Sebastien Carnicella

Subthalamic stimulation in Parkinson’s disease: restoring the balance of motivated behaviours

Addictions to dopaminergic drugs or to pleasant behaviours are frequent and potentially devastating neuropsychiatric disorders observed in Parkinsons disease. They encompass impulse control disorders, punding and dopamine dysregulation syndrome. A relationship with dopaminergic treatment is strongly suggested. Subthalamic stimulation improves motor complications and allows for drastic reductions in medication. This treatment might, therefore, be considered for patients with behavioural addictions, when attempts to reduce dopaminergic medication have failed. However, conflicting data have reported suppression, alleviation, worsening or new onset of behavioural addictions after subthalamic stimulation. Non-motor fluctuations are also a disabling feature of the disease. We prospectively investigated behaviour in a cohort of 63 patients with Parkinsons disease, before and 1 year after subthalamic stimulation using the Ardouin scale, with systematic evaluation of functioning in overall appetitive or apathetic modes, non-motor fluctuations, dopaminergic dysregulation syndrome, as well as behavioural addictions (including impulse control disorders and punding) and compulsive use of dopaminergic medication. Defined drug management included immediate postoperative discontinuation of dopamine agonists and reduction in levodopa. Motor and cognitive statuses were controlled (Unified Parkinsons Disease Rating Scale, Mattis Dementia Rating Scale, frontal score). After surgery, the OFF medication motor score improved (-45.2%), allowing for a 73% reduction in dopaminergic treatment, while overall cognitive evaluation was unchanged. Preoperative dopamine dysregulation syndrome had disappeared in 4/4, behavioural addictions in 17/17 and compulsive dopaminergic medication use in 9/9 patients. New onset of levodopa abuse occurred in one patient with surgical failure. Non-motor fluctuations were significantly reduced with improvements in off-dysphoria (P ≤ 0.001) and reduction in on-euphoria (P ≤ 0.001). There was an inversion in the number of patients functioning in an overall appetitive mode (29 before versus 2 after surgery, P ≤ 0.0001) to an overall apathetic mode (3 before versus 13 after surgery, P < 0.05). Two patients attempted suicide. Improvement in motor fluctuations is linked to the direct effect of stimulation on the sensory-motor subthalamic territory, while improvement in dyskinesias is mainly explained by an indirect effect related to the decrease in dopaminergic drugs. Our data suggest that non-motor fluctuations could similarly be directly alleviated through stimulation of the non-motor subthalamic territories, and hyperdopaminergic side effects might improve mainly due to the decrease in dopaminergic medication. We show an overall improvement in neuropsychiatric symptomatology and propose that disabling non-motor fluctuations, dopaminergic treatment abuse and drug-induced behavioural addictions in Parkinsons disease may be considered as new indications for subthalamic stimulation.

Ethanol induces long-term facilitation of NR2B-NMDA receptor activity in the dorsal striatum: implications for alcohol drinking behavior.

Addiction is characterized by compulsive alcohol or drug taking and seeking, and the dorsal striatum has been implicated in such maladaptive persistent habits. The NMDA receptor (NMDAR), which is a major target of alcohol, is implicated in striatal-based habit learning. We found that, in the dorsal striatum, alcohol (ethanol) exposure produced an increase in the phosphorylation of the NR2B subunit of the NMDAR, and a corresponding increase in the activity of Fyn kinase, which phosphorylates NR2B. We further observed an ethanol-mediated long-term facilitation (LTF) of the activity of NR2B-containing NMDARs (NR2B-NMDARs) in the dorsal striatum. This LTF is Fyn kinase dependent, because it was observed in Fyn wild-type but not in Fyn knock-out mice. Importantly, none of these biochemical and physiological changes was observed in the ventral striatum. Finally, dorsal but not ventral striatum infusion of a Fyn or NR2B-NMDAR inhibitor reduced rat operant self-administration of ethanol. Our results suggest that the Fyn-mediated phosphorylation and LTF of NR2B-NMDAR activity in the dorsal striatum after exposure to ethanol may underlie aberrant plasticity that contributes to mechanisms underlying alcohol drinking behavior.

Long-Lasting Adaptations of the NR2B-Containing NMDA Receptors in the Dorsomedial Striatum Play a Crucial Role in Alcohol Consumption and Relapse

