Adolescent social isolation increases anxiety-like behavior and ethanol intake and impairs fear extinction in adulthood: Possible role of disrupted noradrenergic signaling

Abstract

Alcohol use disorder, anxiety disorders, and post-traumatic stress disorder (PTSD) are highly comorbid, and exposure to chronic stress during adolescence may increase the incidence of these conditions in adulthood. Efforts to identify the common stress-related mechanisms driving these disorders have been hampered, in part, by a lack of reliable preclinical models that replicate their comorbid symptomatology. Prior work by us, and others, has shown that adolescent social isolation increases anxiety-like behaviors and voluntary ethanol consumption in adult male Long-Evans rats. Here we examined whether social isolation also produces deficiencies in extinction of conditioned fear, a hallmark symptom of PTSD. Additionally, as disrupted noradrenergic signaling may contribute to alcoholism, we examined the effect of anxiolytic medications that target noradrenergic signaling on ethanol intake following adolescent social isolation. Our results confirm and extend previous findings that adolescent social isolation increases anxiety-like behavior and enhances ethanol intake and preference in adulthood. Additionally, social isolation is associated with a significant deficit in the extinction of conditioned fear and a marked increase in the ability of noradrenergic therapeutics to decrease ethanol intake. These results suggest that adolescent social isolation not only leads to persistent increases in anxiety-like behaviors and ethanol consumption, but also disrupts fear extinction, and as such may be a useful preclinical model of stress-related psychopathology. Our data also suggest that disrupted noradrenergic signaling may contribute to escalated ethanol drinking following social isolation, thus further highlighting the potential utility of noradrenergic therapeutics in treating the deleterious behavioral sequelae associated with early life stress.

Effects of Repeated Stress on Age-Dependent GABAergic Regulation of the Lateral Nucleus of the Amygdala

“…Consistent with the current results, postweaning social isolation, which shares features of chronic stress during adolescence, causes an increase of behaviors, or reduced extinction of behaviors, which rely on the BLA, such as learned fear responses to cues (Lukkes et al, 2009;Skelly et al, 2015;Walasek et al, 2002), but see (Morrissey et al, 2011). It also increases the responsiveness of neurons across the BLA in c-Fos studies (Toth et al, 2012), increases NMDA receptors (Gan et al, 2014), and increases the excitability of neurons in the basal nucleus (Rau et al, 2015), although the LAT has not yet been studied.…”

Early-Life Social Isolation Stress Increases Kappa Opioid Receptor Responsiveness and Downregulates the Dopamine System

“…These data are consistent with previous studies demonstrating adolescent SI-induced escalations in ethanol intake (McCool and Chappell, 2009;Chappell et al, 2013;Skelly et al, 2015) and cocaine self-administration (Baarendse et al, 2014) in adulthood. Other stressors, such as footshock and forced swim stress, also potentiate cocaine seeking (Buffalari and See, 2009) and ethanol consumption (Sperling et al, 2010), respectively.…”

“…Chronic adolescent SI increases anxiety-like behaviors and ethanol consumption during adulthood and significantly disrupts mesolimbic DA signaling in rats Skelly et al, 2015). The KOR system modulates DA in the NAc and is involved in regulating both anxiety-like and drug-seeking behaviors (Sperling et al, 2010;Walker et al, 2012;Berger et al, 2013).…”

“…The intermittent drinking paradigm has previously been shown to produce relatively high levels of ethanol intake in male Long-Evans rats (Wise, 1973;Simms et al, 2008). Furthermore, this drinking paradigm has been shown to engender elevated ethanol intake in SI compared with GH rats (Chappell et al, 2013;Skelly et al, 2015).…”

Effects of physical exercise and social isolation on anxiety-related behaviors in two inbred rat strains

“…However, most studies use socially isolated animals, at least in some periods of time (e.g., during training). This procedure allows one to monitor PE levels for each individual; however, social isolation (SI) per se may be associated with anxiety-like behaviors (Butler et al, 2014;Skelly et al, 2015), cognitive dysfunction (Li et al, 2016) and depressive behaviors (Zanier-Gomes et al, 2015) in rodents, which could confound data interpretation. The Lewis (LEW) and Spontaneously Hypertensive Rats (SHR) inbred rat strains show contrasting levels of anxiety-related behavior, with the former exhibiting increased levels of anxiety-like behavior (Chiavegatto et al, 2009).…”