Collectively, this and the above studies provide compelling evidence that high levels of estrogen, whether occurring naturally or experimentally, can produce a sensitivity to the detrimental effects of stress in the PFC (Figure lb). The possible mechanisms by which estrogen confers this sensitivity have only just begun to be illuminated. The PFC receives sizeable afférents from midbrain catecholaminergic

nuclei locus coeruleus Inhibitors,research,lifescience,medical (LC),19 the primary source of norepinephrine (NE), and ventral tegmental area (VTA), the primary source of dopamine (DA). The influence of these projections on PFC functioning has been extensively studied, and it is widely accepted that the relationship between catecholamine levels in the PFC and working memory performance is manifest in an “inverted U” curve.20 Specifically, experimental or agerelated catecholamine Inhibitors,research,lifescience,medical depletion produces PFC-mediated cognitive deficits In monkeys and rodents21 that can be reversed with administration of DA or NE receptor agonists.22?23 However, extreme increases In mPFC catecholamine levels can also have a detrimental effect on PFC function Inhibitors,research,lifescience,medical (Figure 2), exerting their actions through the very

receptors that restore performance In animals whose catecholamine systems have been compromised. Such increases in catecholamine release are seen with stress,24 and it has been shown In male rats that Inhibitors,research,lifescience,medical stressinduced PFC dysfunction is due in part to binding of the DA T>1 receptor, and the subsequent activation of the protein kinase A (PKA) intracellular signaling pathway.25,26 Conversely, stress-induced impairments can be reversed through stimulation of the NE α-2 receptor,27 whose activation leads to an inhibition of PKA activity. Figure

2. The correlation between www.selleckchem.com/products/MLN-2238.html accuracy of delayed alternation performance in the rat and the ratio of DOPAC to dopamine in the prefrontal cortex. Rats were given vehicle or FG7142 (20 mg/kg) before being tested on delayed Inhibitors,research,lifescience,medical alternation, and were sacrificed immediately … To examine whether estrogen’s enhancement of stressinduced PFC dysfunction was due to actions at the NE α-2 receptor, OVX and OVX + E animals were coadministered an impairing dose of FG7142 and a dose of the α-2 agonist guanfacine (GFC) known to SB-3CT restore stress-related performance deficits in males, and then tested on the delayed alternation task. Although OVX animals required almost three times as much FG7142 as OVX + E in order to show impairment, OVX showed complete reversal of the impairment with GFC, while OVX + E showed no improvement (Figure 3). These results suggest that estrogen might cause sensitivity to stress-induced PFC dysfunction through suppression of an animal’s responsiveness to NE α-2 stimulation.