Altered anxiety-like behavior and long-term potentiation in the bed nucleus of the stria terminalis in adult mice exposed to chronic social isolation, unpredictable stress, and ethanol beginning in adolescence

Abstract

Alcohol and chronic stress exposure, especially during adolescence, can lead to an increased risk in adulthood of developing alcohol use disorders (AUDs). To date, however, no study has assessed the potential long-term effects of chronic intermittent and unpredictable ethanol (EtOH) exposure in mice chronically stressed beginning in adolescence on brain function and anxiety-like behaviors in adulthood. In particular, alterations in function of the bed nucleus of the stria terminalis (BNST), a brain region heavily implicated in anxiety-related behaviors and altered plasticity following EtOH exposure, may play a key role in the pathological responses to chronic stress and EtOH. In the present study, adolescent and adult C57Bl/6J mice were exposed to a regimen of chronic social isolation and unpredictable stressors and EtOH (or air (sham); CSI-CUS-EtOH and CSI-CUS-Sham, respectively) for 8-10 weeks. In adulthood, mice were tested for altered anxietylike behavior [elevated plus maze (EPM) and modified social interaction (SI) test]. Following behavioral testing, mice were re-exposed to CSI-CUS-EtOH (and CSI-CUS-Sham for controls) for an additional three days. 4-6 hours following the final EtOH (or air) exposure, field potential recordings of the dorsal-lateral (dl)BNST were performed. Mice first exposed during adolescence to CSI-CUS-EtOH displayed lower levels of anxiety-like behavior on the EPM compared to mice first exposed to CSI-CUS-EtOH during adulthood and control mice only exposed to CSI-CUSSham, regardless of age of first exposure. However, mice first exposed to CSI-CUS-EtOH during adulthood displayed lower levels of anxiety-like behavior on the SI test compared to mice first exposed during adolescence and control CSI-CUS-Sham mice. CSI-CUS-EtOH exposure, regardless of age, produced blunted expression of long-term potentiation (LTP) in the dlBNST compared to CSI-CUS-Sham mice. This study demonstrates age-dependent effects of chronic unpredictable ethanol exposure in chronically stressed mice on anxiety-like behaviors during

Chronic Intermittent Ethanol Exposure Produces Persistent Anxiety in Adolescent and Adult Rats

“…It is possible that the effect of CIE on anxiety is both age and dose dependent. However, the previous work that utilized high BEC, coupled with the work from Conrad and Winder (2011) who used ethanol vapor resulting in lower BEC levels of approximately 150–200 mg/dL, produced similar results, which suggests that CIE-induced anxiety is not dose dependent. Clearly additional research is needed on these topics.…”

“…Long-term potentiation in the extended amygdala, including the bed nucleus of the stria terminalis, is persistently suppressed by CIE exposure during adolescence, which co-occurs with increased anxiety-like behavior on the EPM (Conrad & Winder, 2011). Additionally, CIE exposure increases the functional expression of NR2B-containing receptors in the ventral bed nucleus of the stria terminalis (Kash et al, 2009).…”

Corticotropin-Releasing Factor Modulation of Forebrain GABAergic Transmission has a Pivotal Role in the Expression of Anabolic Steroid-Induced Anxiety in the Female Mouse

“…It is provocative to consider a mirror mechanism by which AAS-dependent increases in CRF at the synapse may 'de-saturate' transmission between the CeA and dlBnST by enhancing GABAergic inhibition, extending the response range in this critical circuit in the extended amygdala and thus allowing the more pronounced expression of sustained fear/anxiety to stressful stimuli that was observed in these animals. It will be of great interest to ascertain whether or not chronic AAS exposure also alters glutamate receptor-mediated synaptic plasticity at the CeA to dlBnST synapse as changes in anxiety-like behaviors in animals exposed to social isolation conditions and to ethanol result in blunted LTP in the dlBnST (Conrad and Winder, 2011).…”

The Sturm und Drang of anabolic steroid use: angst, anxiety, and aggression

“…Although some molecular targets have not been assessed in all of these key regions for both classes of drugs, the available data converge to suggest potential mechanisms by which both AAS exposure and ethanol withdrawal (EtOH-w) augment the expression of corticotropin releasing factor (CRF) in key regions of the anxiety circuitry, including the BnST [24,103], the CeA [25,84,85,100–102], and the DRN [102]. AAS and/or alcohol-dependent changes in CRF may, in turn, alter classical neurotransmission mediated by both GABA A Rs [25,84,85] and glutamate (as assessed by vesicular glutamate transporter 2, VGLUT2) [36] and glutamate receptors (GluRs) [56,103–105]. Finally, AAS and alcohol may significantly alter the activity of 5-HT neurons in the DRN [106] through GABAergic afferents to this region [90,107].…”