Norepinephrine: New Vistas for an Old Neurotransmitter| Volume 46, ISSUE 9, P1153-1166, November 01, 1999

The role of corticotropin-releasing factor–norepinephrine systems in mediating the effects of early experience on the development of behavioral and endocrine responses to stress

  • Darlene D Francis
    Developmental Neuroendocrinology Laboratory, Douglas Hospital Research Centre, Departments of Psychiatry, and Neurology and Neurosurgery, McGill University, Montreal, Canada (DDF, CC, FC, MJM)
    Search for articles by this author
  • Christian Caldji
    Developmental Neuroendocrinology Laboratory, Douglas Hospital Research Centre, Departments of Psychiatry, and Neurology and Neurosurgery, McGill University, Montreal, Canada (DDF, CC, FC, MJM)
    Search for articles by this author
  • Frances Champagne
    Developmental Neuroendocrinology Laboratory, Douglas Hospital Research Centre, Departments of Psychiatry, and Neurology and Neurosurgery, McGill University, Montreal, Canada (DDF, CC, FC, MJM)
    Search for articles by this author
  • Paul M Plotsky
    Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia, USA (PMP)
    Search for articles by this author
  • Michael J Meaney
    Address reprint requests to Michael J. Meaney, Douglas Hospital Research Center, 6875 LaSalle Blvd., Montréal (Québec) Canada, H4H 1R3
    Developmental Neuroendocrinology Laboratory, Douglas Hospital Research Centre, Departments of Psychiatry, and Neurology and Neurosurgery, McGill University, Montreal, Canada (DDF, CC, FC, MJM)
    Search for articles by this author


      Naturally occurring variations in maternal care in early postnatal life are associated with the development of individual differences in behavioral and hypothalamic–pituitary–adrenal responses to stress in the rat. These effects appear to be mediated by the influence of maternal licking and grooming on the development of central corticotropin-releasing factor (CRF) systems, which regulate the expression of behavioral, endocrine, and autonomic responses to stress through activation of forebrain noradrenergic systems. These findings provide a neurobiologic basis for the observed relationship between early life events and health in adulthood. In more recent studies, we explored the behavioral transmission of individual differences in stress reactivity, and thus, vulnerability to stress-induced illness, across generations.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Ader R.
        • Grota L.J.
        Effects of early experience on adrenocortical reactivity.
        Physiol Behav. 1969; 4: 303-305
        • Alberts J.R.
        Learning as adaptation of the infant.
        Acta Paediatr Suppl. 1994; 397: 77-85
        • Anisman H.
        • Zaharia M.D.
        • Meaney M.J.
        • Merali Z.
        Do early life events permanently alter behavioral and hormonal responses to stressors?.
        Int J Dev Neurosci. 1998; 16: 149-164
        • Barnett S.A.
        Sci Am. 1967; 21: 79-85
        • Baxter J.D.
        • Tyrrell J.B.
        The adrenal cortex.
        in: Felig P. Baxter J.D. Broadus A.E. Frohman L.A. Endocrinology and Metabolism. McGraw-Hill, New York1987: 385-511
        • Bell R.W.
        • Nitschke W.
        • Gorry T.H.
        • Zachman T.
        Infantile stimulation and ultrasonic signaling.
        Dev Psychobiol. 1971; 4: 181-191
        • Berman C.M.
        Intergenerational transmission of maternal rejection rates among free-ranging rhesus monkeys on Cayo Santiago.
        Anim Behav. 1990; 44: 247-258
        • Bhatnagar S.
        • Shanks N.
        • Meaney M.J.
        Hypothalamic–pituitary–adrenal function in handled and nonhandled rats in response to chronic stress.
        J Neuroendocrinol. 1995; 7: 107-119
        • Bifulco A.
        • Brown G.W.
        • Adler Z.
        Early sexual abuse and clinical depression in aduult life.
