.

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Deep Brain Stimulation of the Nucleus Accumbens Shell Attenuates Cocaine Reinstatement through Local and Antidromic Activation

Journal of Neuroscience ◽

10.1523/jneurosci.4804-12.2013 ◽

2013 ◽

Vol 33 (36) ◽

pp. 14446-14454 ◽

Cited By ~ 66

Author(s):

F. M. Vassoler ◽

S. L. White ◽

T. J. Hopkins ◽

L. A. Guercio ◽

J. Espallergues ◽

...

Keyword(s):

Deep Brain Stimulation ◽

Nucleus Accumbens ◽

Brain Stimulation ◽

Nucleus Accumbens Shell ◽

Antidromic Activation ◽

Deep Brain ◽

Stimulation Of ◽

Cocaine Reinstatement

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Deep Brain Stimulation of the Nucleus Accumbens Shell Attenuates Cocaine Priming-Induced Reinstatement of Drug Seeking in Rats

Journal of Neuroscience ◽

10.1523/jneurosci.5277-07.2008 ◽

2008 ◽

Vol 28 (35) ◽

pp. 8735-8739 ◽

Cited By ~ 127

Author(s):

F. M. Vassoler ◽

H. D. Schmidt ◽

M. E. Gerard ◽

K. R. Famous ◽

D. A. Ciraulo ◽

...

Keyword(s):

Deep Brain Stimulation ◽

Nucleus Accumbens ◽

Brain Stimulation ◽

Nucleus Accumbens Shell ◽

Drug Seeking ◽

Deep Brain ◽

Stimulation Of

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Deep Brain Stimulation Reveals a Dissociation of Consummatory and Motivated Behaviour in the Medial and Lateral Nucleus Accumbens Shell of the Rat

PLoS ONE ◽

10.1371/journal.pone.0033455 ◽

2012 ◽

Vol 7 (3) ◽

pp. e33455 ◽

Cited By ~ 46

Author(s):

Geoffrey van der Plasse ◽

Regina Schrama ◽

Sebastiaan P. van Seters ◽

Louk J. M. J. Vanderschuren ◽

Herman G. M. Westenberg

Keyword(s):

Deep Brain Stimulation ◽

Nucleus Accumbens ◽

Brain Stimulation ◽

Nucleus Accumbens Shell ◽

Lateral Nucleus ◽

Deep Brain

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Amelioration of Binge Eating by Nucleus Accumbens Shell Deep Brain Stimulation in Mice Involves D2 Receptor Modulation

Journal of Neuroscience ◽

10.1523/jneurosci.3237-12.2013 ◽

2013 ◽

Vol 33 (17) ◽

pp. 7122-7129 ◽

Cited By ~ 71

Author(s):

C. H. Halpern ◽

A. Tekriwal ◽

J. Santollo ◽

J. G. Keating ◽

J. A. Wolf ◽

...

Keyword(s):

Deep Brain Stimulation ◽

Nucleus Accumbens ◽

Binge Eating ◽

Brain Stimulation ◽

D2 Receptor ◽

Nucleus Accumbens Shell ◽

Receptor Modulation ◽

Deep Brain

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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

10.1101/438507 ◽

2018 ◽

Author(s):

Jenni Kononoff ◽

Philippe A. Melas ◽

Johanna S. Qvist ◽

Giordano de Guglielmo ◽

Marsida Kallupi ◽

...

Keyword(s):

Deep Brain Stimulation ◽

Locomotor Activity ◽

Nucleus Accumbens ◽

Brain Stimulation ◽

High Frequency ◽

Cocaine Addiction ◽

Central Nucleus ◽

Self Administration ◽

Cocaine Seeking ◽

Deep Brain

AbstractBackgroundCocaine 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).ObjectiveAlthough 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.MethodsRats 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 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits 1 and 2 (GluR1/GluA1 and GluR2/GluA2) after DBS were investigated.ResultsContrary 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.ConclusionsThese 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.HighlightsHigh-frequency DBS of the NAcc shell for the treatment of cocaine addiction is proposedDBS of the NAcc shell does not decrease cocaine intake in cocaine-dependent ratsDBS increases the level of GluR1 specifically in the central nucleus of the amygdala

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Deep brain stimulation of the nucleus accumbens core but not shell reduces motivational components of heroin taking and seeking in rats

Brain and Neuroscience Advances ◽

10.1177/2398212817711083 ◽

2017 ◽

Vol 1 ◽

pp. 239821281771108

Author(s):

Maria C. Schippers ◽

Mathijs Gaastra ◽

Tanja Mesman ◽

Dustin Schetters ◽

Yvar van Mourik ◽

...

Keyword(s):

Deep Brain Stimulation ◽

Nucleus Accumbens ◽

Brain Stimulation ◽

Progressive Ratio ◽

Ratio Schedule ◽

Progressive Ratio Schedule ◽

Self Administration ◽

Extinction Learning ◽

Drug Induced ◽

Deep Brain

Background: Deep brain stimulation is explored as a new intervention for treatment-resistant substance use dependence. A candidate brain region is the nucleus accumbens, due to its involvement in reward and motivation. This study aimed to explore effects of NAcore and NAshell deep brain stimulation on aspects of heroin taking and seeking in a self-administration model for rats. Methods: NAcore and NAshell deep brain stimulation was applied during 25 or 100 µg/kg/infusion heroin self-administration on an FR4 schedule of reinforcement and during cue- and heroin-induced reinstatement. In a separate group, effects of NAcore deep brain stimulation on heroin self-administration on a progressive ratio schedule and the first extinction session were examined. Results: NAcore and NAshell deep brain stimulation did not alter heroin self-administration on an FR4 schedule. NAcore deep brain stimulation decreased cue – but not drug-induced reinstatement of heroin seeking, whereas NAshell deep brain stimulation did not affect reinstatement responding. In the second experiment, NAcore deep brain stimulation reduced responding during a progressive ratio schedule of heroin reinforcement. Finally, deep brain stimulation facilitated extinction from day 1 throughout the course of extinction learning. Conclusion: Taken together, the differential effects of NAcore and NAshell deep brain stimulation on heroin taking and seeking are in line with the distinct functional roles of these sub-regions therein. Conditioned cues have been shown to be very powerful stimuli for the persistence of addiction and relapse to drug use. Therefore, the present findings that NAcore deep brain stimulation decreases motivation for heroin taking and cue-conditioned behaviour and facilitates extinction learning are very promising, supporting the positive findings from clinical case studies.

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