LAUSR

Drug addiction results in long-term synaptic potentiation at excitatory synapses in the brain reward circuitry, especially in the ventral tegmental area (VTA) and nucleus accumbens (NAc), central parts of the mesolimbic dopamine system, and then progresses to other cortical regions [1, 2]. It has been proposed that a drug-induced increase in the AMPAR/NMDAR (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor/N-methyl-D-aspartate receptor) ratio in VTA dopamine (DA) neurons accounts for the synaptic potentiation by inserting Ca-permeable AMPARs [3], and low-conductance Ca-impermeable GluN3A-containing NMDARs in the same synapse [4]. Taken together, the enhanced excitatory synaptic transmission might contribute to altering DA neuron firing and therefore its release in target regions. However, it remained elusive whether the intrinsic excitability of DA neurons changes following acute cocaine exposure. A recent study published in The Journal of Neuroscience by Creed et al. (2016) provides a further exploration of the excitability of VTA DA neurons following cocaine exposure, and points out unexpected roles of NMDAR remodeling in the process [5]. The authors report that the cocaine-evoked excitability of VTA DA neurons is largely modulated by hyperpolarization-activated cyclic nucleotide–gated channels and small-conductance Caactivated K (SK) channels [5]. It is known that blocking SK channels increases the burst firing of DA neurons. A previous study also demonstrated that SK channels and NMDARs form a Ca-mediated feedback loop; blocking SK channels facilitates neuronal membrane hyperpolarization and decreases the afterhyperpolarization current (IAHP) due to voltage-dependent Mg 2? blockade of the NMDARs. The authors found a dramatic decrease in the amplitude of the SK channel-mediated IAHP in VTA DA neurons from cocaine-treated mice, indicating impairment of the SK channels. As a result, apamin (an SK2/3 channel blocker) fails to further enhance the firing in VTA DA neurons after cocaine exposure [5]. Considering the fact that cocaine induces the insertion of Ca-impermeable NMDARs [4], this might disrupt the NMDAR-SK channel loop and contribute to the malfunction of SK channels after cocaine exposure. Creed et al. (2016) further tested this hypothesis on GluN3A-knockout mice, and confirmed the role of GluN3A-containing NMDARs in controlling the neuronal excitability after cocaine exposure. In addition, activating Group I metabotropic glutamate receptors (mGluRs) restores the GluR composition after cocaine exposure [4], and Creed et al. (2016) further reported the restoration of the firing increases and the IAHP decrements in DA neurons. Collectively, Creed et al. (2016) have demonstrated an unexpected role of non-canonical, Ca-impermeable NMDARs in modifying neuronal excitability, by changing the functioning of Ca-activated K channels. Nevertheless, it is worthwhile investigating whether the SK channel protein expression or activation mechanism changes after cocaine exposure. In addition, DA neurons display different firing patterns with different SK channel subunits; for instance, SK2 contributes to the firing precision but SK3 influences the firing frequency [6]. Multiple Ca sources can activate SK channels, including voltage-gated Ca channels, NMDARs, Xiaodan Huang and Wei Ni have contributed equally to this work.