KCNQ3 normalizes hyperactivity of VTA-NAcLat circuit and attenuates methamphetamine addiction in mice

The brain circuit projecting from the ventral tegmental area (VTA) to the lateral shell nucleus accumbens (NAcLat) has a key role in methamphetamine (MA) addiction. As different VTA dopamine (DA) neuronal subpopulations participate in different neuronal circuits, it is still a challenge to isolate these DA subtype cells. Using retrograde tracing, Patch-seq in MA-addicted mice, we isolated the DA neurons of the VTA-NAcLat circuit and profiled its gene expression. We found that in this circuit the KCNQ3 (Kv7.3) gene, encoding K+ channel protein, was among the differentially expressed genes. Injection of the Kv7.3 channels agonist ICA069673 or overexpression of Kv7.3 channels in the VTA-NacLat circuit could reverse MA addiction. Furthermore, enhancement of Kv7.3 channels activity decreased neural oscillation, neuronal excitability, synaptic plasticity and DA release in the VTA-NacLat circuit of MA-addicted mice. Activation of Kv7.3 channels in the VTA may become a potential novel treatment strategy for MA addiction.