A growing number of studies suggest that the development of compulsive drug seeking and taking depends on dorsostriatal mechanisms. We previously observed that ex vivo acute exposure of the dorsal striatum to, and withdrawal from, alcohol induces long-term facilitation (LTF) of the activity of NR2B-containing NMDA receptors (NR2B-NMDARs) in a mechanism that requires the Src family protein tyrosine kinase (PTK), Fyn (Wang et al., 2007). In the present study, we first compared alcohols actions in rat dorsomedial (DMS) and the dorsolateral (DLS) subregions of the striatum, which differ in their anatomical connectivity and function. We found that alcohol-mediated induction of LTF of NR2B-NMDAR activity is centered in the DMS. Next, we tested whether in vivo exposure of rats to alcohol leads to long-term adaptations of the NMDAR system in the DMS. We observed that repeated daily administration of alcohol results in a long-lasting increase in the activity of the NR2B-NMDARs in the DMS. The same procedure leads to a prolonged activation of Fyn, increased NR2B phosphorylation, and membrane localization of the subunit. Importantly, similar electrophysiological and biochemical modifications were observed in the DMS of rats that consumed large quantities of alcohol. Finally, we show that inhibition of NR2B-NMDARs or Src family PTKs in the DMS, but not in the DLS, significantly decreases operant self-administration of alcohol and reduces alcohol-priming-induced reinstatement of alcohol seeking. Our results suggest that the upregulation of NR2B-NMDAR activity within the DMS by alcohol contributes to the maladaptive synaptic changes that lead to excessive alcohol intake and relapse.

Endogenous BDNF in the Dorsolateral Striatum Gates Alcohol Drinking

We previously found that brain-derived neurotrophic factor (BDNF)-haplodeficient mice exhibit greater ethanol-induced place preference and psychomotor sensitization, and greater ethanol consumption after deprivation, than control mice. We further observed that, in mice, voluntary ethanol intake increases BDNF expression in the dorsal striatum (DS). Here, we determined whether BDNF within the DS regulates ethanol self-administration in Long–Evans rats trained to self-administer a 10% ethanol solution. We observed a greater increase in BDNF expression after ethanol self-administration in the dorsolateral striatum (DLS) than in the dorsomedial striatum (DMS). We further found that downregulation of endogenous BDNF using viral-mediated siRNA in the DLS, but not in the DMS, significantly increased ethanol self-administration. Infusion of exogenous BDNF (0.25 μg/μl/side into the DMS; 0.25 and 0.75 μg/μl/side into the DLS) attenuated responding for ethanol when infused 3 h before the beginning of the self-administration session. Although the decrease in ethanol intake was similar in the DLS and DMS, BDNF infused in the DLS, but not in the DMS, induced an early termination of the drinking episode. Furthermore, the action of BDNF in the DLS was specific for ethanol, as infusion of the neurotrophic factor in the DMS, but not DLS, resulted in a reduction of sucrose intake. Together, these findings demonstrate that the BDNF pathway within the DLS controls the level of ethanol self-administration. Importantly, our results suggest that an endogenous signaling pathway within the same brain region that mediates drug-taking behavior also plays a critical role in gating the level of ethanol intake.

Role for mammalian target of rapamycin complex 1 signaling in neuroadaptations underlying alcohol-related disorders

Alcohol addiction is a chronically relapsing disorder that includes certain maladaptive learning and memory. The serine and threonine kinase complex, mammalian target of rapamycin complex 1 (mTORC1), has been implicated in synaptic plasticity, learning, and memory by controlling protein translation. Here we show that administration of alcohol and excessive voluntary consumption of alcohol induce the activation of the mTORC1-mediated signaling pathway in the nucleus accumbens (NAc) of rodents. We further show that the protein expression levels of GluR1 and Homer, two synaptic proteins whose translation has been shown to be modulated by mTORC1, are up-regulated in the NAc of rodents with a history of excessive alcohol consumption. In addition, our results document that the Food and Drug Administration-approved inhibitor of mTORC1, rapamycin, decreases expression of alcohol-induced locomotor sensitization and place preference, as well as excessive alcohol intake and seeking in preclinical rodent models of alcohol abuse. Together, our results suggest that mTORC1 within the NAc is a contributor to molecular mechanisms underlying alcohol-drinking behaviors. Furthermore, despite its massive health and socioeconomic impact worldwide, pharmacotherapies for alcohol abuse and addiction remain limited. Our data therefore put forward the possibility that targeting the mTORC1 signaling cascade is an innovative and valuable strategy for the treatment of alcohol use and abuse disorders.

Loss of dopaminergic nigrostriatal neurons accounts for the motivational and affective deficits in Parkinson's disease.

Parkinson’s disease (PD) involves the degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) that is thought to cause the classical motor symptoms of this disease. However, motivational and affective impairments are also often observed in PD patients. These are usually attributed to a psychological reaction to the general motor impairment and to a loss of some of the neurons within the ventral tegmental area (VTA). We induced selective lesions of the VTA and SNc DA neurons that did not provoke motor deficits, and showed that bilateral dopamine loss within the SNc, but not within the VTA, induces motivational deficits and affective impairments that mimicked the symptoms of PD patients. Thus, motivational and affective deficits are a core impairment of PD, as they stem from the loss of the major group of neurons that degenerates in this disease (DA SNc neurons) and are independent of motor deficits.

Nucleus accumbens-derived glial cell line-derived neurotrophic factor is a retrograde enhancer of dopaminergic tone in the mesocorticolimbic system.

