Prefrontal Cortex KCa2 Channels Regulate mGlu5-Dependent Plasticity and Extinction of Alcohol-Seeking Behavior.
Identifying novel treatments that facilitate extinction learning could enhance cue-exposure therapy and reduce high relapse rates in alcoholics. Activation of mGlu5receptors in the infralimbic prefrontal cortex (IL-PFC) facilitates learning during extinction of cue-conditioned alcohol-seeking behavior. Small-conductance calcium-activated potassium (KCa2) channels have also been implicated in extinction learning of fear memories, and mGlu5receptor activation can reduce KCa2 channel function. Using a combination of electrophysiological, pharmacological, and behavioral approaches, this study examined KCa2 channels as a novel target to facilitate extinction of alcohol-seeking behavior in rats. This study also explored related neuronal and synaptic mechanisms within the IL-PFC that underlie mGlu5-dependent enhancement of extinction learning. Using whole-cell patch-clamp electrophysiology, activation of mGlu5inex vivoslices significantly reduced KCa2 channel currents in layer V IL-PFC pyramidal neurons, confirming functional downregulation of KCa2 channel activity by mGlu5receptors. Additionally, positive modulation of KCa2 channels prevented mGlu5receptor-dependent facilitation of long-term potentiation in the IL-PFC. Systemic and intra-IL-PFC treatment with apamin (KCa2 channel allosteric inhibitor) significantly enhanced extinction of alcohol-seeking behavior across multiple extinction sessions, an effect that persisted for 3 weeks, but was not observed after apamin microinfusions into the prelimbic PFC. Positive modulation of IL-PFC KCa2 channels significantly attenuated mGlu5-dependent facilitation of alcohol cue-conditioned extinction learning. These data suggest that mGlu5-dependent facilitation of extinction learning and synaptic plasticity in the IL-PFC involves functional inhibition of KCa2 channels. Moreover, these findings demonstrate that KCa2 channels are a novel target to facilitate long-lasting extinction of alcohol-seeking behavior.SIGNIFICANCE STATEMENTAlcohol use disorder is a chronic relapsing disorder that is associated with compulsive alcohol-seeking behavior. One of the main causes of alcohol relapse is the craving caused by environmental cues that are associated with alcohol. These cues are formed by normal learning and memory principles, and the understanding of the brain mechanisms that help form these associations can lead to the development of drugs and/or behavior therapies that reduce the impact that these cues have on relapse in alcoholics.
Department of Neuroscience.|Department of Psychiatry & Behavioral Sciences, and.
Reginald
R
Cannady
Department of Neuroscience.
Justin T
JT
McGonigal
Department of Neuroscience.
Ryan J
RJ
Newsom
Department of Neuroscience.|Department of Psychiatry & Behavioral Sciences, and.
John J
JJ
Woodward
Department of Neuroscience, gass@musc.edu mulholl@musc.edu.|Department of Psychiatry & Behavioral Sciences, and.
Patrick J
PJ
Mulholland
Department of Neuroscience, gass@musc.edu mulholl@musc.edu.|Department of Psychiatry & Behavioral Sciences, and.|Charleston Alcohol Research Center, Addiction Sciences Division, College of Health Professions, Medical University of South Carolina, Charleston, South Carolina 29425.
Justin T
0000-0002-6829-6261
JT
Gass
D000437:Alcoholism / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D058999:Drug-Seeking Behavior; D005108:Extinction, Psychological; D017774:Long-Term Potentiation; D008297:Male; D017397:Prefrontal Cortex / Q000378:metabolism / Q000502:physiology*; D017966:Pyramidal Cells / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*
C578937:Grm5 protein, rat; D064529:Receptor, Metabotropic Glutamate 5; D051640:Small-Conductance Calcium-Activated Potassium Channels
SK channels; addiction; alcohol; cues; extinction; infralimbic cortex; mGlu5