The experiments in this proposal are designed to continue our investigations into cellular electrophysiological processes controlling dopamine (DA) modulation of responses mediated by activation of ionotropic glutamate receptors (iGluRs) in medium-sized spiny neurons of the striatum (MSSNs). The complex interactions between DA and iGluR-mediated neurotransmission within the striatum form the underpinnings of movement sequencing, motivation and reward responses, and psychological normalcy, just to provide a few examples. Imbalances in the interplay of these neurotransmitters have devastating consequences that are apparent in prevalent neurological and neuropsychiatric diseases such as Parkinson's and Huntington's diseases, attention deficit hyperactivity disorder (ADHD), schizophrenia, Tourette's syndrome, and many addictions. We have shown that DA, via D1 receptor activation enhances responses mediated by NMDA receptors while D2 receptor activation attenuates responses mediated by non-NMDA receptors (AMPA/KA). For example, when a D1 agonist was applied and a response was mediated by NMDA receptors, 98% of the time the response was enhanced. When a D2 agonist was applied and a response was mediated by non-NMDA receptors the response was attenuated 100% of the time. Other combinations (D2-DMDA, D1-non-NMDA) were less predictable. We will continue to focus on these interactions as an underlying theme, but will evaluate new areas pertaining to DA modulation. First, we will assess DA-iGluR interactions in a novel mouse model of ADHD that has the DA transporter (DAT) knocked down to 10% of basal levels. This produces a hyperDA state. Our working hypothesis is that DA modulation of iGluR transmission is altered in this genetic model and we have preliminary data to support it. Second, we will further examine mechanisms that control the predictability of DA modulation of GluR responses determining why the D2-NMDA and D1-non-NMDA receptor interactions are less predictable. Our hypothesis is that if factors controlling these interactions can be reduced, the interactions become predictable. We will use a novel mouse model in which enhanced green fluorescent protein is expressed under the control of the promoters for the D1 or D2 DA receptors or the M4 muscarinic acetylcholine receptor. This will allow electrophysiological recording in identified MSSNs that make up the direct or indirect output pathways of the striatum. Third, we will begin to dissect the NMDA receptor in MSSNs to determine how DA modulation is affected when selective subunits or their components (NR2A, NR2A-C-terminal, NR2B) have been removed or blocked pharmacologically. Our working hypothesis is that MSSN subunit composition of the NMDA receptor is an important determinant in predicting the outcome of D1 modulation. Together, these studies will provide important and new information about the physiological uniqueness and fundamental characteristics in ADHD, new information about the factors underlying the direction of DA modulation of iGluR neurotransmission and distinguish the contribution of NMDA receptors to DA modulation. We possess the unique tools and reagents to perform these studies and they will contribute to development of novel drug strategies to intervene in the treatment of ADHD as well as other diseases involving DA-iGluR interactions. ? ?
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