What ethologically based models have taught us about the neural systems underlying fear and anxiety

Classical Pavlovian fear conditioning to painful stimuli has provided the generally accepted view of a core system centered in the central amygdala to organize fear responses. Ethologically based models using other sources of threat likely to be expected in a natural environment, such as predators or aggressive dominant conspecifics, have challenged this concept of a unitary core circuit for fear processing. We discuss here what the ethologically based models have told us about the neural systems organizing fear responses. We explored the concept that parallel paths process different classes of threats, and that these different paths influence distinct regions in the periaqueductal gray - a critical element for the organization of all kinds of fear responses. Despite this parallel processing of different kinds of threats, we have discussed an interesting emerging view that common cortical-hippocampal-amygdalar paths seem to be engaged in fear conditioning to painful stimuli, to predators and, perhaps, to aggressive dominant conspecifics as well. Overall, the aim of this review is to bring into focus a more global and comprehensive view of the systems organizing fear responses.

What ethologically based models have taught us about the neural systems underlying fear and anxiety.

Classical Pavlovian fear conditioning to painful stimuli has provided the generally accepted view of a core system centered in the central amygdala to organize fear responses. Ethologically based models using other sources of threat likely to be expected in a natural environment, such as predators or aggressive dominant conspecifics, have challenged this concept of a unitary core circuit for fear processing. We discuss here what the ethologically based models have told us about the neural systems organizing fear responses. We explored the concept that parallel paths process different classes of threats, and that these different paths influence distinct regions in the periaqueductal gray - a critical element for the organization of all kinds of fear responses. Despite this parallel processing of different kinds of threats, we have discussed an interesting emerging view that common cortical-hippocampal-amygdalar paths seem to be engaged in fear conditioning to painful stimuli, to predators and, perhaps, to aggressive dominant conspecifics as well. Overall, the aim of this review is to bring into focus a more global and comprehensive view of the systems organizing fear responses.

Tachyphylactic properties of angiotensin II analogs with bulky and hydrophobic substituents at the N-terminus.

Tachyphylaxis, defined as the acute loss of response of some smooth muscles upon repeated stimulations with angiotensin II (Ang II), has been shown to be dependent mainly on the N-terminal region of the ligand. To further study the structural requirements for the induction of tachyphylaxis we have synthesized Ang II analogs containing the bulky and very lipophilic substituents 9-fluorenylmethyloxycarbonyl (Fmoc) and 9-fluorenylmethyl ester (OFm) at the alpha-amino (Nalpha-Fmoc-Ang II) or the beta-carboxyl ([Asp(OFm)1]-Ang II) groups of the Asp1 residue, respectively. In binding assays with Chinese hamster ovary cells transfected with the AT1 Ang II receptor, Nalpha-Fmoc-Ang II bound with high affinity, whereas [Asp(OFm)1]-Ang II showed lower affinity. In biological assays, these two analogs were full agonists and showed 30 and 3%, respectively, of the Ang II potency in contracting the guinea-pig ileum smooth muscle. The two analogs induced tachyphylaxis, in spite of the lack of a free amino group in Nalpha-Fmoc-Ang II. Thus, analogs with Fmoc- or OFm-type groups coupled to the Asp1 residue, whether at the amino or carboxyl functions, induce tachyphylaxis through an unreported mechanism. Based in these findings and those available from the literature, an alternate molecular interaction mode between Ang II N-terminal portion and the AT1 receptor is proposed to explain the tachyphylactic phenomenon.