The brain is made up of many different types of neurons. For example, one class of neuron in the striatum is called the medium spiny neuron (MSN). These spiny neurons are so called because they contain dendritic spines that form connections, called synapses, with glutamate-containing axons from the cortex and dopamine containing axons from the substantia nigra. The dendritic spines on the MSNs contain signaling and scaffolding molecules in an electron dense area called the postsynaptic density. Psychostimulant drugs of abuse act to increase dopamine release from nigral dopaminergic neurons, which has downstream effects on proteins that are localized to MSN dendritic spines. One protein, spinophilin, is increased upon chronic exposure to psychostimulant drugs of abuse. Striatal MSNs can be subdivided into two classes, direct and indirect pathway neurons. Currently there are very few ways to evaluate the function of synaptic proteins in the different classes of MSNs. This is important because the two classes of MSNs have different responses to psychostimulant exposure. The goal of our proposal is to determine the function of spinophilin in the two classes of MSNs in regulating responses to chronic non-toxic and toxic regimens of psychomotor stimulants such as cocaine and amphetamines. Determining the cell-specific role of spinophilin in mediating pathologies associated with these drugs of abuse will identify new pathways that can be targeted for treatment of addiction and disorders associated with long-term methamphetamine abuse, such as Parkinson disease (PD). In this proposal, we hypothesize that spinophilin plays a unique role in the two MSN populations in mediating psychostimulant-induced pathologies. This hypothesis will be tested using the following specific aims: Aim 1. (R21). Generate and validate mouse lines expressing tamoxifen-inducible, iCre in direct and indirect pathway MSNs. We will generate mouse lines that express a tamoxifen-inducible, improved Cre (iCre) recombinase in direct or indirect pathway MSNs. Aim 2. (R21). Generate and validate floxed spinophilin (Spinofl/fl) mice. We will generate a novel transgenic mouse line that will be crossed with the iCre animals generated in aim 1 to create MSN-specific spinophilin KO animals. Aim 3. (R33). Determine the role of spinophilin in direct and indirect pathway MSNs on psychostimulant sensitization. We will use mice created in aims 1 and 2 to determine the function of spinophilin in the two MSN populations on the regulation of pathologies associated with psychostimulant-induced sensitization Aim 4. (R33). Determine the role of spinophilin in direct and indirect pathway MSNs on METH toxicity. We will use mice created in aims 1 and 2 to determine the function of spinophilin in the two MSN populations on the regulation of pathologies associated with methamphetamine-induced toxicity.