Individual Differences in Ethanol Drinking and Seeking Behaviors in Rats Exposed to Chronic Intermittent Ethanol Vapor Exposure is Associated with Altered CaMKII Autophosphorylation in the Nucleus Accumbens Shell.

Sucharita S Somkuwar,Chitra D Mandyam

doi:10.3390/brainsci9120367

Abstract

Chronic intermittent ethanol vapor exposure (CIE) in rodents produces reliable and high blood ethanol concentration and behavioral symptoms associated with moderate to severe alcohol use disorder (AUD)—for example, escalation of operant ethanol self-administration, a feature suggestive of transition from recreational to addictive use, is a widely replicated behavior in rats that experience CIE. Herein, we present evidence from a subset of rats that do not demonstrate escalation of ethanol self-administration following seven weeks of CIE. These low responders (LR) maintain low ethanol self-administration during CIE, demonstrate lower relapse to drinking during abstinence and reduced reinstatement of ethanol seeking triggered by ethanol cues when compared with high responders (HR). We examined the blood ethanol levels in LR and HR rats during CIE and show higher levels in LR compared with HR. We also examined peak corticosterone levels during CIE and show that LR rats have higher levels compared with HR rats. Lastly, we evaluated the levels of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in the nucleus accumbens shell and reveal that the activity of CaMKII, which is autophosphorylated at site Tyr-286, is significantly reduced in HR rats compared with LR rats. These findings demonstrate that dysregulation of the hypothalamic–pituitary–adrenal axis activity and plasticity-related proteins regulating molecular memory in the nucleus accumbens shell are associated with higher ethanol-drinking and -seeking in HR rats. Future mechanistic studies should evaluate CaMKII autophosphorylation-dependent remodeling of glutamatergic synapses in the ventral striatum as a plausible mechanism for the CIE-induced enhanced ethanol drinking and seeking behaviors.

Highlights

Progressive escalation of voluntary alcohol intake is a hallmark of moderate to severe alcohol use disorder (AUD)
We evaluated the levels of Ca2+ /calmodulin-dependent protein kinase II (CaMKII) in the nucleus accumbens shell and reveal that the activity of CaMKII, which is autophosphorylated at site Tyr-286, is significantly reduced in high responders (HR) rats compared with low responders (LR) rats
Rats were separated into HR and LR based on escalation criteria (defined as >150% change in active lever responses during chronic intermittent ethanol vapor exposure (CIE) compared with pre-CIE sessions, after a median split analysis on their reinforced lever responses during CIE sessions; Figure 1c)

Summary

Introduction

Progressive escalation of voluntary alcohol intake is a hallmark of moderate to severe alcohol use disorder (AUD). The Diagnostic and Statistical Manual-V (DSM V) presents AUD criteria like drinking “more or longer that you intended” and could not “cut down or stop drinking” which may be interpreted as a description of escalation [1]. It is not surprising, that escalation of voluntary alcohol intake is considered a major face validity criteria for any animal model of AUD [2]. Understanding the mechanisms that underlie individual vulnerability to moderate to severe AUD may help enhance the number of effective treatment strategies for AUD and reduce the economic burden associated with the disorder [9,10]

Objectives

Methods

Results

Conclusion