Projed 3 combines the research efforts of Dre. Scott Hemby, Steve Childere and Allyn Howlett. The overall goal is to identity biochemical adaptetions with chronic cocaine self-administration and determine the degree to which topiramate and other candidate medications can reveree or attenuate cocaine-induced alterations in specific brain regions. Studies will utilize a combination of procedures to evaluate neuronal plasticity in receptore and their signal transdudion resulting from cocaine administration and the effeds of potential b-eatment agents. The studies will determine changes in gene and protein expression as well as fundional fine-tuning manifested as phosphorylation modifications in discrete brain regions from rodents and nonhuman primates following cocaine self-administration and treatment with the candidate medications. Numerous studies indicate dysregulation of dopaminergic pathways and signaling in humans and animal models, yet pharmacotherapies that diredly target dopamine signaling have proven only moderately successful. An alternative strategy Is to identity medications that target neuroti^ansmitter systems that augment dopaminergic signaling diredty and/or indiredty. Identification of key biochemical processes associated with efficacious medications will provide the basis for development and optimization of next generation pharmacotherapies that can better target cocaine abuse as well as further our underetanding of neurobiological basis of cocaine reinforcement.
Specific Aim 1 (Childere and Howlett labs) will charaderize the effeds of candidate medications on the biochemical neuroadaptations associated with chronic cocaine exposure in rodent models by 1) determining changes in receptor binding properties of ionotropic and metabofropic receptore as well as fondional adivation of GPCR's using GTPyS binding and 2) examining changes In signal transdudion via activation of protein kinase pathways.
Specific Aim 2 (Hemby lab) will assess biochemical neuroadaptations of candidate medication efficacy associated with chronic cocaine exposure in riiesus monkeys by 1) examining mRNA and protein expression of ionotropic glutamate and GABA receptore and related synaptic proteins, as well as targeted proteomic analysis of receptor subunit complexes to provide a more compreliensive underetanding of coordinate synaptic protein alterations and 2) assess mRNA and protein expression of BDNF, frkB and related signaling pathway alterations (akt, PLCg, ERK) in the nucleus accumbens and caudate/putamen.
Identifying the molecular and neurochemical targets that mediate the actions of potential pharmacotherapies to reduce cocaine reinforcement will provide a better understanding of the neurobiological mechanisms of cocaine addiction, as well as provide ways to develop therapeutic agents with higher efficacies and less side effects.
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