        Br J Psychiatry. 1991; 159: 115-122
        • Brady L.S.
        • Gold P.W.
        • Herkenham M.
        • Lynn A.B.
        • Whitfield H.W.
        The antidepressants fluoxetine, idazoxan and phenelzine alter corticotropin-releasing hormone and tyrosine hydroxylase mRNA levels in rat brain.
        Brain Res. 1992; 572: 117-125
        • Bridges R.S.
        The role of lactogenic hormones in maternal behavior in female rats.
        Acta Paediatr Suppl. 1994; 397: 33-39
        • Bridges R.S.
        • Freemark M.S.
        Human placental lactogen infusions into the medial preoptic area stimulate maternal behavior in steroid-primed, nulliparous female rats.
        Horm Behav. 1995; 29: 216-226
        • Brindley D.N.
        • Rolland Y.
        Possible connections between stress, diabetes, obesity, hypertension and altered lipoprotein metabolism that may result in atherosclerosis.
        Clin Sci. 1989; 77: 453-461
        • Brown G.R.
        • Anderson B.
        Psychiatric morbidity in adult inpatients with childhood histories of sexual and physical abuse.
        Am J Psychiatry. 1993; 148: 55-61
        • Butler P.D.
        • Weiss J.M.
        • Stout J.C.
        • Nemeroff C.B.
        Corticotropin-releasing factor produces fear-enhancing and behavioral activating effects following infusion into the locus coeruleus.
        J Neurosci. 1990; 10: 176-183
        • Cahill L.
        • McGaugh J.L.
        Mechanisms of emotional arousal and lasting declarative memory.
        Trend Neurosci. 1998; 21: 294-299
      1. Caldji C, Diorio J, Francis DD, Sharma S, Meaney MJ (in press): Maternal care during infancy regulates the expression of GABAergic receptor subunit expression.

        • Caldji C.
        • Diorio J.
        • Plotsky P.M.
        • Meaney M.J.
        Multiple central benzodiazepine/GABAA receptor subunits regulated by maternal behavior in infancy.
        Soc Neurosci Abstr. 1999; 25: 616
        • Caldji C.
        • Tannenbaum B.
        • Sharma S.
        • Francis D.
        • Plotsky P.M.
        • Meaney M.J.
        Maternal care during infancy regulates the development of neural systems mediating the expression of behavioral fearfulness in adulthood in the rat.
        Proc Nat Acad Sci U S A. 1998; 95: 5335-5340
        • Calhoun J.B.
        The Ecology and Sociology of the Norway Rat. H.E.W. Public Health Service, Bethesda, MD1962
        • Canetti L.
        • Bachar E.
        • Galili-Weisstub E.
        • De-Nour A.K.
        • Shalev A.Y.
        Parental bonding and mental health in adolescence.
        Adolescence. 1997; 32: 381-394
        • Chrousos G.P.
        • Gold P.W.
        The concepts of stress and stress system disorders.
        JAMA. 1992; 267: 1244-1252
        • Coplan J.D.
        • Andrews M.W.
        • Rosenblum L.A.
        • Owens M.J.
        • Friedman S.
        • et al.
        Persistent elevations of cerebrospinal fluid concentrations of corticotropin-releasing factor in adult nonhuman primates exposed to early-life stressors.
        Proc Nat Acad Sci U S A. 1996; 93: 1619-1623
        • Coplan J.D.
        • Trost R.C.
        • Owens M.J.
        • Cooper T.B.
        • Gorman J.A.M.
        • Nemeroff C.B.
        • et al.
        Cerebrospinal fluid concentrations of somatostatin and biogenic amines in grown primates reared by mothers exposed to manipulated foraging conditions.
        Arch Gen Psychiatry. 1998; 55: 473-477
        • Daly M.
        Early stimulation of rodents.
        Br J Psychol. 1973; 64: 435-460
        • DeBellis M.D.
        • Chrousos G.P.
