Morphological and functional evidence of increased excitatory signaling in the prelimbic cortex during ethanol withdrawal

Abstract

Excessive alcohol consumption in humans induces deficits in decision making and emotional processing, which indicates a dysfunction of the prefrontal cortex (PFC). The present study aimed to determine the impact of chronic intermittent ethanol (CIE) inhalation on mouse medial PFC pyramidal neurons. Data were collected 6-8 days into withdrawal from 7 weeks of CIE exposure, a time point when mice exhibit behavioral symptoms of withdrawal. We found that spine maturity in prelimbic (PL) layer 2/3 neurons was increased, while dendritic spines in PL layer 5 neurons or infralimbic (IL) neurons were not affected. Corroborating these morphological observations, CIE enhanced glutamatergic transmission in PL layer 2/3 pyramidal neurons, but not IL layer 2/3 neurons. Contrary to our predictions, these cellular alterations were associated with improved, rather than impaired, performance in reversal learning and strategy switching tasks in the Barnes maze at an earlier stage of chronic ethanol exposure (5-7 days withdrawal from 3 to 4 weeks of CIE), which could result from the anxiety-like behavior associated with ethanol withdrawal. Altogether, this study adds to a growing body of literature indicating that glutamatergic activity in the PFC is upregulated following chronic ethanol exposure, and identifies PL layer 2/3 pyramidal neurons as a sensitive target of synaptic remodeling. It also indicates that the Barnes maze is not suitable to detect deficits in cognitive flexibility in CIE-withdrawn mice.

A novel multichoice touchscreen paradigm for assessing cognitive flexibility in mice

“…Cognitive inflexibility in addictions including alcohol use disorders (AUDs) can prevent effective disengagement from destructive patterns of drug-seeking (Jentsch and Taylor 1999;Belin et al 2016). In laboratory settings, measures of cognitive flexibility such as reversal learning are slowed in AUD patients (Vanes et al 2014;Le Berre et al 2017), while rodents chronically exposed to alcohol or other drugs of abuse (e.g., cocaine), exhibit abnormalities in reversal performance and other forms of cognitive flexibility, including attentional set-shifting (Schoenbaum et al 2004;Coleman et al 2012;DePoy et al 2013;Trantham-Davidson et al 2014;Hu et al 2015;Varodayan et al 2018). In turn, these behavioral disturbances have been attributed to drug-induced adaptations in certain cortical and striatal regions that are known substrates for these cognitive processes (Schoenbaum and Shaham 2008;Moorman 2018).…”

Aberrations in Incentive Learning and Responding to Heroin in Male Rats After Adolescent or Adult Chronic Binge‐Like Alcohol Exposure

“…The pedunculopontine tegmental and laterodorsal tegmental nuclei that give rise to the main cholinergic projections to VTA DA cells are severely affected by chronic alcohol consumption (Pereira et al, 2019). Similarly, alcohol exposure leads to persistent alterations in the prefrontal cortex (Alasmari et al, 2018; Jury et al, 2017; McGinnis et al, 2019; Morales et al, 2018; Pascual et al, 2009; Varodayan et al, 2018) whose glutamatergic neurons are known to innervate the VTA DA system and control reward‐directed behaviors. Thus, it is conceivable that CIE exposure, by disrupting glutamatergic and cholinergic inputs to the VTA DA system, impairs conditioned reward learning.…”

Nicotine and alcohol: the role of midbrain dopaminergic neurons in drug reinforcement

“…Stimulation of another ethanol target, the j-opioid receptor, also suppresses ethanol consumption and preference in rats (Nestby et al, 1999;Lindholm et al, 2001;Logrip et al, 2009) Effects of ethanol withdrawal and stress on VTA DA neurons Repeated exposure to ethanol and withdrawal creates an imbalance between excitatory and inhibitory mechanisms controlling VTA DA neurons, and also increases the frequency of negative affect and stresstwo main drivers to relapse. The main effects of alcohol withdrawal on synaptic physiology and behavior have been extensively studied in other brain regions such as the AMG and PFC (Roberto & Varodayan, 2017;Varodayan et al, 2018), including withdrawal affects on the excitability and synaptic transmission of DA neurons and impact on reinforcement.…”