Restoration of Kv7 Channel-Mediated Inhibition Reduces Cued-Reinstatement of Cocaine Seeking.

Autor:	Parrilla-Carrero J; Department of Neuroscience.; Neurobiology of Addiction Research Center, Medical University of South Carolina, Charleston, South Carolina 29425., Buchta WC; Department of Neuroscience.; Neurobiology of Addiction Research Center, Medical University of South Carolina, Charleston, South Carolina 29425., Goswamee P; Department of Neuroscience.; Neurobiology of Addiction Research Center, Medical University of South Carolina, Charleston, South Carolina 29425., Culver O; Department of Neuroscience.; Neurobiology of Addiction Research Center, Medical University of South Carolina, Charleston, South Carolina 29425., McKendrick G; Department of Neuroscience.; Neurobiology of Addiction Research Center, Medical University of South Carolina, Charleston, South Carolina 29425., Harlan B; Department of Neuroscience.; Neurobiology of Addiction Research Center, Medical University of South Carolina, Charleston, South Carolina 29425., Moutal A; Department of Pharmacology, University of Arizona, Tucson, Arizona 85724, and., Penrod R; Department of Neuroscience.; Neurobiology of Addiction Research Center, Medical University of South Carolina, Charleston, South Carolina 29425., Lauer A; Department of Public Health Sciences., Medical University of South Carolina, Charleston, SC 29425., Ramakrishnan V; Department of Public Health Sciences., Medical University of South Carolina, Charleston, SC 29425., Khanna R; Department of Pharmacology, University of Arizona, Tucson, Arizona 85724, and., Kalivas P; Department of Neuroscience.; Neurobiology of Addiction Research Center, Medical University of South Carolina, Charleston, South Carolina 29425., Riegel AC; Department of Neuroscience, riegel@musc.edu.; Neurobiology of Addiction Research Center, Medical University of South Carolina, Charleston, South Carolina 29425.
Jazyk:	angličtina
Zdroj:	The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2018 Apr 25; Vol. 38 (17), pp. 4212-4229. Date of Electronic Publication: 2018 Apr 10.
DOI:	10.1523/JNEUROSCI.2767-17.2018
Abstrakt:	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 addictive drugs may produce persistent maladaptations in intrinsic excitability within sparse subsets of PFC pyramidal neurons. Using a model 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. SIGNIFICANCE STATEMENT Long after the cessation of drug use, cues associated with cocaine still elicit drug-seeking behavior, in part by activation of the prelimbic prefrontal cortex (PL-PFC). The underlying cellular mechanisms governing these activated neurons remain unclear. Using a rat model of relapse to cocaine seeking, we identified a population of PL-PFC neurons that become hyperexcitable following chronic cocaine self-administration. These neurons show persistent loss of spike frequency adaptation, reduced afterhyperpolarizations, decreased sensitivity to dopamine, and reduced Kv7 channel-mediated inhibition. Stabilization of Kv7 channel function with retigabine normalized neuronal excitability, restored Kv7 channel currents, and reduced drug-seeking behavior when administered into the PL-PFC before reinstatement. These data highlight a persistent adaptation in a subset of PL-PFC neurons that may contribute to relapse vulnerability. (Copyright © 2018 the authors 0270-6474/18/384212-18$15.00/0.)
Databáze:	MEDLINE
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