        • Dom L.D.
        • Burke L.
        • Helmers K.
        • Kling M.A.
        • et al.
        Hypothalamic pituitary adrenal dysregulation in sexually abused girls.
        J Clin Endocrinol Metab. 1994; 78: 249-255
        • de Kloet E.R.
        Brain corticosteroid receptor balance and homeostatic control.
        Neuroendocrinology. 1991; 12: 95-164
        • Denenberg V.H.
        Early experience and emotional development.
        Sci Am. 1963; 208: 138-146
        • Denenberg V.H.
        Critical periods, stimuli input, and emotional reactivity.
        Psychol Rev. 1964; 71: 335-351
        • Eisenberg L.
        The biosocial context of parenting in human families.
        in: Krasnegor N.A. Bridges R.S. Mammalian Parenting. Oxford University Press, New York1990: 9-16
        • Fairbanks L.M.
        Individual differences in maternal style.
        Adv Study Behav. 1996; 25: 579-611
        • Fairbanks L.Y.
        Early experience and cross-generational continuity of mother–infant contact in Vervet monkeys.
        Dev Psychobiol. 1989; 22: 669-681
        • Farrington D.A.
        • Gallagher B.
        • Morley L.
        • St Ledger R.J.
        • West D.J.
        Are there any successful men from criminogenic backgrounds?.
        Psychiatry. 1988; 51: 116-130
        • Field T.
        Maternal depression effects on infants and early interventions.
        Prev Med. 1998; 27: 200-203
        • Fleming A.
        • Corter C.
        Factors influencing maternal responsiveness in humans.
        Psychoneuroendocrinology. 1988; 13: 189-212
        • Fleming A.S.
        Factors influencing maternal responsiveness in humans.
        Psychoneuroendocrinology. 1988; 13: 189-212
        • Fleming A.S.
        • Anderson V.
        Affect and nurturance.
        Prog Neuropsychopharmacol Biol Psychiatry. 1987; 11: 121-127
        • Fleming A.S.
        • Cheung U.
        • Myhal N.
        • Kessler Z.
        Effects of maternal hormones on “timidity” and attraction to pup-related odors in female rats.
        Physiol Behav. 1989; 46: 449-453
      2. Francis D, Liu D, Brake W, Meaney MJ (1999): Variations in maternal care: What exactly does it regulate. Society for Behavioral Neuroendocrinology Abstract, #42.

        • Francis D.
        • Sharma S.
        • Liu D.
        • Pearson D.
        • Plotsky P.M.
        • Meaney M.J.
        Variations in maternal care form the basis for a non-genomic mechanism of inter-generational transmission of individual differences in behavioral and endocrine responses to stress.
        Soc Neurosci Abs. 1998; 24: 452
        • Gray J.A.
        The Psychology of Fear and Stress. Cambridge University Publications, Cambridge, UK1987
      3. Gray TS (1990): The organization and possible function of amygdaloid corticotropin-releasing factor pathways. In: De Souza EB, Nemeroff CB, editors. Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide. Boca Raton, FL: CRC Press, 53–68.

        • Gray T.S.
        • Bingaman E.W.
        The amygdala.
        Crit Rev Neurobiol. 1996; 10: 155-168
        • Heim C.
        • Owens M.J.
        • Plotsky P.M.
        • Nemeroff C.H.
        The role of early adverse life events in the etiology of depression and posttraumatic stress disorder.
        Ann N Y Acad Sci. 1997; 821: 194-207
        • Hess J.L.
        • Denenberg V.H.
        • Zarrow M.X.
        • Pfeifer W.D.
        Modification of the corticosterone response curve as a function of handling in infancy.
        Physiol Behav. 1969; 4: 109-112
        • Higley J.D.
        • Haser M.F.
        • Suomi S.J.
        • Linnoila M.
        Nonhuman primate model of alcohol abuse.
