Ketamine and MAG Lipase Inhibitor-Dependent Reversal of Evolving Depressive-Like Behavior During Forced Abstinence From Alcohol Drinking

Abstract

Although alcoholism and depression are highly comorbid, treatment options that take this into account are lacking, and mouse models of alcohol (ethanol (EtOH)) intake-induced depressive-like behavior have not been well established. Recent studies utilizing contingent EtOH administration through prolonged two-bottle choice access have demonstrated depression-like behavior following EtOH abstinence in singly housed female C57BL/6J mice. In the present study, we found that depression-like behavior in the forced swim test (FST) is revealed only after a protracted (2 weeks), but not acute (24 h), abstinence period. No effect on anxiety-like behavior in the EPM was observed. Further, we found that, once established, the affective disturbance is long-lasting, as we observed significantly enhanced latencies to approach food even 35 days after ethanol withdrawal in the novelty-suppressed feeding test (NSFT). We were able to reverse affective disturbances measured in the NSFT following EtOH abstinence utilizing the N-methyl D-aspartate receptor (NMDAR) antagonist and antidepressant ketamine but not memantine, another NMDAR antagonist. Pretreatment with the monoacylglycerol (MAG) lipase inhibitor JZL-184 also reduced affective disturbances in the NSFT in ethanol withdrawn mice, and this effect was prevented by co-administration of the CB1 inverse agonist rimonabant. Endocannabinoid levels were decreased within the BLA during abstinence compared with during drinking. Finally, we demonstrate that the depressive behaviors observed do not require a sucrose fade and that this drinking paradigm may favor the development of habit-like EtOH consumption. These data could set the stage for developing novel treatment approaches for alcohol-withdrawal-induced mood and anxiety disorders.

Preclinical voluntary drinking models for alcohol abstinence‐induced affective disturbances in mice

“…The NMDARs are known to be targets of both acute (Lovinger et al 1989) and chronic EtOH exposure (Kalluri et al 1998;Sheela Rani & Ticku 2006), and NMDAR antagonists have been hypothesized to have therapeutic benefit for patients with AUDs (Nagy 2004). In accordance with this, we found that ketamine was able to completely reverse the negative affective behavior observed in mice following 2 weeks of EtOH abstinence (Holleran et al 2016).The voluntary rodent EtOH drinking models described here have also allowed for delineation of circuitry governing the behaviors displayed. In particular, the amygdala and extended amygdala appear to play an important role in the negative affect observed following cessation of EtOH in these paradigms.…”

“…We found that, in the basolateral amygdala, both 2‐arachadonylglycerol (2‐AG) and anandamide were reduced after 2 weeks of forced abstinence from EtOH compared with mice on the final day of drinking. Increasing availability of 2‐AG through the inhibition of its degradation enzyme (monacylglycerol lipase) by systemic treatment with JZL‐184 was capable of reducing EtOH abstinence‐induced depression‐like behaviors to control levels (Holleran et al ). In addition, JZL‐184's antidepressant‐like effects were completely blocked by coadministration of the cannabinoid receptor 1 (CB1) antagonist, rimonabant.…”

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

“…Non-drinking control mice received continuous access to two water bottles only throughout the experiment. Escalation of alcohol drinking and forced abstinence were modeled off of Holleran & Winder (2016).…”

“…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.…”