Drug addiction is defined as a compulsive pattern of drug-seeking and drug-taking behavior that takes places atthe expense of most other activities. To address the question why addicts find it so difficult to stop using drugs,much research has been aimed at characterization of brain systems that mediate the rewarding effects ofaddictive drugs. The brain reward circuits include dopaminergic innervations from ventral tegmental area andsubstantia nigra to the nucleus accumbens (ventral striatum) and caudate putamen (dorsal stnatum) as well asglutamate inputs from the prefrontal cortex, amygdala and hippocampus. The dendritic spines of medium spinyneurons in striatum are the cellular location for the integration of dopamine and glutamate transmission both ofwhich are important for development and expression of the adaptive effects of psychostimulants. Because of thelong lasting aspects of drug addiction, reorganization of synaptic connections and their maintenance have beensuggested as a cellular mechanism of learning and enduring memory associated with addictive behaviors.However, the function and molecular mechanism of psychostimulant-induced dendritic spine proliferation arenot fully understood. We propose to investigate cocaine-induced spine proliferation and its physiologicalsignificance in two major neuronal subpopulations in striatum: striatonigral and striatopallidal neurons (Aim I).We hypothesize that reorganization of actin filaments may underlie the mechanisms involved in spineproliferation induced by psychostimulants. Regulators of the actin cytoskeleton may play an essential role indrug-induced spine formation. We therefore propose to study five regulators of actin dynamics as targets ofpsychostimulants in spine proliferation:
Cdk5 (Aim II), WAVE1 (Aim III) as a new substrate of Cdk5,spmophilin (Aim IV), neurabin (Aim IV) and Lfc (Aim IV) as a new molecule interacting withspinpphilin/neurabin. In order to address the role of the five key regulators in psychostimulants-induced spineproliferation, we will analyze the biochemical, cell morphological, electrophysiological and behavioralresponses to administration of cocaine in neuronal type-specific or conventional knockout mice and wild typemice. Furthermore, to identify novel targets involved in the actions of psychostimulants on spine formation, wepropose to perform quantitative proteomic analysis of purified post-synaptic density after chronic treatmentwith cocaine (Aim I). Taken together, these studies will lead to elucidation of molecular mechanism(s) leadingto spine formation after repeated exposure to addictive drugs and the role of spine formation in the actions ofpsychostimulants.
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