        Proc Natl Acad Sci U S A. 1991; 88: 7261-7265
        • Holmes S.J.
        • Robins L.N.
        The influence of childhood disciplinary experience on the development of alcoholism and depression.
        J Child Psychol Psychiatry. 1987; 28: 399-415
        • Holmes S.J.
        • Robins L.N.
        The role of parental disciplinary practices in the development of depression and alcoholism.
        Psychiatry. 1988; 51: 24-36
        • Jacobson L.
        • Sapolsky R.M.
        The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenal axis.
        Endocrinol Rev. 1991; 12: 118-134
        • Jans J.
        • Woodside B.C.
        Nest temperature.
        Dev Psychobiol. 1990; 23: 519-534
        • Koegler-Muly S.M.
        • Owens M.J.
        • Ervin G.N.
        • Kilts C.D.
        • Nemeroff C.B.
        Potential corticotropin-releasing factor pathways in the rat brain as determined by bilateral electrolytic lesions of the central amygdaloid nucleus and paraventricular nucleus of the hypothalamus.
        J Neuroendocrinol. 1993; 5: 95-98
        • Kraemer G.W.
        • Ebert M.H.
        • Schmidt D.E.
        • McKinney W.T.
        A longitudinal study of the effect of different social rearing conditions on cerebrospinal fluid norepinephrine and biogenic amine metabolites in rhesus monkeys.
        Neuropsychopharmacology. 1989; 2: 175-189
        • Ladd C.O.
        • Owens M.J.
        • Nemeroff C.B.
        Persistent changes in corticotropin-releasing factor neuronal systems induced by maternal deprivation.
        Endocrinology. 1996; 137: 1212-1218
        • Lavicky J.
        • Dunn A.J.
        Corticotropin-releasing factor stimulates catecholamine release in hypothalamus and prefrontal cortex in freelymoving rats as assessed by microdialysis.
        J Neurochem. 1993; 60: 602-612
        • Lee M.H.S.
        • Williams D.I.
        Changes in licking behaviour of rat mother following handling of young.
        Anim Behav. 1974; 22: 679-681
        • Lee M.H.S.
        • Williams D.I.
        Long term changes in nest condition and pup grouping following handling of rat litters.
        Dev Psychobiol. 1975; 8: 91-95
        • Lee Y.
        • Schulkin J.
        • Davis M.
        Effect of corticosterone on the enhanced acoustic startle reflex by corticotropin-releasing factor.
        Brain Res. 1994; 666: 93-99
        • Levine S.
        Infantile experience and resistance to physiological stress.
        Science. 1957; 126: 405-406
        • Levine S.
        Plasma-free corticosteroid response to electric shock in rats stimulated in infancy.
        Science. 1962; 135: 795-796
        • Levine S.
        Psychosocial factors in growth and development.
        in: Levi L. Society, Stress and Disease. Oxford University Press, London1975: 43-50
        • Levine S.
        The ontogeny of the hypothalamic–pituitary–adrenal axis. The influence of maternal factors.
        Ann N Y Acad Sci. 1994; 746: 275-288
        • Levine S.
        • Haltmeyer G.C.
        • Karas G.G.
        • Denenberg V.H.
        Physiological and behavioral effects of infantile stimulation.
        Physiol Behav. 1967; 2: 55-63
      4. Liu D, Caldji C, Sharma S, Plotsky PM, Meaney MJ (in press): The effects of early life events on in vivo release of norepinephrine in the paraventricular nucleus of the hypothalamus and hypothalamic–pituitary–adrenal responses during stress. J Neuroendocrinol.

        • Liu D.
        • Tannenbaum B.
        • Caldji C.
        • Francis D.
        • Freedman A.
        • Sharma S.
        • et al.
        Maternal care, hippocampal glucocorticoid receptor gene expression and hypothalamic–pituitary–adrenal responses to stress.
        Science. 1997; 277: 1659-1662
        • Lupien S.
