Ketamine administration during a critical period after forced ethanol abstinence inhibits the development of time-dependent affective disturbances

Abstract

Forced abstinence from chronic two bottle-choice ethanol drinking produces the development of negative affective states in female C57BL/6J mice. We previously reported that this disrupted behavior is acutely reversed by administration of ketamine 30 min-prior to testing. Here we assessed whether ketamine can be used as an inoculant against the development of abstinence- dependent affective disturbances. In parallel, we examined the impact of ketamine administration on long-term potentiation (LTP) in the bed nucleus of the stria terminalis (BNST), a region implicated in affective disturbances. We administered ketamine (3 mg/kg i.p.) to female C57BL/6J mice with a history of chronic ethanol drinking at either the onset, two, or 6 days- post-abstinence and observed its impact on affective behavior in the elevated plus maze (EPM), the Novelty Suppressed Feeding Test (NSFT), and the Forced Swim Test (FST). In addition, we assessed BNST synaptic plasticity with field potential electrophysiology two to 3 weeks into abstinence. We found that early abstinence was associated with disrupted behavior on the EPM. Ketamine administered at the onset of forced abstinence prevented both the deficit in early EPM behavior, and the delayed deficits in NSFT and FST. However, ketamine administered either two or 6 days post-abstinence failed to prevent the abstinence-induced affective disturbances. To begin to explore potential alterations in neural circuit activity that accompanies these actions of ketamine, we assessed the impact of ketamine administration at the onset of forced abstinence and measured LTP induction in the BNST. We find that early ketamine administration persistently increased the capacity for LTP within the BNST. These findings suggest a critical period at the onset of forced abstinence in which ketamine inoculation can prevent the development of affective disturbances, in part by enhancing plasticity within the BNST.

Forced Abstinence from Alcohol Induces Sex-Specific Depression-like Behavioral and Neural Adaptations in Somatostatin Neurons in Cortical and Amygdalar Regions

“…A lack of observable differences in anxiety-like behaviors in the EPM and OFT between control and FAexposed mice in our study could indicate a transition from the heightened anxious state associated with acute withdrawal and early abstinence (Lee et al, 2015; to a more depressive-like state during protracted abstinence (Driessen, 2001;Heilig et al, 2010;Stevenson et al, 2009). Previous studies using the same two-bottle choice paradigm demonstrated that female mice develop a heightened depressive-like behavioral phenotype during protracted abstinence from alcohol, as indicated by longer time spent immobile in the FST and longer latency to feed in the novelty-suppressed feeding test (NSFT), that can be alleviated by physical activity (Pang et al, 2013) or administration of the novel fast-acting antidepressant ketamine (Holleran et al, 2016;Vranjkovic et al, 2018). Interestingly, here we observed a more robust depressive-like behavioral phenotype in the FST in FA-exposed male mice, and not FA-exposed female mice.…”

“…Previous research has shown that forced abstinence (FA) from alcohol produces depressive-like behavior and a variety of neurobiological changes in rodent models. For instance, Vranjkovic et al (2018) demonstrated that following six weeks of alcohol drinking, female C57BL/6J mice showed decreased time spent in the open arm of the elevated plus maze (EPM), and increased latency to feed in the novelty suppression of feeding test (NSFT), two commonly used models of anxiety-like behavior. In addition, this model produced increased immobility in the forced swim test (FST), though it should be noted males were not investigated in these studies (Holleran et al, 2016;Vranjkovic et al, 2018).…”

“…For instance, Vranjkovic et al (2018) demonstrated that following six weeks of alcohol drinking, female C57BL/6J mice showed decreased time spent in the open arm of the elevated plus maze (EPM), and increased latency to feed in the novelty suppression of feeding test (NSFT), two commonly used models of anxiety-like behavior. In addition, this model produced increased immobility in the forced swim test (FST), though it should be noted males were not investigated in these studies (Holleran et al, 2016;Vranjkovic et al, 2018). Similarly, Valdez & Harshberger (2012) demonstrated that male Wistar rats exposed to chronic alcohol show increased immobility in the FST, and that this effect is further enhanced during protracted withdrawal.…”

“…Dao et al Forced Abstinence in Cortico-Amygdalar Regions 4 AUD and major depressive disorder (MDD) are highly comorbid disorders with overlapping etiology. Novel fast acting antidepressants are able to reduce both binge drinking and depressive-like behavior following alcohol exposure (Holleran et al, 2016;Vranjkovic et al, 2018) further highlighting the potential overlapping neural circuitry involved in AUD and MDD. Importantly, both the clinical and preclinical depression literature has continuously pointed to a novel subpopulation of gamma aminobutyric acidergic (GABAergic) neurons as a protective, resiliency-conferring population.…”

Kcnn3 as a target for treating aberrant behaviors in stressed, ethanol-dependent mice

“…AUD is frequently comorbid with affective mood disorders (3,4) and this fact often limits available treatment interventions (5). The negative affective disturbances that tend to develop during abstinence from drinking can drive relapse-like behaviors in both humans and rodent models (6)(7)(8)(9)(10)(11)(12). This is further complicated by preclinical and clinical evidence that links increased alcohol drinking with the use of drugs such as SSRIs that are commonly used to treat depression and anxiety (13,14).…”