Estradiol potentiates inhibitory synaptic transmission in the oval bed nucleus of the striaterminalis of male and female rats.

17ß-Estradiol (E2) is a potent neuromodulator capable of producing changes in inhibitory synaptic transmission by either changing pre-synaptic GABA release or post-synaptic GABAA receptor function. Physiologically, E2 is important for energy homeostasis, influencing food consumption, body weight, adipose tissue metabolism and energy expenditure. E2 may influence energy homeostasis through estrogen receptor-rich regions such as the oval bed nucleus of the stria-terminalis (ovBNST). However, the neurophysiological effects of estradiol within the ovBNST remain largely unknown. Understanding how E2 affects inhibitory transmission may elucidate the ovBNST's contribution to energy homeostasis. Here, using brain slice electrophysiology, we saw that E2 produced a long-term potentiation (LTP) of GABAA synaptic transmission (LTPGABA) in the ovBNST in male rats. E2 acted on estrogen receptors α and G-protein coupled estrogen receptors (GPER), involved protein kinase activation and required an intact endocannabinoid system. The effects of E2 in males were sensitive to 24 h of food deprivation. In females, E2 was 100-fold more potent at producing LTPGABA ovBNST compared to male rats and involved all three known subtypes of estrogen receptors (ERα, ERß, and GPER). These results demonstrate that E2 is a potent neuromodulator of inhibitory synaptic transmission within the ovBNST of both sexes to potentially regulate energy homeostasis.

A Key Role for Neurotensin in Chronic-Stress-Induced Anxiety-Like Behavior in Rats.

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.

Is it stress? The role of stress related systems in chronic food restriction-induced augmentation of heroin seeking in the rat.

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.