        • Meaney M.J.
        Stress, glucocorticoids, and hippocampus aging in rat and human.
        in: Wang E. Snyder S. Handbook of Human Aging. Academic Press, New York1998: 19-50
        • Maestripieri D.
        Parenting styles of abusive mothers in group-living rhesus macaques.
        Anim Behav. 1998; 55: 1-11
        • Maestripieri D.
        Consistency and change in the behavior of rhesus macaque abusive mothers with successive infants.
        Dev Psychobiol. 1999; 34: 29-35
        • McCarty R.
        • Gold P.E.
        Catecholamine, stress, and disease.
        Psychosom Med. 1996; 58: 590-597
        • McEwen B.S.
        Stress, adaptation, and disease. Allostasis and allostatic load.
        Ann N Y Acad Sci. 1998; 940: 33-44
      5. McEwen BS, de Leon MJ, Lupien S, Meaney MJ (in press): Corticosteroids, the aging brain and cognition. Trend Endocrinol Metab.

        • McEwen B.S.
        • Steller E.
        Stress and the individual.
        Arch Intern Med. 1993; 153: 2093-2101
      6. Meaney MJ (in press): Early experience effects on HPA function—a basis for individual differences. In: McEwen BS and Steller E, editors. Handbook of Physiology: Coping with the Environment. New York: Oxford University Press.

        • Meaney M.J.
        • Aitken D.H.
        The effects of early postnatal handling on the development of hippocampal glucocorticoid receptors.
        Dev Brain Res. 1985; 22: 301-304
        • Meaney M.J.
        • Aitken D.H.
        • Sapolsky R.M.
        Environmental regulation of the adrenocortical stress response in female rats and its implications for individual differences in aging.
        Neurobiol Aging. 1991; 12: 31-38
        • Meaney M.J.
        • Aitken D.H.
        • Sharma S.
        • Viau V.
        • Sarrieau A.
        Postnatal handling increases hippocampal type II, glucocorticoid receptors and enhances adrenocortical negative-feedback efficacy in the rat.
        Neuroendocrinology. 1989; 51: 597-604
        • Meaney M.J.
        • Diorio J.
        • Widdowson J.
        • LaPlante P.
        • Caldji C.
        • Seckl J.R.
        • et al.
        Early environmental regulation of forebrain glucocorticoid receptor gene expression.
        Dev Neurosci. 1996; 18: 49-72
        • Miller L.
        • Kramer R.
        • Warner V.
        • Wickramaratne P.
        • Weissman M.
        Intergenerational transmission of parental bonding among women.
        J Am Acad Child Adolesc Psychiatry. 1997; 36: 1134-1139
        • Moga M.M.
        • Gray T.S.
        Evidence for corticotropin-releasing factor, neurotensin, and somatostatin in the neural pathway from the central nucleus of the amygdala to the parabranchial nucleus.
        J Comp Neurol. 1989; 241: 275-284
        • Moore C.L.
        • Lux B.A.
        Effects of lactation on sodium intake in fischer-344 and Long-Evans rats.
        Dev Psychobiol. 1998; 32: 51-56
        • Moore C.L.
        • Wong L.
        • Daum M.C.
        • Leclair O.U.
        Mother–infant interactions in two strains of rats.
        Dev Psychobiol. 1997; 30: 301-312
        • Munck A.
        • Guyre P.M.
        • Holbrook N.J.
        Physiological functions of glucocorticoids in stress and their relations to pharmacological actions.
        Endocr Rev. 1984; 5: 25-44
        • Nemeroff C.B.
        The corticotropin-releasing factor (CRF) hypothesis of depression.
        Mol Psychiatry. 1996; 1: 336-342
        • Nemeroff C.B.
        • Bisette G.
        • Akil H.
        • Fink M.
        Neuropeptide concentrations in the cerebrospinal fluid of depressed patients treated with electroconvulsive therapy.
