In Vitro Study of ADHD Treatment Impacts on Dopamine Neurons: Modulation of Neurotransmitter Sensitivity after Chronic Activation of the D2 Dopamine Autoreceptor

Grant Type
Basic
Grant Year
2008-2009
Institution Location
Foreign
Institution Organization Name
University of Montreal Canada
Investigators Name
Fasano, Caroline, PhD

Tourette Syndrome (TS) is considered to be a genetic neuropsychiatric disorder that frequently occurs with Attention-Deficit and HyperactivityDisorder (ADHD). The drug most commonly prescribed for ADHD patients is methylphenidate (RitalinTH) which specifically blocks dopamine reuptake. The daily intake of methylphenidate causes a sustained increase in dopamine concentration in the brain that in turn activates dopamine receptors. The consequences of chronic activation of the dopamine system are not clearly established although it has been demonstrated that activation of the D2 dopamine receptor (D2R) can induce a form of structural plasticity of dopaminergic neurons. Based on a multi-disciplinary approach this project will determine how structural plasticity is associated with functional plasticity of dopamine neurons. With the TSA funding, I will attempt to determine whether the neurotransmitter sensitivity of dopamine neurons is modulated directly by activation of the D2R receptor or indirectly by the methylphenidate itself. Direct activation of the D2R will be achieved using a chemical called quinpirole which binds to the receptor. The study I propose will be performed using postnatal mouse neurons in primary culture. Over a period of several days I will treat young dopamine neurons cultured from a transgenic mouse with either methylphenidate or with quinpirole. In addition, I will evaluate the sensitivity of the principal neurotransmitters that regulate dopamine neurons in the brain: i) glutamate, released by the cortical inputs, ii) GABA, released by interneurons and striatal projection neurons and iii) dopamine itself which is released both from the axonal and somatodendritic compartments of dopamine neurons. In the end, I hope that this study will help us better understand some of the adaptive and maladaptive changes occurring during ADHD treatment of TS patients. Hopefully this study will contribute to the development of new pharmacological strategies to improve the quality of life for many people with TS. Caroline Fasano, Ph.D. University of Montreal, Quebec, Canada Award: $8,000 (Fellowship) Tourette Association of America Inc. – Research Grant Award 2008-2009