Restoration of Kv7 channel-mediated inhibition reduces cued-reinstatement of cocaine seeking

Jeffrey Parrilla-Carrero, William C. Buchta, Priyodarshan Goswamee, Oliver Culver, Greer McKendrick, Benjamin Harlan, Aubin Moutal, Rachel Penrod, Abigail Lauer, Viswanathan Ramakrishnan, Rajesh Khanna, Peter Kalivas, Arthur C. Riegel

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Cocaine addicts display increased sensitivity to drug-associated cues, due in part to changes in the prelimbic prefrontal cortex (PL-PFC). The cellular mechanisms underlying cue-induced reinstatement of cocaine seeking remain unknown. Reinforcement learning for addictivedrugsmayproducepersistentmaladaptationsinintrinsicexcitabilitywithinsparsesubsetsofPFCpyramidalneurons.Usingamodel of relapse in male rats, we sampled >600 neurons to examine spike frequency adaptation (SFA) and afterhyperpolarizations (AHPs), two systems that attenuate low-frequency inputs to regulate neuronal synchronization. We observed that training to self-administer cocaine or nondrug (sucrose) reinforcers decreased SFA and AHPs in a subpopulation of PL-PFC neurons. Only with cocaine did the resulting hyperexcitability persist through extinction training and increase during reinstatement. In neurons with intact SFA, dopamine enhanced excitability by inhibiting Kv7 potassium channels that mediate SFA. However, dopamine effects were occluded in neurons from cocaine-experienced rats, where SFA and AHPs were reduced. Pharmacological stabilization of Kv7 channels with retigabine restored SFA and Kv7 channel function in neuroadapted cells. When microinjected bilaterally into the PL-PFC 10 min before reinstatement testing, retigabine reduced cue-induced reinstatement of cocaine seeking. Last, using cFos-GFP transgenic rats, we found that the loss of SFA correlated with the expression of cFos-GFP following both extinction and re-exposure to drug-associated cues. Together, these data suggest that cocaine self-administration desensitizes inhibitory Kv7 channels in a subpopulation of PL-PFC neurons. This subpopulation of neurons may represent a persistent neural ensemble responsible for driving drug seeking in response to cues.

Original languageEnglish (US)
Pages (from-to)4212-4229
Number of pages18
JournalJournal of Neuroscience
Volume38
Issue number17
DOIs
StatePublished - Apr 25 2018

Keywords

  • Afterhyperpolarization
  • Cocaine
  • Dopamine
  • Kv7 ion channels
  • Prefrontal cortex
  • Spike-frequency adaptation

ASJC Scopus subject areas

  • Neuroscience(all)

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    Parrilla-Carrero, J., Buchta, W. C., Goswamee, P., Culver, O., McKendrick, G., Harlan, B., Moutal, A., Penrod, R., Lauer, A., Ramakrishnan, V., Khanna, R., Kalivas, P., & Riegel, A. C. (2018). Restoration of Kv7 channel-mediated inhibition reduces cued-reinstatement of cocaine seeking. Journal of Neuroscience, 38(17), 4212-4229. https://doi.org/10.1523/JNEUROSCI.2767-17.2018