Portal de Periódicos da CAPES

Acid-sensing ion channels contribute to synaptic transmission and inhibit cocaine-evoked plasticity

2014; Nature Portfolio; Volume: 17; Issue: 8 Linguagem: Inglês

10.1038/nn.3750

1546-1726

Collin J. Kreple, Yuan Lü, Rebecca J. Taugher, Andrea L Schwager-Gutman, Jianyang Du, Madeliene Stump, Yimo Wang, Ali Ghobbeh, Rong Fan, Caitlin V. Cosme, Levi P. Sowers, Michael J. Welsh, Jason J. Radley, Ryan T. LaLumiere, John A. Wemmie,

Regulation of Appetite and Obesity

Exposure to psychostimulants such as cocaine induces synaptic plasticity within the nucleus accumbens (NAc) and alters behavior. Here the authors find a new role for the acid-sensing channel 1A (ASIC1A) in excitatory transmission and plasticity within the NAc that contributes to cocaine-induced learning and self-administration. Acid-sensing ion channel 1A (ASIC1A) is abundant in the nucleus accumbens (NAc), a region known for its role in addiction. Because ASIC1A has been suggested to promote associative learning, we hypothesized that disrupting ASIC1A in the NAc would reduce drug-associated learning and memory. However, contrary to this hypothesis, we found that disrupting ASIC1A in the mouse NAc increased cocaine-conditioned place preference, suggesting an unexpected role for ASIC1A in addiction-related behavior. Moreover, overexpressing ASIC1A in rat NAc reduced cocaine self-administration. Investigating the underlying mechanisms, we identified a previously unknown postsynaptic current during neurotransmission that was mediated by ASIC1A and ASIC2 and thus well positioned to regulate synapse structure and function. Consistent with this possibility, disrupting ASIC1A altered dendritic spine density and glutamate receptor function, and increased cocaine-evoked plasticity, which resemble changes previously associated with cocaine-induced behavior. Together, these data suggest that ASIC1A inhibits the plasticity underlying addiction-related behavior and raise the possibility of developing therapies for drug addiction by targeting ASIC-dependent neurotransmission.