Trait Impulsivity and Anhedonia: Two Gateways for the Development of Impulse Control Disorders in Parkinson's Disease?

Apathy and impulsivity are two major comorbid syndromes of Parkinson's disease (PD) that may represent two extremes of a behavioral spectrum modulated by dopamine-dependent processes. PD is characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta to which are attributed the cardinal motor symptoms of the disorder. Dopamine replacement therapy (DRT), used widely to treat these motor symptoms, is often associated with deficits in hedonic processing and motivation, including apathy and depression, as well as impulse control disorders (ICDs). ICDs comprise pathological gambling, hypersexuality, compulsive shopping, binge eating, compulsive overuse of dopaminergic medication, and punding. More frequently observed in males with early onset PD, ICDs are associated not only with comorbid affective symptoms, such as depression and anxiety, but also with behavioral traits, such as novelty seeking and impulsivity, as well as with personal or familial history of alcohol use. This constellation of associated risk factors highlights the importance of inter-individual differences in the vulnerability to develop comorbid psychiatric disorders in PD patients. Additionally, withdrawal from DRT in patients with ICDs frequently unmasks a severe apathetic state, suggesting that apathy and ICDs may be caused by overlapping neurobiological mechanisms within the cortico-striato-thalamo-cortical networks. We suggest that altered hedonic and impulse control processes represent distinct prodromal substrates for the development of these psychiatric symptoms, the etiopathogenic mechanisms of which remain unknown. Specifically, we argue that deficits in hedonic and motivational states and impulse control are mediated by overlapping, yet dissociable, neural mechanisms that differentially interact with DRT to promote the emergence of ICDs in vulnerable individuals. Thus, we provide a novel heuristic framework for basic and clinical research to better define and treat comorbid ICDs in PD.This is the final published version. It first appeared at http://journal.frontiersin.org/article/10.3389/fpsyt.2016.00091/full

Nigrostriatal Dopaminergic Denervation Does Not Promote Impulsive Choice in the Rat: Implication for Impulse Control Disorders in Parkinson’s Disease

Impulse control disorders (ICDs) are frequent behavioral complications of dopaminergic (DA) replacement therapies (DRTs) in Parkinson’s disease (PD). Impulsive choice, which refers to an inability to tolerate delays to reinforcement, has been identified as a core pathophysiological process of ICDs. Although impulsive choices are exacerbated in PD patients with ICDs under DRTs, some clinical and preclinical studies suggest that the DA denervation of the dorsal striatum induced by the neurodegenerative process as well as a pre-existing high impulsivity trait, may both contribute to the emergence of ICDs in PD. We therefore investigated in a preclinical model in rats, specifically designed to study PD-related non-motor symptoms, the effect of nigrostriatal DA denervation on impulsive choice, in relation to pre-existing levels of impulsivity, measured in a Delay Discounting Task (DDT). In this procedure, rats had the choice between responding for a small sucrose reinforcer delivered immediately, or a larger sucrose reinforcer, delivered after a 0, 5, 10 or 15 s delay. In two different versions of the task, the preference for the large reinforcer decreased as the delay increased. However, and in contrast to our initial hypothesis, this discounting effect was neither exacerbated by, or related to, the extent of the substantia nigra pars compacta (SNc) DA lesion, nor it was influenced by pre-existing variability in impulsive choice. These results therefore question the potential implication of the nigrostriatal DA system in impulsive choice, as well as the DA neurodegenerative process as a factor contributing significantly to the development of ICDs in PD

Élaboration d’un modèle de psychose délirante chez le rat ayant une validité théorique

Au plan cognitif, le délire se caractérise par la présence d’un raisonnement anormal. Des études récentes chez l’homme suggèrent que le mécanisme à l’origine du délire repose sur l’inaptitude des patients à utiliser les informations contextuelles pour traiter de façon appropriée les informations cibles. À titre d’exemple, le sens du mot « baguette » — information cible — change selon le contexte sémantique utilisé dans une histoire parlant de boulangerie (pain) ou de musique (instrument de percussion). Pour modéliser ce processus chez le rat, nous avons utilisé une préparation pavlovienne datant de la fin des années 1960, la contingence dégradée, qui oblige l’animal à utiliser le contexte de conditionnement pour traiter de façon appropriée le stimulus cible, un son. Nos travaux ont permis de mettre en évidence que l’atropine, une substance cholinergique inductrice de délire chez l’homme, supprimait spécifiquement le processus d’utilisation de l’information contextuelle chez le rat. En terme de modélisation et de façon tout à fait intéressante au plan phylogénétique, nous avons constaté que le rat, tout comme l’homme, active un module cognitif localisé au niveau du cortex préfrontal pour effectuer ce processus. Enfin, au plan thérapeutique nous avons montré que les effets délétères de l’atropine sur ce processus de traitement de l’information et sur son module cérébral n’étaient supprimés que par les substances pharmacologiques ayant un profil antipsychotique

