Differential activation of limbic circuitry associated with chronic ethanol withdrawal in DBA/2J and C57BL/6J mice

Abstract

Although no animal model exactly duplicates clinically defined alcoholism, models for specific factors, such as the withdrawal syndrome, are useful for identifying potential neural determinants of liability in humans. The well-documented difference in withdrawal severity following chronic ethanol exposure, between the DBA/2J and C57BL/6J mouse strains, provides an excellent starting point for dissecting the neural circuitry affecting predisposition to physical dependence on ethanol. To induce physical dependence, we used a paradigm in which mice were continuously exposed to ethanol vapor for 72 hr. Ethanol-exposed and air-exposed (control) mice received daily injections of pyrazole hydrochloride, an alcohol dehydrogenase inhibitor, to stabilize blood ethanol levels. Ethanol-dependent and air-exposed mice were killed seven hours after removal from the inhalation chambers. This time point corresponds to the time of peak ethanol withdrawal severity. The brains were processed to assess neural activation associated with ethanol withdrawal indexed by c-Fos immunostaining. Ethanol-withdrawn DBA/2J mice showed significantly (p<0.05) greater neural activation than ethanol-withdrawn C57BL/6J mice in the dentate gyrus, hippocampus CA3, lateral septum, basolateral and central nuclei of the amygdala, and prelimbic cortex. Taken together with results using an acute model, our data suggest that progression from acute ethanol withdrawal to the more severe withdrawal associated with physical dependence following chronic ethanol exposure involves recruitment of neurons in the hippocampal formation, amygdala and prelimbic cortex. To our knowledge, these are the first studies to use c-Fos to identify the brain regions and neurocircuitry that distinguish between chronic and acute ethanol withdrawal severity using informative animal models.

Ethosuximide reduces electrographical and behavioral correlates of alcohol withdrawal seizure in DBA/2J mice

“…However, other reports suggest that the kindling phenomenon is only one potential mechanism for the development of alcohol withdrawal symptoms and is relevant only in certain situations (Wojnar, Bizoń, & Wasilewski, 1999). T channels are one of many factors that may contribute to hyperexcitability and regional specific effects of ethanol withdrawal (Chen, Reilly, Kozell, Hitzemann, & Buck, 2009; Reilly, Milner, Shirley, Crabbe, & Buck, 2008). The observation of “kindling-like” effects, while they may be due to multiple targets of ethanol, nevertheless underscores the importance of early intervention.…”

Genetic studies of alcohol dependence in the context of the addiction cycle

“…Finally, a quantitative trait gene, the multiple PDZ domain protein (MPDZ), mediates drug withdrawal responses in mice and humans (Shirley et al, 2004; Fehr et al, 2002; Reilly et al, 2008; Milner et al, 2015; Chen and Buck, 2010; Chen et al, 2011). MPDZ is critical for serotonin type 2 receptor signaling and likely mediates variation in alcohol withdrawal severity via alterations in serotonin signaling fidelity (Reilly et al, 2008; Chen et al, 2009; Buck et al, 2004). Thus, SNPs within HTR1A associated with alcohol dependence (Zuo et al, 2012) could alter compulsive drug seeking behavior which predominates during the preoccupation-anticipation stage of addiction.…”

Acute Ethanol Withdrawal Impairs Contextual Learning and Enhances Cued Learning

“…By altering the activity of a number of ion channels and receptors, alcohol modulates synaptic function and plasticity (Zorumski et al, 2014). Additionally, the function of brain regions that play key roles in learning are significantly altered by ethanol exposure and withdrawal (White and Best, 2000; Chen et al, 2009; Holmes et al, 2012; DePoy et al, 2013). The effects of alcohol on long-term learning and memory are thought to underlie, at least in part, the development and maintenance of addiction.…”