Role of dopamine-glutamate receptor heteromers and downstream nuclear calcium signaling in addiction

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Addiction, like other psychiatric disorders, is associated with an imbalance of dopamine (DA) and glutamate (Glu) mediated synaptic transmission in the brain. A central goal of this proposal is to establish means of targeting the crosstalk between DA receptors (DARs) and NMDA-type glutamate receptors (NMDARs), rather than the functions of the individual receptors, which may provide the basis for novel, more specific and effective therapies. Heteromers that are formed by the interaction of DA D1 receptors (D1Rs) and NMDARs in the striatum control synaptic plasticity and cocaine-induced signaling. We will explore the role of DAR/NMDAR heteromers and their downstream nuclear calcium signaling in the development of addiction and identify key targets for the design of novel pharmacological tools to combat addiction. Partners 1 and 2 set up novel approaches to detect DAR/NMDAR heteromers and to block the signaling events associated with them. The modulation of D1R/GluN1 and D2R/GluN2B heteromers will be studied in the entire reward circuitry during cocaine-induced psychomotor sensitization and in the context of natural reward. Our preliminary data indicate a dramatic increase of D1R/GluN1 heteromers in the striatum of mice during psychomotor sensitization. Viral-based approaches will be developed to block, in a region-specific and temporally controlled manner, heteromer formation in order to determine their functions in cocaine addiction. Disruption of D1R/GluN1 heteromers inhibits the generation of nuclear calcium signals in cultured striatal medium-size spiny neurons (MSNs). Partner 3 has established that nuclear calcium transients are critical events linking changes in neuronal activity to gene transcription and memory consolidation. Partners 1 and 3 will study the role of this particular pool of calcium in the context of addiction. Partner 3 will study the dynamics of nuclear calcium signals in the striatum in D1R-MSN or D2R-MSN in freely moving mice during cocaine-induced psychomotor sensitization with or without pretreatment with blockers of heteromer formation. Blockers of nuclear calcium signaling will be used to establish causal links to long-term behavioral adaptations, changes of the neuronal morphology and gene expression profiles. To address the difficulties associated with the use of peptides in pre-clinical/clinical studies, partner 4 will screen a library for non-peptide compounds that target specifically DAR/NMDAR heteromers. Lead compounds will be tested in vitro and in vivo for their ability to disrupt endogenous heteromers, their downstream nuclear calcium signaling and cocaine addiction associated behavioral alterations. This project may lead to a major step forward towards identifying new targets with therapeutic potentials not only for addiction but also for various other psychiatric diseases that are accompanied by dysfunctions of the reward system due to an imbalance of DA and Glu mediated synaptic transmission in the striatum.