Dopamine efflux in the rat striatum evoked by electrical stimulation of the subthalamic nucleus: potential mechanism of action in Parkinson's disease

Lee, Kendall H.; Blaha, Charles D.; Harris, Brent T.; Cooper, Shannon; Hitti, Frederick L.; Leiter, James C.; Roberts, David W.; Kim, Uhnoh

doi:10.1111/j.1460-9568.2006.04638.x

Cited by 132 publications

(115 citation statements)

References 62 publications

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“…The loss of excitatory input of the STN under DBS may thus lower the basal level of dopaminergic neuron activity in these structures and ultimately alter their reactivity to food and cocaine reward. It is interesting to note however that some studies suggest that STN DBS may result in increased activity of the DA system (35). The dissociation of STN effects, when low workload and high workload were required, such as in the FR1 and PR schedule of reinforcement, has been previously observed after manipulation of the DA system.…”

Section: Discussionmentioning

confidence: 99%

Reducing the desire for cocaine with subthalamic nucleus deep brain stimulation

Rouaud

Lardeux

Panayotis

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

180

131

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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.O ver the past decade, there has been an increasing interest in neurosurgical procedures using deep brain stimulation (DBS) to treat neurological and psychiatric disorders, such as Parkinson disease (1, 2) and Huntington disease (3), as well as depression (4) and obsessive compulsive disorders (5).A recent study showing that the effects of subthalamic nucleus (STN) DBS mainly result from a stimulation of the cortico-STN fibers questioned the inactivation of STN by DBS (6). However, there was previously a consensus to consider that action of STN DBS as an inactivation of the cell bodies of the targeted structure with an activation of the passing fibers (7). The mechanisms of DBS remain thus a matter of debate.From the clinical point of view, DBS represents a reversible way to inactivate a particular structure in the brain, a strategy that is preferred to ablative surgery in most cases. The choice of the targeted structure is adapted to the disease.In the case of drug addiction, a devastating disorder whose hallmark feature is an uncontrolled motivation to take the drug while naturally rewarding activities are forsaken, it is crucial to decrease the compulsive motivation for the drug, at the same time preventing decreased motivation for alternative rewarding activities.Because cocaine acts by blocking the dopaminergic transporter, and therefore temporarily increases the amount of dopamine (DA) available in the brain, early treatments for addiction targeted DA system to counteract cocaine effects. However, it is now largely accepted that interfering with the ...

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Section: Discussionmentioning

confidence: 99%

Reducing the desire for cocaine with subthalamic nucleus deep brain stimulation

Rouaud

Lardeux

Panayotis

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

180

131

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“…60,61 High-frequency stimulation of the STN may directly activate nigrostriatal and pallidonigral fiber tracts and thus contribute to a therapeutic effect by modulating the release of dopamine. [62][63][64][65][66] Although animal studies have shown a significant increase in striatal dopamine with STN HFS and have offered an attractive explanation for improvement of PD symptoms coincident with a reduction in antiparkinsonian medication, to date there is no evidence that a similar process occurs in humans. Several PET studies using [ 11 C]raclopride to measure dopamine binding have failed to show changes during STN HFS, suggesting that the therapeutic effects of STN stimulation are not mediated by striatal dopamine release.…”

