Project Summary mTORC1 as an essential signaling pathway for drug addiction. In its canonical role, mTORC1 responds to the energy and nutrient status of cells to control fundamental processes that control cell growth and reestablish homeostasis. mTORC1 is also dynamically activated by cocaine in neurons that express D1 dopamine receptors (D1R) and inhibition of mTORC1 prevents behavioral effects of cocaine including cocaine self- administration. Accordingly, it is important to understand how mTORC1 is activated in neurons and how mTORC1 signaling contributes to effects of cocaine. Aim 1 tests the hypothesis that mTORC1 signaling is induced as part of the homeostatic scaling process that controls the strength of excitatory synapses. Preliminary studies indicate that Rheb1, which is essential for mTORC1 activation, associates with group 1 metabotropic glutamate receptors and endosomes that move synaptic proteins from the postsynaptic spine to sites of protein degradation in the dendrite. Studies will examine trafficking of Rheb1 and test the role of adaptor proteins that may couple Rheb1 to glutamate receptors and play a role in mTORC1 activation. The role of the amino acid sensor GATOR2 will also be examined in mTORC1 activation in neurons. Aim 2 examines the hypothesis that mTORC1 functions as a co-stimulatory pathway for D1R signaling. This hypothesis builds upon use state of the art mass spectroscopic analysis of phosphoproteins to identify signaling crosstalk between mTORC1 and D1R. Studies will also test the hypothesis that persistent activation of mTORC1 can block D1R behaviors by “occluding” D1R signaling. Aim 3 tests the relevance of biochemical signaling pathways in behaviors relevant to cocaine addiction including self-administration and reinstatement after extinction. These studies will define essential mechanisms of mTORC1-D1R signaling important for drug addiction.