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Role of ASIC1A in Regulating the NAc Proteome in Both the Drug Naïve and Cocaine Withdrawn States

Rebecca Taugher, Department of Psychiatry, University of Iowa

Substance use disorders produce an enormous burden, yet our understanding of their underlying pathophysiology remains remarkably limited. Drugs of abuse, such as cocaine, evoke long-lasting synaptic changes which may underlie the development and persistence of substance use disorders. Thus, understanding drug-induced synaptic adaptations that increase vulnerability to substance abuse may be critical in order to identify novel treatment strategies. We recently identified a novel role for synaptic pH and acid-sensing ion channel-1A (ASIC1A) in opposing drug-seeking behaviors involving cocaine and morphine and further suggest a role for ASICA in regulating dendritic spine morphology and synaptic plasticity in medium spiny neurons in the nucleus accumbens (NAc) (Kreple et al., 2014). This pilot project seeks to increase our understanding of how ASIC1A regulates synaptic physiology by testing the effects of Asic1a disruption on the NAc neuroproteome. We will isolate proteins from the NAc and use an unbiased proteomics approach to identify proteins that change in response to ASIC1A-dependent synaptic activity and cocaine withdrawal. We will then extend these analyses to analyze fractions enriched in synaptic terminals. Follow-up validation studies will hopefully be able to use targeted proteomic methods to analyze post-synaptic proteins. Comparing the proteomes of naïve and cocaine withdrawn Asic1a+/+ and Asic1a-/- mice may help reveal mechanisms by which ASIC1A regulates synapse morphology and plasticity and predisposes animals toward enhanced cocaine sensitivity. Thus, these studies may provide insight into the therapeutic potential of targeting ASIC1A for the treatment of substance abuse.

Literature Cited

Kreple, C.J., et al., (2014) Acid-sensing ion channels contribute to synaptic transmission and inhibit cocaine-evoked plasticity. Nat. Neurosci. 17(8): 1083-91.