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

Abstract

Cocaine addicts display increased sensitivity to drug-associated cues, due in part to pathological changes in the prelimbic 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 male rat model of relapse to cocaine-seeking, we sampled over 600 neurons to examine spike frequency adaptation (SFA) and after-hyperpolarizations (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 sub-population of PL-PFC neurons, but only with cocaine did the resulting hyper-excitability 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 minutes prior to reinstatement testing, retigabine reduced cue-induced reinstatement of cocaine seeking. Lastly, 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. Taken together, these data suggest that cocaine self-administration desensitizes inhibitory Kv7 channels in a subpopulation of PL-PFC neurons. This sub-population of neurons may represent a persistent neural ensemble responsible for driving drug seeking in response to cues.Significance StatementLong after the cessation of drug use, cues associated with cocaine still elicit drug-seeking behavior, in part by activation of the prelimbic 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 after-hyperpolarizations, 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 prior to reinstatement. These data highlight a persistent adaptation in a subset of PL-PFC neurons that may contribute to relapse vulnerability.

Cell-Type-Specific Decrease of the Intrinsic Excitability of Motor Cortical Pyramidal Neurons in Parkinsonism

“…Indeed, it has been proposed that impaired function or inactivation of BK channels that underlies AP repolarization and/or fAHPs could slow the de-inactivation of Nav channels during AP and reduce Nav availability for the subsequent AP generation, leading to a decreased excitability (Bean, 2007;Jaffe et al, 2011). A progressive and accumulative Nav inactivation is consisted with our observations that PTNs in 6-OHDA mice showed stronger spike adaptation during repetitive firing relative to those from controls (Fleidervish et al, 1996), though the contribution of the other mechanisms such as the M-current can't be discounted (Buchta et al, 2017;Parrilla-Carrero et al, 2018). It is intriguing that in the presence of BAPTA PTNs from 6-OHDA mice exhibited narrower APs than those from controls ( Figures 6D, E).…”

Dynamic CRMP2 Regulation of CaV2.2 in the Prefrontal Cortex Contributes to the Reinstatement of Cocaine Seeking

“…The persistence of this plasticity and related behaviors may involve neuroadaptations in synaptic strength [9] and gene expression [14; 40], as well as cytoskeletal re-arrangement [13]. Conversely, disrupting these adaptations reduces drug-induced alterations in excitability and associated behaviors [38]. It is unclear if these abnormalities are a precedent or an antecedent of addiction.…”

“…Surgery. Surgical procedures included implanting catheters for intravenous cocaine infusions and intracranial canulae for injection of pharmacological compounds directly to the mPFC, as previously described [38]. Rats were anaesthetized using a ketamine HCl / xylazine mixture (0.57 / 0.87 mg/kg, respectively, i.p.)…”