SAMENTA - Santé Mentale - Addictions

Etiological and pathophysiological contributions of impulsivity trait and anhedonia to impulse control disorders in Parkinson's disease – IMAPARK

Etiological and pathophysiological contributions of impulsivity trait and anhedonia to impulse control disorders in Parkinson's disease

Study of the role of some personnality traits (impulsivity, depression, anhedonia) and neurobiological dysfunctions in the development of impulse control disorders in parkinsonian patients.

Is an impulsive trait or anhedonia favor the development of impulse control disorders in parkinsonian patients?

This project aims at better understanding the pathophysiological mechanisms underlying the development of impulsive and compulsive behaviors in Parkinson's disease. We are trying to answer to the following question with multidisciplinary and translational approaches:<br />T1. Determine in rats whether impulsive trait is a factor of vulnerability to develop Parkinson's disease.<br />T2. Determine whether dopaminergic medications leads to to the development of impulsive and compulsive behaviors, depending on on the denervation state and impulsive traits.<br />T3. Understand the molecular and cellular mechanisms that underlie such behaviors.<br />T4. Identify in parkinsonian patients the nature of impulsive traits, its dimensional relationship with compulsive behaviors and whether premorbid impulsivity may contribute to early-onset PD and ICBs thanks to sibling studies.

- 5-choice (5-CSRTT) and delay-discounting task to evaluate motor and cognitive impulsivity respectively, as well as motivation.
- Lesional approach with the neurotoxin 6-OHDA (non motor rodent model of Parkinson's disease, Drui et al. Mol Psychiatry, 2014).
- Systemic administration of pramipexole, as a dopaminergic treatment that induces impulse control disorders in some parkinsonian patients.
- Autoradiography in order to assess the function of the dopamine receptors in the striatum.
- Molecular approaches and electrophysiogy to investigate mechanisms of synaptic plasticity.
- Longitudinal clinical study of parkinsonian patients with or without impulse control disorders and their siblings.

We first showed that pramipexole increases cognitive impulsivity in rodents.
This effect might be underlined, as suggested by our autoradiographic and molecular studies, by important modifications of the expression of specific dopamine receptors and activities of some signaling pathways.
On the clinical side, the recruitement phase is well advanced and the neuropsychological evaluations started.

- We are currently testing whether pramipexole will have the same effect on motor impulsivity.
- Confirmation of relevant molecular markers of the aberrant behaviors we observed under pramipexole.
- Initiation of the electrophsyiological studies.
- Continuation of the clinical study with neuropsychological evaluation and functional imagery.

Scientic articles :
- Houeto JL, Magnard R, Dalley J Belin D, Carnicella S. High impulsivity trait and anhedonia: two gateways? for the development of impulse control disorders in Parkinson's disease? (2016) Front Psychiatry 7:91.

- Magnard R, Vachez Y, Carcenac C, Krack P, David O, Savasta M, Boulet S, Carnicella S. What rodent model can tell us about apathy and associated neuropsychiatric symptoms in Parkinson’s disease? (2016) Transl Psychiatry 6:e753.

- Favier M, Carcenac C, Drui S, Vachez Y, Boulet S, Savasta M, Carnicella S. Role of dorsostriatal D3 receptors in motivational processes: implication for the neuropsychiatric symptoms in Parkinson’s disease. In revision.

Idiopathic Parkinson’s disease (PD) is a neurodegenerative disorder resulting mainly from the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc), but neither the neurobiological mechanisms, nor the etiopathogenic factors of this degeneration are understood. At the clinical level, the general wisdom has long been that early symptoms of PD are movement deficits eventually spreading later on to cognitive and psychiatric processes. However, there is increasing evidence that not only can the latter appear before the onset of the former but also that cognitive and psychiatric impairments greatly contribute to patients’ morbidity and quality of life.
These non-motor symptoms range from dramatic deficits in hedonic processes, including decrease in motivated behaviors (apathy) and depression to behavioral complications such as pathological gambling or compulsive overuse of DA medication, termed as Impulsive Compulsive Behaviors (ICBs) and observed in up to 17% of - prevalently early-onset - PD patients. Interestingly, the epidemiology and phenomenology of ICBs, suggest that impulsivity, a maladaptative behavior characterized by poorly conceived, prematurely expressed, unduly risky or inappropriate actions often resulting in undesirable consequences, underlined by hyperdopaminergic activity in the mesolimbic system, lies at the core of these symptoms.
At the neurobiological level, non-motor symptoms have been considered to depend upon alterations of the DA mesolimbic system, with apathy and depression suggested to result from lesion-associated decrease in DA tone, while ICBs may result from DA Replacement (especially D2/D3 DA receptors agonists-based) Therapy (DRT). However, this wisdom has been challenged by a recent experimental model we have developed. Indeed, in rats with bilateral selective lesions of either the ventral tegmental area (VTA) or the SNc, neither resulting in major motor deficits thereby facilitating an accurate measure of the respective role of the mesolimbic vs nigrostriatal systems in motivational and affective processes, we have shown that apathetic-related behaviors may stem specifically from the loss of SNc DA neurons, suggesting a strong pathophysiological implication of the DA nigrostriatal system in the occurrence of some PD non-motor symptoms, thereby representing a major public health issue.
This whole set of data is of marked interest when considered that ICBs may depend upon altered D2/D3 DA receptors function and associated plasticity within the ventral and/or the dorsal striatum respectively. The development of ICBs following chronic DRT exposure in PD may therefore reflect a determinant interaction between the disease process itself (i.e., SNc DA loss) and the neurobiological mechanisms that underlie the propensity of individuals to expressed ICBs. If this assumption is correct, it may further imply that premorbid high impulsivity trait and its associated DA phenotype (exacerbated DA activity), may be a risk factor to develop early-onset PD and associated increased vulnerability to develop ICBs.
In this context, this proposal will lead to a better physiopathological and clinical knowledge of ICBs in PD and will address four main questions: 1) Does high impulsive trait represents a risk factor to develop early-onset PD and associated ICBs? 2) Does lesion of the SNc DA neurons interact with high impulsive trait to promote ICBs? 3) Does DRT facilitate the emergence of ICBs after SNc DA lesion in rats with or without premorbid impulsivity? 4) What are the underlying cellular and molecular mechanisms?
By implementing a unique translational strategy, we will combine correlational and dimensional studies in PD patients and causal manipulations of the DA system in rats identified as high or low impulsive in association with neuroanatomical, electrophysiological and molecular approaches.

Project coordination

Sebastien Carnicella (Centre de Recherche Inserm U836 - Grenoble Institut des Nerosciences) – sebastien.carnicella@inserm.fr

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

INSERM Centre de Recherche Inserm U836 - Grenoble Institut des Nerosciences
INSERM INSERM CIC-P 1402 / CHU de Poitiers

Help of the ANR 469,764 euros
Beginning and duration of the scientific project: March 2014 - 48 Months

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