Chronic stress is a major cause of anxiety disorders that can be reliably modeled preclinically, providing insight into alternative therapeutic targets for this mental health illness. Neuropeptides have been targeted in the past to no avail possibly due to our lack of understanding of their role in pathological models. In this study we use a rat model of chronic stress-induced anxiety-like behaviors and hypothesized that neuropeptidergic modulation of synaptic transmission would be altered in the bed nucleus of the stria terminalis (BNST), a brain region suspected to contribute to anxiety disorders. We use brain slice neurophysiology and behavioral pharmacology to compare the role of locally released endogenous neuropeptides on synaptic transmission in the oval (ov) BNST of non-stressed (NS) or chronic unpredictably stressed (CUS) rats. We found that in NS rats, post-synaptic depolarization induced the release of vesicular neurotensin (NT) and corticotropin-releasing factor (CRF) that co-acted to increase ovBNST inhibitory synaptic transmission in 59% of recorded neurons. CUS bolstered this potentiation (100% of recorded neurons) through an enhanced contribution of NT over CRF. In contrast, locally released opioid neuropeptides decreased ovBNST excitatory synaptic transmission in all recorded neurons, regardless of stress. Consistent with CUS-induced enhanced modulatory effects of NT, blockade of ovBNST NT receptors completely abolished stress-induced anxiety-like behaviors in the elevated plus maze paradigm. The role of NT has been largely unexplored in stress and our findings highlight its potential contribution to an important behavioral consequence of chronic stress, that is, exaggerated avoidance of open space in rats.

Drug addiction is a chronic disease characterized by recurring episodes of abstinence and relapse. The precise mechanisms underlying this pattern are yet to be elucidated, but stress is thought to be a major factor in relapse. Recently, we reported that rats under withdrawal and exposed to a mild chronic stressor, prolonged food restriction, show increased heroin seeking compared to sated controls. Previous studies demonstrated a critical role for corticotropin-releasing factor (CRF) and corticosterone, hormones involved in the stress response, in acute food deprivation-induced reinstatement of extinguished drug seeking. However, the role of CRF and corticosterone in chronic food restriction-induced augmentation of drug seeking remains unknown. Here, male Long-Evans rats were trained to self-administer heroin for 10 days in operant conditioning chambers. Rats were then removed from the training chambers, and subjected to 14 days of unrestricted (sated rats) or a mildly restricted (FDR rats) access to food, which maintained their body weight (BW) at 90% of their baseline weight. On day 14, different groups of rats were administered a selective CRF1 receptor antagonist (R121919; 0.0, 20.0 mg/kg; s.c.), a non-selective CRF receptor antagonist (α-helical CRF; 0.0, 10.0, 25.0 μg/rat; i.c.v.) or a glucocorticoid receptor antagonist (RU486; 0.0, 30.0 mg/kg; i.p.), and underwent a 1 h drug seeking test under extinction conditions. An additional group of rats was tested following adrenalectomy. All FDR rats showed a statistically significant increase in heroin seeking compared to the sated rats. No statistically significant effects for treatment with α-helical CRF, R121919, RU486 or adrenalectomy were observed. These findings suggest that stress may not be a critical factor in the augmentation of heroin seeking in food-restricted rats.

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23Compulsions, defined by debilitating repetitive actions, permeate many mental illnesses and are 24 challenging to treat partly because of a limited understanding of their neurobiological 25 underpinnings. Accumulating evidence suggests the rodent model of Schedule-Induced Polydipsia 26 (SIP) as a promising pre-clinical assay to elucidate the neurobiological and behavioural 27 manifestations of compulsivity. In the rodent SIP paradigm, susceptible rats develop adjunctive 28 excessive drinking when they are chronically food restricted and presented with food pellets 29 according to a fixed-time schedule. We found that normally, bi-directional plasticity of GABA 30 synapses in the oval bed nucleus of the stria terminalis (ovBNST) tightly followed the rats' satiety 31 state where low-frequency stimulation-induced potentiation (LTPGABA) prevailed in sated rats 32 whilst food restriction uncovered long-term depression (LTDGABA). In rats that developed 33 excessive drinking during SIP, removing the caloric restriction failed at reverting LTDGABA to 34 LTPGABA whereas bi-directional plasticity at ovBNST GABA synapses was unaltered in low-35 drinking SIP-trained rats. Excessive drinking ceased in polydipsic rats removed from their caloric 36 restriction; however, these rats retained a form of compulsive schedule-induced checking (SIC) 37 and impaired plasticity at ovBNST GABA synapses for several days following termination of the 38 caloric restriction. We conclude that altered bi-directional plasticity at ovBNST GABA synapses 39 is a neurophysiological trace of compulsivity in susceptible rats in the SIP model. 40 41 42Compulsions are time-consuming, repetitive actions that cause significant distress and 43 impairments in both the function and quality of daily life (American Psychiatric Association, 44 2013). Compulsive behaviours are symptomatic of many psychiatric disorders including 45 obsessive-compulsive disorder (OCD), addictions, and schizophrenia (Berman et al., 1995; 46 Drubach, 2015; Everitt and Robbins, 2005; Hariprasad et al., 1980). Despite common etiological 47 characteristics across psychiatric diagnoses, the underlying neurophysiology of compulsivity 48 remains largely unknown. Existing preclinical rodent models may help elucidate where and how 49 in the brain is pathological compulsivity represented (Everitt and Robbins, 2016; Szechtman et al., 50 2017). 51In the schedule-induced polydipsia (SIP) paradigm, food-restricted rats develop adjunctive 52 excessive drinking when presented with food pellets according to a fixed-time schedule (Falk, 53 1966; Platt et al., 2008). Interestingly, only a subset of rats within any given cohort develops 54 excessive drinking suggesting a powerful pre-clinical tool to understand how environment and 55 genetics interact to trigger the maladaptive behaviour (Moreno and Flores, 2012; Rosenzweig-56 Lipson et al., 2007; Toscano et al., 2008). Although the drinking behaviour in SIP is clearly 57 excessive, non-physiological, and maladaptive due to the r...