There is increasing evidence for an important role of adverse early experience on the development of major psychiatric disorders in adulthood. Corticotropinreleasing factor (CRF), an endogenous neuropeptide, is the primary physiological regulator of the mammalian stress response. Grown nonhuman primates who were exposed as infants to adverse early rearing conditions were studied to determine if long-term alterations of CRF neuronal systems had occurred following the early stressor. In comparison to monkeys reared by mothers foraging under predictable conditions, infant monkeys raised by mothers foraging under unpredictable conditions exhibited persistently elevated cerebrospinal fluid (CSF) concentrations of CRF. Because hyperactivity of CRF-releasing neurons has been implicated in the pathophysiology of certain human affective and anxiety disorders, the present finding provides a potential neurobiological mechanism by which early-life stressors may contribute to adult psychopathology.Considerable evidence from genetic, neurochemical, pharmacological, and neuroanatomical studies obtained over the past three decades supports a biological basis for many of the major neuropsychiatric disorders (1). Prior to the modern era of biological psychiatry, psychoanalytic theory pioneered by Freud prevailed. Freud's theories emphasized the importance of early rearing conflicts in the pathogenesis of adult psychopathology (2). More recent studies indicate that psychosocial factors, including abuse and neglect in early life as well as untoward life events in adulthood, contribute to the development of mood and anxiety disorders (3, 4). An integration of biological and developmental approaches may illuminate further the role of adverse early life experience on subsequent neurodevelopment. Using random-assignment study designs, nonhuman primate models of psychopathology, produced by an unpredictable early rearing environment, provide for the experimental exclusion of genetic influences on development, a strategy rarely feasible in humans (5-9).The present study presents evidence for persistent hyperactivity of corticotropin-releasing factor (CRF)-releasing neurons in the central nervous system (CNS) of grown nonhuman primates who, as infants, were reared by mothers exposed to environmental unpredictability. A neurochemically based hypothesis is proposed whereby emotionally adverse early experiences may antecede psychiatric disorders through the induction of persistently elevated neuronal release of CRF.The CRF-containing parvocellular neurons of the hypothalamic paraventricular nucleus (PVN) represent the cephalicThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. component of the hypothalamic-pituitary-adrenal (HPA) axis, which serves as the primary endocrine response of mammalian organisms to stress (10-12). Hypothalamic CRF release increases HPA axis activity by ...

Considerable evidence has accrued in the last two decades to support the hypothesis that alterations in serotonergic neuronal function in the central nervous system occur in patients with major depression. These findings include the following: (a) reduced cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of serotonin (5-HT) in drug-free depressed patients; (b) reduced concentrations of 5-HT and 5-HIAA in postmortem brain tissue of depressed and (or) suicidal patients; (c) decreased plasma tryptophan concentrations in depressed patients and a profound relapse in remitted depressed patients who have responded to a serotonergic antidepressant when brain tryptophan availability is reduced; (d) in general, all clinically efficacious antidepressants augment 5-HT neurotransmission following chronic treatment; (e) clinically efficacious antidepressant action by all inhibitors of 5-HT uptake; (f) increases in the density of 5-HT2 binding sites in postmortem brain tissue of depressed patients and suicide victims, as well as in platelets of drug-free depressed patients; (g) decreased number of 5-HT transporter (determined with [3H]imipramine or [3H]paroxetine) binding sites in postmortem brain tissue of suicide victims and depressed patients and in platelets of drug-free depressed patients. In our studies, this reduction in platelet 5-HT transporter binding is not due to prior antidepressant treatment of hypercortisolemia and is not observed in mania, Alzheimer disease, schizophrenia, panic disorder, fibromyalgia, or atypical depression. In a pilot study, this deficit predicted treatment response to an experimental antidepressant. These findings support the hypothesis that alterations in 5-HT neurons play a role in the pathophysiology of depression.

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