Postsynaptic acid-sensing ion chan-nel 1A (ASIC1A) has been found to promote hippocampal synaptic plasticity and learning; however, little is known about the role that the channel might have in the nucleus accumbens (NAc), a brain region that is involved in addiction-related learning and behaviour. Now, a study by Kreple et al. shows that ASIC1A in the NAc inhibits cocaine-induced synaptic plasticity and cocaine-conditioned behaviour in rodents.

The authors observed that in a cocaine-conditioned place prefer-ence test, mice that lacked ASIC1A (Asic1a–/– mice) showed greater preference for the cocaine-associated context than did Asic1a+/+ controls. Injection of an adeno-associated virus encoding Asic1a (AAV-Asic1a) into the NAc restored conditioned place preference of Asic1a–/– mice to control levels; thus, ASIC1A specifi-cally in the NAc constrains cocaine-conditioned place preference.

To investigate the cellular mechanisms underlying this effect of ASIC1A, Kreple et al. took whole-cell voltage-clamp recordings from post-synaptic NAc medium spiny neurons (MSNs) in mouse brain slices.

They identified an MSN excitatory postsynaptic current (EPSC) that was reduced by the ASIC antagonist amiloride, but not by antagonists of AMPA receptors, NMDA receptors or GABA type A receptors, indicating that the current was dependent on ASIC1A. In the NAc from Asic1a–/– mice, MSNs had more ‘stubby’ excitatory spines and, consistent with increased excitatory transmission, showed a higher frequency of minia-ture EPSCs compared with Asic1a+/+ NAc MSNs, suggesting that ASIC1A may regulate synaptic formation and excitatory synaptic transmission in the NAc.

Previous research has demon-strated that repeated administration of cocaine increases the number of inwardly rectifying calcium-permeable AMPA channels in the NAc, and that in the NAc of cocaine-withdrawn — but not drug-naive — mice, a single dose of cocaine reduces the ratio of AMPA to NMDA channels. Kreple et al. found that the NAc of Asic1a–/– mice resembled that of cocaine-withdrawn animals — the AMPA-to-NMDA ratio in the NAc of Asic1a–/– mice was higher than in the NAc of Asic1a+/+ controls. In

addition, upon activation, NAc AMPA receptors from Asic1a–/– mice were more inwardly rectifying than those from Asic1a+/+ mice. Moreover, in Asic1a–/– mice — but not in Asic1a+/+ mice — a single intraperitoneal injection of cocaine reduced the NAc AMPA-to-NMDA ratio. These find-ings suggest that ASIC1A may prevent cocaine-associated plastic changes in the composition of NAc synapses.

To investigate the behavioural rel-evance of these findings, the authors assessed whether overexpression of ASIC1A in the NAc of rats would alter cocaine-induced behaviour; strikingly, after 3 weeks, AAV-Asic1a-injected rats self-administered less cocaine than did control rats.

Altogether, this study provides evidence that, contrary to its posi-tive effects on associative learning in the hippocampus, ASIC1A in the NAc inhibits cocaine-induced synaptic plasticity and may oppose addiction-related behaviour.

Natasha Bray

A D D I C T I O N

ASIC inhibits addiction

ORIGINAL RESEARCH PAPER Kreple, C. J. et al. Acid-sensing ion channels contribute to synaptic transmission and inhibit cocaine-evoked plasticity. Nature Neurosci. http://dx.doi.org/10.1038/nn.3750 (2014)

AAV‑Asic1a‑ injected rats self‑administered less cocaine

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NATURE REVIEWS | NEUROSCIENCE VOLUME 15 | AUGUST 2014

Nature Reviews Neuroscience | AOP, published online 9 July 2014; doi:10.1038/nrn3789

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