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 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. 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.

Biphasic effect of abstinence duration following cocaine self-administration on spine morphology and plasticity-related proteins in prelimbic cortical neurons projecting to the nucleus accumbens core

“…This interpretation is supported by findings showing that overexpression of CREB in a subset of amygdala neurons increases the likelihood that these neurons are involved in a neuronal ensemble encoding a fear memory context (Han et al 2007), perhaps through CREB-mediated increases in intrinsic excitability (Yiu et al 2014; Han et al 2007) or stabilization of individual excitatory synapses (Lisman et al 2018). The increase in nuclear pCREB and the potential for subsequent increased excitability following abstinence from cocaine SA are supported by recent data indicating that extinction from cocaine SA increases the intrinsic excitability of layer V PrL neurons, an effect required for cue-induced reinstatement (Sepulveda-Orengo et al 2017; Parrilla-Carrero et al 2018). Similarly, cocaine conditioned place preference (CPP) training increases evoked AMPA receptor-mediated excitatory transmission in layer V PrL cortical neurons and normalization of this adaptation prevents subsequent CPP memory retrieval (Otis and Mueller 2017).…”

Nicotine Enhances Firing Activity of Layer 5 Pyramidal Neurons in the Medial Prefrontal Cortex through Inhibition of Kv7 Channels

“…It should be noted that DHβE antagonizes not only α4β2 nAChRs but also other subtypes such as α4β4 nAChRs. 31) Thus, we could not exclude the possible involvement of nAChR subtypes other than α4β2 in the nicotineinduced excitatory effects in mPFC layer 5 pyramidal neurons.…”

Dynamic CRMP2 regulation of CaV2.2 in the prefrontal cortex contributes to the reinstatement of cocaine seeking

“…Surgery. Surgical procedures included implanting catheters for intravenous cocaine infusions and intra-cranial 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.)…”

“…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.…”