The hypothalamo-pituitary-adrenal (HPA) axis is hyperactive in major depressive disorder (MDD), and baseline cortisol levels are usually elevated in MDD patients, with alterations of the circadian hormone secretion pattern. The dexamethasone (DEX) suppression test (DST) has been extensively applied to diagnose a dysregulation of the HPA axis in MDD, but it has only a limited sensitivity to, and specificity for, depression. The DEX/CRH test, which combines the DST with a corticotropin-releasing hormone (CRH) challenge, has proved more reliable to show HPA axis dysfunction in MDD. We have applied these two tests to a putative model of vulnerability to depression in rodents, the Roman high-(RHA) and low-(RLA) Avoidance rat lines. As compared to RHA, RLA rats are behaviorally inhibited, they show an exaggerated response of the HPA axis to stress, and are more prone to develop depressive-like features when exposed to chronic stress. Our results show that (a) there were no significant differences in circadian plasma corticosterone (CORT) levels and/or secretion patterns between the two lines; (b) in the DST test, CORT was suppressed to the same extent in RHA and RLA rats; and c) in the DEX/CRH test, areas-under-the-curve (AUCs) and CORT delta (peak minus baseline) responses were significantly larger in RLA rats. One possible interpretation of these data is that an increased response to CRH could be a trait marker (or endophenotype) for depression, whereas alterations of circadian glucocorticoid secretion patterns and non-suppression of the daily glucocorticoid rise by dexamethasone could be state markers, i.e. features that are only present during depressive episodes.

We have previously shown that exposure of rats to constant light (LL) induced a decrease in NO synthase (NOS) activity in the pineal gland. We present here the evidence that chronic (5 days) norepinephrine (NE) or isoproterenol treatment prevents the effect of LL and enhances pineal NOS activity in LL animals. This effect of NE appears to be mediated by beta-adrenoceptors, because it was not mimicked by the alpha-agonist phenylephrine. Pineal NOS activity was reduced in 16-h light/8-h dark animals treated for 4 days with the beta-adrenergic antagonist propranolol but not with the alpha(1)-antagonist prazosin, indicating again an involvement of beta-adrenergic receptor in the control of NOS. Treatment with adrenergic antagonists did not affect cortical NOS activity, suggesting that the control of NOS is different in these two tissues or that the pineal expresses a specific isoform of the enzyme. Taken together, these data suggest that NE controls NOS in the pineal gland through beta-adrenergic receptors. To our knowledge, this represent the first demonstration of a regulation of NOS by a neurotransmitter in the CNS, as assayed under V-max conditions.

