Downregulation of Small-Conductance Potassium Channels in Cortical Pyramidal Neurons of the Supplementary Motor Cortex Underlies High Cocaine-Seeking Behaviors.

BACKGROUND

Drug relapse remains the primary challenge in treating addiction. Despite substantial research into the neural mechanisms of relapse, particularly in the medial prefrontal cortex associated with drug craving, effective treatments are still elusive. We recently reported that the excitability of cortical pyramidal neurons (CPNs) in the supplementary motor cortex (M2), but not in the primary cortex (M1), is crucial in regulating relapse risk, although the mechanisms are unclear.

METHODS

We used a model of cocaine seeking in male rats, tested 45 days after withdrawal (WD45) from five 1-hour daily sessions of intravenous self-administration (IVSA), to investigate mechanisms behind CPN hyperexcitability in M2 following prolonged withdrawal.

RESULTS

We observed increased cocaine seeking on WD45, when the hyperexcitability of CPNs in M2, but not M1, was detected using whole-cell patch-clamp recordings ex vivo. Although CPN excitability could be attributable to changes in cell membrane input resistance and capacitance, confocal microscopy of M2 CPNs revealed few differences in neuronal size or dendritic complexity on WD45 after saline versus cocaine IVSA. Interestingly, we detected a reduction of the amplitude of medium afterhyperpolarization (mAHP), but not fast AHP, on WD45 after cocaine IVSA. Further tests demonstrated that on WD45, intra-M2 microinjection of the small-conductance potassium (SK) channel activator 1-EBIO increased mAHP amplitude, reduced M2 CPN excitability, and attenuated cocaine-seeking behaviors.

CONCLUSIONS

Cocaine IVSA weakens SK channel-mediated mAHP, which can be ameliorated to reduce relapse risk. Thus, the SK channel is a potential target within a newly recognized brain region to combat addiction relapse.