Section: Activation Of Fiber Tracts Of Passagementioning

confidence: 99%

Mechanisms and Targets of Deep Brain Stimulation in Movement Disorders

et al. 2008

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Summary:Chronic electrical stimulation of the brain, known as deep brain stimulation (DBS), has become a preferred surgical treatment for medication-refractory movement disorders. Despite its remarkable clinical success, the therapeutic mechanisms of DBS are still not completely understood, limiting opportunities to improve treatment efficacy and simplify selection of stimulation parameters. This review addresses three questions essential to understanding the mechanisms of DBS. 1) How does DBS affect neuronal tissue in the vicinity of the active electrode or electrodes? 2) How do these changes translate into therapeutic benefit on motor symptoms? 3) How do these effects depend on the particular site of stimulation? Early hypotheses proposed that stimulation inhibited neuronal activity at the site of stimulation, mimicking the outcome of ablative surgeries. Recent studies have challenged that view, suggesting that although somatic activity near the DBS electrode may exhibit substantial inhibition or complex modulation patterns, the output from the stimulated nucleus follows the DBS pulse train by direct axonal excitation. The intrinsic activity is thus replaced by high-frequency activity that is time-locked to the stimulus and more regular in pattern. These changes in firing pattern are thought to prevent transmission of pathologic bursting and oscillatory activity, resulting in the reduction of disease symptoms through compensatory processing of sensorimotor information. Although promising, this theory does not entirely explain why DBS improves motor symptoms at different latencies. Understanding these processes on a physiological level will be critically important if we are to reach the full potential of this powerful tool.

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“…This hypothesis has been raised on the basis of the observation that similarly to lesions to the OFC, lesions to the subthalamic nucleus increase compulsive lever-pressing and decrease dopamine and serotonin (but not glutamate and GABA) in the striatum (Winter et al, 2008a). It is also noteworthy that pharmacological inactivation and high-frequency stimulation of the subthalamic nucleus, that exert an anticompulsive effect in the signal attenuation model (Klavir et al, 2009), have been reported to increase dopamine levels in the striatum (Bruet et al, 2001;Meissner et al, 2001;Lee et al, 2006). To the best of our knowledge there are no studies that assessed the effects of these manipulations on striatal serotonin.…”

Section: Ofc Lesionmentioning

confidence: 99%

The Role of the Striatum in Compulsive Behavior in Intact and Orbitofrontal-Cortex-Lesioned Rats: Possible Involvement of the Serotonergic System

Schilman

Klavir

Winter

et al. 2010

Neuropsychopharmacol

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In the signal attenuation rat model of obsessive-compulsive disorder (OCD), 'compulsive' behavior is induced by attenuating a signal indicating that a lever-press response was effective in producing food. We have recently found that lesions to the rat orbitofrontal cortex (OFC) led to an increase in compulsive lever-pressing that was prevented by systemic administration of the selective serotonin reuptake inhibitor paroxetine, and paralleled by an increase in the density of the striatal serotonin transporter. This study further explored the interaction between the OFC, the striatum, and the serotonergic system in the production of compulsive lever-pressing. Experiment 1 revealed that OFC lesions decrease the content of serotonin, dopamine, glutamate, and GABA in the striatum. Experiment 2 showed that intrastriatal administration of paroxetine blocked OFC lesion-induced increased compulsivity, but did not affect compulsive responding in intact rats. Experiments 3 and 4 found that pre-training striatal lesions had no effect on compulsive lever-pressing, whereas post-training striatal inactivation exerted an anticompulsive effect. These results strongly implicate the striatum in the expression of compulsive lever-pressing in both intact and OFC-lesioned rats. Furthermore, the results support the possibility that in a subpopulation of OCD patients a primary pathology of the OFC leads to a dysregulation of the striatal serotonergic system, which is manifested in compulsive behavior, and that antiobsessional/anticompulsive drugs exerts their effects, in these patients, by normalizing the dysfunctional striatal serotonergic system.

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Dopamine efflux in the rat striatum evoked by electrical stimulation of the subthalamic nucleus: potential mechanism of action in Parkinson's disease

Cited by 132 publications

References 62 publications

Reducing the desire for cocaine with subthalamic nucleus deep brain stimulation

Reducing the desire for cocaine with subthalamic nucleus deep brain stimulation

Mechanisms and Targets of Deep Brain Stimulation in Movement Disorders

The Role of the Striatum in Compulsive Behavior in Intact and Orbitofrontal-Cortex-Lesioned Rats: Possible Involvement of the Serotonergic System

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