Spontaneous firing of ventral tegmental area (VTA) dopamine (DA) neurons provides ambient levels of DA in target areas such as the nucleus accumbens (NAc) and the prefrontal cortex (PFC). Here we report that the glial cell line-derived neurotrophic factor (GDNF), produced in one target region, the NAc, is retrogradely transported by DA neurons to the VTA where the growth factor positively regulates the spontaneous firing activity of both NAc- and PFC-projecting DA neurons in a mechanism that requires the activation of the mitogen-activated protein kinase (MAPK) pathway. We also show that the consequence of GDNF-mediated activation of the MAPK signaling cascade in the VTA is an increase in DA overflow in the NAc. Together, these results demonstrate that NAc-produced GDNF serves as a retrograde enhancer that upregulates the activity of the mesocorticolimbic DA system.

Emotional manifestations of PD: Neurobiological basis

Neuropsychiatric symptoms are common and disabling in PD. Their neurobiological bases are complex, partly because of the disease itself and partly because of the dopaminergic treatment. The aim of this review is to focus on the emotional manifestations stemming from the neurodegenerative process itself. We focus on depression, anxiety, apathy, and fatigue, which can all be part of the clinical spectrum of premotor disease and may be improved or masked by medications targeting parkinsonian motor signs or psychiatric symptoms as the disease progresses. Findings from clinical, neuroimaging, and animal studies are reviewed, showing a major contribution of the dopaminergic system to the pathophysiology of these disabling symptoms. Degeneration of noradrenergic and serotonergic projection systems also has an impact on psychiatric symptoms of PD. The available literature is reviewed, but at present there is a lack of studies that would allow disentangling the separate contribution of each of the monoaminergic systems. The use of a pragmatic classification of all these symptoms under the umbrella of hypodopaminergic behavioral syndrome seems clinically useful, as it emphasizes the crucial, although not exclusive, nature of their dopaminergic neurobiological basis, which has important implications in the clinical management of PD.

Pramipexole reverses Parkinson's disease‐related motivational deficits in rats

Recent evidence suggests that Parkinsons disease affects not only movement, but also cognitive and psychiatric functions. Among these nonmotor complications, apathy, which is defined as a lack of motivation and operationalized as a quantitative reduction in goal‐directed behavior, may even precede motor impairments, disappearing with the introduction of dopaminergic (DA) therapies and possibly reappearing with its discontinuation, suggesting a causal role of DA. We recently developed a lesion‐based model, with stereotaxic infusion of 6‐hydroxydopamine (6‐OHDA) into precise areas of the rat SNc or ventral tegmental area and showed, in several operant tasks, that a partial denervation of the nigrostriatal, but not of the mesocorticolimbic, DA system induced profound motivational deficits during instrumental action. We investigated the time course of the effects of nigrostriatal DA denervation on motivation in rats, by assessing the negative effect of SNc bilateral 6‐OHDA infusion on preacquired operant behavior, and determining whether the induced deficits were sensitive to the introduction and withdrawal of a clinically relevant PD treatment, the DA D2/D3 receptor agonist, pramipexole (PRA). Partial nigrostriatal DA denervation was accompanied by a significant reduction in operant behavior. This deficit, indicative of a decrease in motivation, was fully reversed by PRA and reappeared after treatment withdrawal. This longitudinal preclinical study provides evidence for the implication of the DA nigrostriatal system in PD‐associated apathy. Moreover, by showing a good isomorphy and predictive value, our model highlights the relevance of D2/D3 receptors as potential targets for alleviating apathy in PD.

Regulation of Operant Oral Ethanol Self-Administration: A Dose-Response Curve Study in Rats

BACKGROUND Oral ethanol self-administration procedures in rats are useful preclinical tools for the evaluation of potential new pharmacotherapies as well as for the investigation into the etiology of alcohol abuse disorders and addiction. Determination of the effects of a potential treatment on a full ethanol dose-response curve should be essential to predict its clinical efficacy. Unfortunately, this approach has not been fully explored because of the aversive taste reaction to moderate to high doses of ethanol, which may interfere with consumption. In this study, we set out to determine whether a meaningful dose-response curve for oral ethanol self-administration can be obtained in rats. METHODS Long-Evans rats were trained to self-administer a 20% ethanol solution in an operant procedure following a history of excessive voluntary ethanol intake. After stabilization of ethanol self-administration, the concentration of the solution was varied from 2.5 to 60% (v/v), and operant and drinking behaviors, as well as blood ethanol concentration (BEC), were evaluated following the self-administration of a 20, 40, and 60% ethanol solution. RESULTS Varying the concentration of ethanol from 2.5 to 60% after the development of excessive ethanol consumption led to a typical inverted U-shaped dose-response curve. Importantly, rats adapted their level and pattern of responding to changes in ethanol concentration to obtain a constant level of intake and BEC, suggesting that their operant behavior is mainly driven by the motivation to obtain a specific pharmacological effect of ethanol. CONCLUSION This procedure can be a useful and straightforward tool for the evaluation of the effects of new potential pharmacotherapies for the treatment of alcohol abuse disorders.