Furthermore, lesion of these structures blocks the effects of IS (Amat et al., 2001 and Hammack et al., 2004). However, contrary to the expectation that ES would not then activate these structures and inputs to the DRN, or do so to a lessor degree than does IS, ES produced the same level of activation and input

(Amat et al., 2001). For example, in an extensive series of studies examining LC activation, McDevitt et al. (2009) found that both IS and ES intensely activate the LC as assessed by c-fos mRNA, Fos protein, and tyrosine hydroxylase mRNA, but to exactly the same degree. Before leaving the DRN and 5-HT, it should be noted that intense DRN activation is not restricted to IS as a stressor. For example, social defeat (which is arguably uncontrollable) does so as well www.selleckchem.com/products/17-AAG(Geldanamycin).html (Amat et al., 2010). However, all stressors do not do so, and it has been suggested that stressors have to be prolonged and intense (Takase et al., 2005). In addition, IS and other uncontrollable stressors certainly do more than activate

the DRN, and produce outcomes that are not mediated by the DRN. For example, IS conditions fear to cues that are present, and this is mediated by the standard amygdala circuitry (Maier et al., 1993). Finally, there has recently been a large amount of research devoted to a more general understanding of the role of the DRN in stress-related phenomena than the focus on controllability phenomena that is the subject of this review (Valentino et al., 2010). The research reviewed above indicates that uncontrollable Afatinib in vivo stressor exposure differentially activates DRN 5-HT neurons relative to controllable stressors, but that both types of stressors appear to provide equivalent excitatory input to the DRN. This juxtaposition of findings leaves only one obvious possibility, namely, that controllable stressors lead TCL to an input to the DRN that differentially inhibits 5-HT activity.

That is, both ES and IS induce inputs to the DRN that activate the DRN, but only ES produces an input that inhibits DRN 5-HT. Under this view control does not produce its protective effects passively by lacking something that uncontrollability produces as in the original view, but instead does so actively. If the detection/processing of control were to lead to the inhibition of DRN 5-HT neuronal activity, the cortex would be an obvious source. Interestingly, the DRN receives virtually all of its cortical input from the prelimbic (PL) region of the ventral medial prefrontal cortex (vmPFC) (Peyron et al., 1998 and Vertes, 2004). Importantly, electrical stimulation in this region leads to the inhibition of DRN 5-HT neuronal firing (Hajos et al., 1998). This inhibition occurs because glutamatergic pyramidal output neurons from the PL to the DRN synapse preferentially within the DRN on GABAergic interneurons that in turn inhibit 5-HT cells (Jankowski and Sesack, 2004).