Intermittent ethanol access schedule in rats as a preclinical model of alcohol abuse

One of the major challenges in preclinical studies of alcohol abuse and dependence remains the development of paradigms that will elicit high ethanol intake and mimic the progressive transition from low or moderate social drinking to excessive alcohol consumption. Exposure of outbred rats to repeated cycles of free-choice ethanol intake and withdrawal with the use of intermittent access to 20% ethanol in a 2-bottle choice procedure (IA2BC) has been shown to induce a gradual escalation of voluntary ethanol intake and preference, eventually reaching ethanol consumption levels of 5-6 g/kg/24 h, and inducing pharmacologically relevant blood ethanol concentrations (BECs). This procedure has recently been gaining popularity due to its simplicity, high validity, and reliable outcomes. Here we review experimental and methodological data related to IA2BC, and discuss the usefulness and advantages of this procedure as a valuable pre-training method for initiating operant ethanol self-administration of high ethanol intake, as well as conditioned place preference (CPP). Despite some limitations, we provide evidence that IA2BC and related operant procedures provide the possibility to operationalize multiple aspects of alcohol abuse and addiction in a rat model, including transition from social-like drinking to excessive alcohol consumption, binge drinking, alcohol seeking, relapse, and neuroadaptations related to excessive alcohol intake. Hence, IA2BC appears to be a useful and relevant procedure for preclinical evaluation of potential therapeutic approaches against alcohol abuse disorders

GPCR and Alcohol-Related Behaviors in Genetically Modified Mice

International audienceG protein-coupled receptors (GPCRs) constitute the largest class of cell surface signaling receptors and regulate major neurobiological processes. Accordingly, GPCRs represent primary targets for the treatment of brain disorders. Several human genetic polymorphisms affecting GPCRs have been associated to different components of alcohol use disorder (AUD). Moreover, GPCRs have been reported to contribute to several features of alcohol-related behaviors in animal models. Besides traditional pharmacological tools, genetic-based approaches mostly aimed at deleting GPCR genes provided substantial information on how key GPCRs drive alcohol-related behaviors. In this review, we summarize the alcohol phenotypes that ensue from genetic manipulation, in particular gene deletion, of key GPCRs in rodents. We focused on GPCRs that belong to fundamental neuronal systems that have been shown as potential targets for the development of AUD treatment. Data are reviewed with particular emphasis on alcohol reward, seeking, and consumption which are behaviors that capture essential aspects of AUD. Literature survey indicates that in most cases, there is still a gap in defining the intracellular transducers and the functional crosstalk of GPCRs as well as the neuronal populations in which their signaling regulates alcohol actions. Further, the implication of only a few orphan GPCRs has been so far investigated in animal models. Combining advanced pharmacological technologies with more specific genetically modified animals and behavioral preclinical models is likely necessary to deepen our understanding in how GPCR signaling contributes to AUD and for drug discovery

Noribogaine, but not 18-MC, exhibits similar actions as ibogaine on GDNF expression and ethanol self-administration.

Carnicella S present adress: Grenoble Institut des Neurosciences, Inserm U836International audienceIbogaine is a naturally occurring alkaloid that has been reported to decrease various adverse phenotypes associated with exposure to drugs of abuse and alcohol in human and rodent models. Unfortunately, ibogaine cannot be used as a medication to treat addiction because of severe side effects. Previously, we reported that the desirable actions of ibogaine to reduce self-administration of, and relapse to, alcohol consumption are mediated via the upregulation of the expression of the glial cell line-derived neurotrophic factor (GDNF) in the midbrain ventral tegmental area (VTA), and the consequent activation of the GDNF pathway. The ibogaine metabolite, noribogaine, and a synthetic derivative of ibogaine, 18-Methoxycoronaridine (18-MC), possess a similar anti-addictive profile as ibogaine in rodent models, but without some of its adverse side effects. Here, we determined whether noribogaine and/or 18-MC, like ibogaine, increase GDNF expression, and whether their site of action to reduce alcohol consumption is the VTA. We used SH-SY5Y cells as a cell culture model and found that noribogaine, like ibogaine, but not 18-MC, induces a robust increase in GDNF mRNA levels. Next, we tested the effect of intra-VTA infusion of noribogaine and 18-MC on rat operant alcohol self-administration and found that noribogaine, but not 18-MC, in the VTA decreases responding for alcohol. Together, our results suggest that noribogaine and 18-MC have different mechanisms and sites of action

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

Present adress of Sébastien Carnicella: Grenoble Institute of Neuroscience, Institut National de la Santé et de la Recherche Médicale U836, 38100 Grenoble, France. Equipe 10, Dynamique des réseaux neuronaux du mouvementInternational audienceAlcohol 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