Annals of the New York Academy of SciencesVolume 851, Issue 1 p. 501-510 Genetic Selection and Differential Stress Responses: The Roman Lines/Strains of Rats P. DRISCOLL, P. DRISCOLL ETH, Institut für Natztierwissenschaften, Schorenstrasse 16, CH-8603 Schwerzenbach, SwitzerlandSearch for more papers by this authorR. M. ESCORIHUELA, R. M. ESCORIHUELA Autonomous University of Barcelona, Medical Psychology Unit, E-08193 Bellaterra (Barcelona), SpainSearch for more papers by this authorA. FERNÁNDEZ-TERUEL, A. FERNÁNDEZ-TERUEL Autonomous University of Barcelona, Medical Psychology Unit, E-08193 Bellaterra (Barcelona), Spain University of Santiago de Compostela, Department of Psychobiology, E-15705 Santiago de Compostela, SpainSearch for more papers by this authorO. GIORGI, O. GIORGI University of Cagliari, Department of Toxicology, Viale A. Diaz 182, I-09126 Cagliari, ItalySearch for more papers by this authorH. SCHWEGLER, H. SCHWEGLER University of Magdeburg, Anatomy Institute, Leipzigerstrasse 44, D-39120 Magdeburg, GermanySearch for more papers by this authorTh. STEIMER, Th. STEIMER IUPG, Clinical Psychopharmacology Unit, 100 avenue de Bel-Air, CH-1225 Chêne-Bourg (GE), SwitzerlandSearch for more papers by this authorA. WIERSMA, A. WIERSMA NV Organon, RE 2211, P.O. Box 20, NL-5340 BH Oss, the NetherlandsSearch for more papers by this authorM. G. CORDA, M. G. CORDA University of Cagliari, Department of Toxicology, Viale A. Diaz 182, I-09126 Cagliari, ItalySearch for more papers by this authorJ. FLINT, J. FLINT University of Oxford, Institute of Molecular Medicine, John Radcliffe Hospital, Headington, GB-Oxford OX3 9DU, EnglandSearch for more papers by this authorJ. M. KOOLHAAS, J. M. KOOLHAAS University of Groningen, Department of Animal Physiology, Kerklaan 30, P.O. Box 14, NL-9750 AA Haren, the NetherlandsSearch for more papers by this authorW. LANGHANS, W. LANGHANS ETH, Institut für Natztierwissenschaften, Schorenstrasse 16, CH-8603 Schwerzenbach, SwitzerlandSearch for more papers by this authorP. E. SCHULZ, P. E. SCHULZ IUPG, Clinical Psychopharmacology Unit, 100 avenue de Bel-Air, CH-1225 Chêne-Bourg (GE), SwitzerlandSearch for more papers by this authorJ. SIEGEL, J. SIEGEL University of Delaware, Departments of Psychology and Biology, Newark, Delaware 19716 USASearch for more papers by this authorA. TOBEÑA, A. TOBEÑA Autonomous University of Barcelona, Medical Psychology Unit, E-08193 Bellaterra (Barcelona), SpainSearch for more papers by this author P. DRISCOLL, P. DRISCOLL ETH, Institut für Natztierwissenschaften, Schorenstrasse 16, CH-8603 Schwerzenbach, SwitzerlandSearch for more papers by this authorR. M. ESCORIHUELA, R. M. ESCORIHUELA Autonomous University of Barcelona, Medical Psychology Unit, E-08193 Bellaterra (Barcelona), SpainSearch for more papers by this authorA. FERNÁNDEZ-TERUEL, A. FERNÁNDEZ-TERUEL Autonomous University of Barcelona, Medical Psychology Unit, E-08193 Bellaterra (Barcelona), Spain University of Santiago de Compostela, Department of Psychobiology, E-15705 Santiago de Compostela, SpainSearch for more papers by this authorO. GIORGI, O. GIORGI University of Cagliari, Department of Toxicology, Viale A. Diaz 182, I-09126 Cagliari, ItalySearch for more papers by this authorH. SCHWEGLER, H. SCHWEGLER University of Magdeburg, Anatomy Institute, Leipzigerstrasse 44, D-39120 Magdeburg, GermanySearch for more papers by this authorTh. STEIMER, Th. STEIMER IUPG, Clinical Psychopharmacology Unit, 100 avenue de Bel-Air, CH-1225 Chêne-Bourg (GE), SwitzerlandSearch for more papers by this authorA. WIERSMA, A. WIERSMA NV Organon, RE 2211, P.O. Box 20, NL-5340 BH Oss, the NetherlandsSearch for more papers by this authorM. G. CORDA, M. G. CORDA University of Cagliari, Department of Toxicology, Viale A. Diaz 182, I-09126 Cagliari, ItalySearch for more papers by this authorJ. FLINT, J. FLINT University of Oxford, Institute of Molecular Medicine, John Radcliffe Hospital, Headington, GB-Oxford OX3 9DU, EnglandSearch for more papers by this authorJ. M. KOOLHAAS, J. M. KOOLHAAS University of Groningen, Department of Animal Physiology, Kerklaan 30, P.O. Box 14, NL-9750 AA Haren, the NetherlandsSearch for more papers by this authorW. LANGHANS, W. LANGHANS ETH, Institut für Natztierwissenschaften, Schorenstrasse 16, CH-8603 Schwerzenbach, SwitzerlandSearch for more papers by this authorP. E. SCHULZ, P. E. SCHULZ IUPG, Clinical Psychopharmacology Unit, 100 avenue de Bel-Air, CH-1225 Chêne-Bourg (GE), SwitzerlandSearch for more papers by this authorJ. SIEGEL, J. SIEGEL University of Delaware, Departments of Psychology and Biology, Newark, Delaware 19716 USASearch for more papers by this authorA. TOBEÑA, A. TOBEÑA Autonomous University of Barcelona, Medical Psychology Unit, E-08193 Bellaterra (Barcelona), SpainSearch for more papers by this author First published: 07 February 2006 https://doi.org/10.1111/j.1749-6632.1998.tb09029.xCitations: 98Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume851, Issue1STRESS OF LIFE: FROM MOLECULES TO MANJune 1998Pages 501-510 RelatedInformation

Brain metabolites of progesterone such as tetrahydroprogesterone (THP) act on GABAA receptors and have anxiolytic properties. The formation of THP and its 5α‐reduced precursor, dihydroprogestrone (DHP) was measured in vitro in various microdissected brain areas obtained from males of two psychogenetically selected rat lines, i.e. the Roman High‐(RHA/Verh) and Low‐(RLA/Verh) Avoidance rats, which are known to differ in emotional reactivity and/or anxiety. The behavioural and neuroendocrine responses of these rats were also measured following exposure to a novel environment in two different test situations. The formation of DHP and THP was found to be significantly higher in the frontal cortex (FCX), and DHP in the bed nucleus of the stria terminalis (BST), of the hypoemotional RHA/Verh rats. In addition, enzymatic activity in the FCX was found to be inversely correlated with behavioural measures of anxiety. These results suggest that individual, possibly genetically‐determined differences in brain production of endogenous anxiolytics derived from progesterone may account at least in part for the behavioural differences characterizing these two lines, and provide further evidence that neurosteroids acting on the GABAergic system may play an important role in modulating physiological and/or behavioural responses to environmental stressors.

The Roman high (RHA/Verh)- and low (RLA/Verh)-avoidance rats, originally selected and bred for rapid vs. poor acquisition of a two-way active avoidance response, differ in emotional reactivity and sensitivity to stressors in various other test situations. These behavioral differences are associated with particular neuroendocrine and neurochemical characteristics. The aim of this short review is to present data currently available on the neuroendocrine profiles of RHA/Verh and RLA/Verh rats, together with more recent findings which suggest that differences in peripheral and central hormonal responses, and in hormone action on the brain, may be closely related to emotional reactivity and coping ability. Although genetic factors certainly play a major role, there is also evidence that epigenetic factors, e.g., early environmental influences, can modulate the phenotypic expression of the basic behavioral and neuroendocrine traits characterizing these lines. These psychogenetically selected lines can therefore be used as a model to investigate interactions between genes and the environment in determining each individual's sensitivity to stress and coping abilities ("vulnerability" model). This model may prove particularly useful for studies on the etiology and pathophysiology of anxiety and affective disorders and their neuroendocrine correlates.