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Early life adversity can disrupt development leading to emotional and cognitive disorders. This study investigated the effects of social isolation after weaning on anxiety, body weight and locomotion, and on extracellular dopamine (DA) and glutamate (GLU) in the nucleus accumbens (NAc) and their modulation by corticotropin releasing factor receptor 1. On the day of weaning, male rats were housed singly or in groups for 10 consecutive days. Anxiety-like behaviors were assessed by an elevated plus maze (EPM) and an open field test (OF). Neurotransmitter levels were measured by in vivo microdialysis. Single-housed rats spent less time, and entered more, into the closed arms of an EPM than group-housed rats. They also spent less time in the center of an OF, weighed more and showed greater locomotion. In the NAc, no differences in CRF, or in basal extracellular DA or GLU between groups, were observed. A depolarizing stimulus increased DA release in both groups but to higher levels in isolated rats, whereas GLU increased only in single-housed rats. Blocking CRF-R1 receptors with CP-154,526 decreased DA release in single-housed but not in group-housed rats. The corticotropin releasing factor receptor type 1 receptor antagonist also decreased GLU in group-housed animals. These results show that isolating adolescent rats increases anxiety, body weight and ambulation, as well as the sensitivity of dopaminergic neurons to a depolarizing stimulus. This study provides further evidence of the detrimental effects of social isolation during early development and indicates that dysregulation of the CRF system in the NAc may contribute to the pathologies observed.

During menopause, women have a higher propensity for developing cardiovascular diseases. Recent studies have shown that treatment with selective estrogen receptor modulators (SERMs) improves cardiovascular status in menopausal women. The mechanisms involved, however, have not been elucidated. The present study evaluates the effect of toremifene (10 mg/kg/day), a new member of SERM family, on the vasculature of ovariectomized (Ovx) Sprague-Dawley rats that have been treated with the drug for a 4-week period. Age-matched sham, Ovx-untreated, and Ovx 17beta-estradiol-treated rats were used as controls. Aortic rings from treated and untreated animals were used to determine vascular responses to norepinephrine, acetylcholine, and sodium nitroprusside. Systolic blood pressure (SBP), plasmatic nitric oxide (NO) concentration, estrogen levels, aortic wall thickness, and cholesterol profiles were also determined. Toremifene displaces the concentration-response curve (CRC) for the acetylcholine-induced relaxation to the left and increases the Emax by 34% (from 59.2 +/- 4.2% in Ovx-untreated to 90.2 +/- 3.1% in Ovx-treated rats, n = 9, P.05). Toremifene increases the Emax (by 22%) without modifying the EC5o for the NE-induced contraction. In addition, toremifene amplifies the relaxing responses to sodium nitroprusside compared to Ovx-untreated group (P.05). SBP was significantly reduced in the Ovx toremifene-treated group when compared to the Ovx-untreated group (124 +/- 3.5 mm Hg for Ovx toremifene-treated vs. 161 +/- 4.3 mm Hg for Ovx-untreated, n = 10, P.05). Rats treated chronically with toremifene also exhibited a significantly higher plasmatic NO levels, and a decrease in basal resting tension and aortic wall thickness. The drug, however, did not affect the plasmatic high-density lipoprotein (HDL)/total cholesterol ratio. These results suggest that chronic administration of toremifene improves cardiovascular performance in menopause-induced rats by reversing endothelial dysfunction and decreasing vascular resting tone. Thus, use of toremifene may help to diminish total peripheral resistance and improve cardiovascular status in Ovx rats.