        Br J Psychiatry. 1991; 158: 59-63
        • O’Donnell D.
        • Larocque S.
        • Seckl J.R.
        • Meaney M.J.
        Postnatal handling alters glucocorticoid, but not mineralocorticoid mRNA expression in adult rats.
        Mol Brain Res. 1994; 26: 242-248
        • Owens M.J.
        • Vargas M.A.
        • Knight D.L.
        • Nemeroff C.B.
        The effects of alprazoplam on corticotropin-releasing factor neurons in the rat brain.
        J Pharmacol Exp Therap. 1991; 258: 349-356
        • Pacak K.
        • Palkovits M.
        • Kopin I.
        • Goldstein D.S.
        Stress-induced norepinephrine release in hypothalamic paraventricular nucleus and pituitary-adrenrocortical and sympathoadrenal activity.
        Front Neuroendocrinol. 1995; 16: 89-150
        • Parker G.
        Parental representations of patients with anxiety neurosis.
        Acta Psychiatr Scand. 1981; 63: 33-36
        • Patchev V.K.
        • Montkowski A.
        • Rouskova D.
        • Koranyi L.
        • Holsboer F.
        • Almeida O.F.
        Neonatal treatment of rats with the neuroactive steroid tetrahydordeoxycorticosterone (THDOC) abolishes the behavioral and neuroendocrine consequences of adverse early life events.
        J Clin Invest. 1997; 99: 962-966
        • Pearson D.
        • Sharma S.
        • Plotsky P.M.
        • Pfaus J.G.
        • Meaney M.J.
        The effect of postnatal environment on stress-induced changes in hippocampal FOS-like immunoreactivity in adult rats.
        Soc Neurosci Abst. 1997; 23: 1849
        • Pedersen C.A.
        Oxytocin control of maternal behavior. Regulation by sex steroids and offspring stimuli.
        Ann N Y Acad Sci. 1995; 807: 126-145
        • Plotsky P.M.
        Pathways to the secretion of adrenocorticotropin.
        J Neuroendocrinol. 1991; 3: 1-9
        • Plotsky P.M.
        • Cunningham E.T.
        • Widmaier E.P.
        Catecholaminergic modulation of corticotropin-releasing factor and adrenocorticotropin secretion.
        Endocr Rev. 1989; 10: 437-458
        • Plotsky P.M.
        • Meaney M.J.
        Early, postnatal experience alters hypothalamic corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stress-induced release in adult rats.
        Mol Brain Res. 1993; 18: 195-200
      7. Plotsky PM, Meaney MJ (in press): Early environment alters hypothalamic–pituitary–adrenal responses to a wide range of stressful stimuli. Proc Natl Acad Sci USA.

        • Rivier C.
        • Plotsky P.M.
        Mediation by corticotropin-releasing factor of adenohypophysial hormone secretion.
        Ann Rev Physiol. 1986; 48: 475-489
        • Rosenblatt J.S.
        Psychobiology of maternal behavior.
        Acta Paediatr Suppl. 1994; 397: 3-8
        • Rosenblum L.A.
        • Andrews M.W.
        Influences of environmental demand on maternal behavior and infant development.
        Acta Paediatr Suppl. 1994; 397: 57-63
      8. Rosenblum LA, Coplan JD, Friedman S, Bassoff T, Gorman JM, Andrews MW (in press): Adverse early experiences affect noradrenergic and serotonergic functioning in adult primates. Biol Psychiatry.

        • Rowe W.B.
        • Nicot A.
        • Sharma S.
        • Gully D.
        • Walker C.D.
        • Rostene W.B.
        • et al.
        Central administration of the neurotensin receptor antagonist, SR48692, modulates diurnal and stress-related hypothalamic-pituitary-adrenal activity.
        Neuroendocrinol. 1997; 66: 75-85
        • Russak L.G.
        • Schwartz G.E.
        Feelings of parental care predict health status in midlife.
