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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS033538-09
Application #
6829295
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Refolo, Lorenzo
Project Start
1996-06-01
Project End
2009-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
9
Fiscal Year
2004
Total Cost
$318,368
Indirect Cost
Name
University of California Los Angeles
Department
Psychiatry
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Holley, Sandra M; Wang, Elizabeth A; Cepeda, Carlos et al. (2013) Frontal cortical synaptic communication is abnormal in Disc1 genetic mouse models of schizophrenia. Schizophr Res 146:264-72
Ma, Yao-Ying; Cepeda, Carlos; Chatta, Payush et al. (2012) Regional and cell-type-specific effects of DAMGO on striatal D1 and D2 dopamine receptor-expressing medium-sized spiny neurons. ASN Neuro 4:
Cepeda, Carlos; Levine, Michael S (2012) Dopamine-NMDA receptor interactions: twenty years later. Dev Neurosci 34:2-4
Lam, Hoa A; Wu, Nanping; Cely, Ingrid et al. (2011) Elevated tonic extracellular dopamine concentration and altered dopamine modulation of synaptic activity precede dopamine loss in the striatum of mice overexpressing human ?-synuclein. J Neurosci Res 89:1091-102
Andre, Veronique M; Cepeda, Carlos; Cummings, Damian M et al. (2010) Dopamine modulation of excitatory currents in the striatum is dictated by the expression of D1 or D2 receptors and modified by endocannabinoids. Eur J Neurosci 31:14-28
Wu, Nanping; Joshi, Prasad R; Cepeda, Carlos et al. (2010) Alpha-synuclein overexpression in mice alters synaptic communication in the corticostriatal pathway. J Neurosci Res 88:1764-76
Cummings, Damian M; Yamazaki, Irene; Cepeda, Carlos et al. (2008) Neuronal coupling via connexin36 contributes to spontaneous synaptic currents of striatal medium-sized spiny neurons. J Neurosci Res 86:2147-58
Cepeda, Carlos; Andre, Veronique M; Yamazaki, Irene et al. (2008) Differential electrophysiological properties of dopamine D1 and D2 receptor-containing striatal medium-sized spiny neurons. Eur J Neurosci 27:671-82
Bamford, Nigel S; Zhang, Hui; Joyce, John A et al. (2008) Repeated exposure to methamphetamine causes long-lasting presynaptic corticostriatal depression that is renormalized with drug readministration. Neuron 58:89-103
Hernandez-Echeagaray, Elizabeth; Cepeda, Carlos; Ariano, Marjorie A et al. (2007) Dopamine reduction of GABA currents in striatal medium-sized spiny neurons is mediated principally by the D(1) receptor subtype. Neurochem Res 32:229-40

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