Impulse Control Disorders in Parkinson’s Disease: Pathophysiology, Effect of Genetic Polymorphism and Future Research Directions

Special Article - Parkinson’s Disease & Movement Disorders

Austin J Clin Neurol 2017; 4(1): 1100.

Impulse Control Disorders in Parkinson’s Disease: Pathophysiology, Effect of Genetic Polymorphism and Future Research Directions

Bhattacharjee S*

Department of Neurology, Plymouth Hospital NHS Trust, UK

*Corresponding author: Bhattacharjee S, Department of Neurology, Plymouth Hospital NHS Trust, PL68DH, UK

Received: December 21, 2016; Accepted: January 25, 2017; Published: January 27, 2017

Abstract

Impulse control disorder is a common non- motor feature observed in Parkinson’s disease. Impulse control disorders were reported in up to 13.6% of Parkinson Disease patients. Though there are multiple theories to explain the generation of Impulse control disorders in Parkinson’s disease but the most recent theory suggests that it happens due to the overstimulation of Dopamine type 3 (D3) receptor in the limbic area. Though Dopamine Agonists are well known risk factors for impulse control disorders but recently few studies explored the influence of genetic polymorphism in the generation of impulse control disorders. The existing evidences suggest that genetic polymorphism in Dopamine receptor D1, D2, D3 and the N-Methyl D Aspartate receptor GRIN2Bare the risk factors for the development of impulse control disorders in Parkinson’s disease. Other genetic polymorphism which were found to be associated with ICDs includes Hydroxytryptamine receptor (HTR2A), Dopa Decarboxylase (DDC) and Dopamine Transporter 1 (DAT1) genes. However, the cumulative dose of Levodopa and the ethnicity probably influence the genetic polymorphism in the development of impulse control behaviours. In future large studies involving multiple genes of the dopaminergic and glutamatergic pathways are needed.

Keywords: Dopamine; Glutamate; Impulse; Disorders; Gene; Polymorphism

Introduction

Impulse Control Disorders (ICD) is characterized by the failure to resist an urge or temptation to perform an act which is detrimental to one self or others. Impulse Control Disorder (ICD) is a common nonmotor feature observed with a frequency up to 13.6% in Idiopathic Parkinson’s Disease (PD) population [1]. Common ICDs reported in PD includes pathological gambling, hypersexuality, compulsive eating, excessive buying, excessive intake of Levodopa despite dyskinesia (Dopamine dysregulation syndrome) and punding. Pathological gambling and hypersexuality are more commonly reported in male while excessive buying and binge eating are more common in female PD patients [2].

The neurobiology and pathophysiology of impulse control disorders in parkinson’s disease

The Nigrostriatal, Mesocortical and Mesolimbic Dopaminergic pathways play a crucial role in the pathophysiology and pathogenesis of ICD in PD. The Mesocortical pathway is a connection between the Ventral tegmentum (VTA) of the midbrain and the prefrontal cortex while the Mesolimbic pathway is a connection between the VTA and Nucleus Accumbens (NA) of the limbic system through amygdala and Hippocampus [2]. The NA is important for the reward system and Amygdala is important for the conditioned response.

The exact mechanism of impulse control disorder in PD is not clear. Long term use of Dopamine agonists, a well- known risk factor for the development of ICD leads to down regulation of D2 receptors expression [2]. Consequently, the PD patients seek higher than normal stimuli to obtain sufficient rewards. The second possible reason will be the greater tonic Dopamine release and reduced phasic release. The tonic Dopamine release occurs with any action of greater uncertainty like gambling etc. The phasic Dopamine release happens when a reward is anticipated and is suppressed when the reward is not granted. The greater tonic release of Dopamine will lead to a relative Dopamine deficit and reduced reward sensation. Another possible cause is the over activity of the brain areas involved in reward based learning and impulse control behaviours. The limbic area including the NA area which controls the reward and emotions have greater concentration of dopamine 3 (D3) receptors. Dopamine agonist drugs preferentially act on these D3 receptors instead of D1/D2 receptors and increases the risk of ICDs. D1 and D2 receptors that are more abundant in Caudate nucleus and Putamen are more selectively targeted by Levodopa. As the Caudate Nucleus and Putamen have no major role in impulse control and reward seeking behaviours the risk of ICD with Levodopa is much less. However, ICD is a complex process emanating from the interaction among dopaminergic, Glutamatergic, Serotonergic and Opioid pathways and there are conflicting evidences about the role of various neurotransmitter pathways in the pathogenesis of ICD.

Impact of Genetic polymorphism on the risk of developing ICD in PD and the review of related literature

The influence of genetic polymorphism on ICD in patients with PD is poorly studied. Genetically, the two most widely studied pathways in ICD are the Dopaminergic and Glutamatergic pathways. The Dopamine receptors where genetic polymorphism was found to be associated with the increased risk of ICD are D1, D2 and D3 [2] (Table 1). N-Methyl-D -Aspartate (NMDA) is a Glutamate receptor. The NMDA receptor subunit NR2 has 4 subtypes namely GRIN2A, 2B, 2C and 2D. The GRIN 2B is the most important of the NR2 subtypes where single nucleotide polymorphism was found to have an association with the risk of ICD [3]. GRIN 2B is more commonly expressed in Striatum. Other polymorphism which were found to be associated with ICDs include Hydroxytryptamine receptor (HTR2A), Dopa Decarboxylase (DDC) and Dopamine Transporter 1 (DAT1) genes.

Citation: Bhattacharjee S. Impulse Control Disorders in Parkinson’s Disease: Pathophysiology, Effect of Genetic Polymorphism and Future Research Directions. Austin J Clin Neurol 2017; 4(1): 1100. ISSN:2381-9154