        J Behav Med. 1997; 20: 1-11
        • Sapolsky R.M.
        The physiological relevance of glucocorticoid endangerment of the hippocampus.
        Ann N Y Acad Sci. 1994; 746: 294-304
        • Sarrieau A.
        • Sharma S.
        • Meaney M.J.
        Postnatal development and environmental regulation of hippocampal glucocorticoid and mineralocorticoid receptors in the rat.
        Dev Brain Res. 1988; 43: 158-162
        • Scarr S.
        • McCarthy K.
        How people make their own environments.
        Child Dev. 1983; 54: 424-435
        • Schanberg S.M.
        • Evoniuk G.
        • Kuhn C.M.
        Tactile and nutritional aspects of maternal care.
        Proc Soc Exp Biol Med. 1984; 175: 135-146
        • Schulkin J.
        Corticotropin-releasing hormone signals adversity in both the placenta and the brain.
        J Endocrinol. 1999; 161: 349-356
        • Schulkin J.
        • Gold P.W.
        • McEwen B.S.
        Induction of corticotropin-releasing hormone gene expression by glucocorticoids.
        Psychoneuroendocrinology. 1998; 23: 219-243
        • Seckl J.R.
        • Meaney M.J.
        Early life events and later development of ischaemic heart disease.
        Lancet. 1994; 342: 1236
        • Stern J.M.
        Offspring-induced nurturance.
        Dev Psychobiol. 1997; 31: 19-37
        • Swiergiel A.H.
        • Takahashi L.K.
        • Kahn N.H.
        Attenuation of stress-induced by antagonism of corticotropin-releasing factor receptors in the central amygdala in the rat.
        Brain Res. 1993; 623: 229-234
        • Valentino R.J.
        • Curtis A.L.
        • Page M.E.
        • Pavcovich L.A.
        • Florin-Lechner S.M.
        Activation of the locus cereulus brain noradrenergic system during stress.
        Adv Pharmacol. 1988; 42: 781-784
        • Valentino R.J.
        • Foote S.L.
        Corticotropin-releasing hormone increases tonic but not sensory-evoked activity of noradrenergic locus coeruleus neurons in unanesthetized rats.
        J Neurosci. 1988; 8: 1016-1025
        • van Bockstaele E.J.
        • Colago E.E.O.
        • Valentino R.J.
        Corticotropin-releasing factor-containing axon terminals synapse onto catecholamine dendrites and may presynaptically modulate other afferents in the rostral pole of the nucleus locus coeruleus in the rat brain.
        J Comp Neurol. 1996; 364: 523-534
        • Van der Kooy D.
        • Koda L.Y.
        • McGinty J.F.
        • Gerfen C.R.
        • Bloom F.E.
        The organization of projections from the cortex, amygdala and hypothalamus to the nucleus of the solitary tract in rat.
        J Comp Neurol. 1984; 224: 1-24
        • Viau V.
        • Sharma S.
        • Plotsky P.M.
        • Meaney M.J.
        Increased plasma ACTH responses to stress in nonhandled compared with handled rats require basal levels of corticosterone and are associated with increased levels of ACTH secretagogues in the median eminence.
        J Neurosci. 1993; 13: 1097-1105
        • West M.J.
        • King A.P.
        Settling nature and nurture into an ontogenetic niche.
        Dev Psychobiol. 1987; 20: 549-562
        • Wilson M.A.
        GABA physiology.
        Crit Rev Neurobiol. 1996; 10: 1-37
        • Zaharia M.D.
        • Shanks N.
        • Meaney M.J.
        • Anisman H.
        The effects of postnatal handling on Morris water maze acquisition in different strains of mice.
        Psychopharmacol. 1996; 128: 227-239
        • Zarrow M.X.
        • Campbell P.S.
        • Denenberg V.H.
        Handling in infancy.
        Proc Soc Exp Biol Med. 1972; 356: 141-143